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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Neurosci.</journal-id>
<journal-title>Frontiers in Cellular Neuroscience</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Neurosci.</abbrev-journal-title>
<issn pub-type="epub">1662-5102</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fncel.2024.1360242</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular Neuroscience</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>B cells and the stressed brain: emerging evidence of neuroimmune interactions in the context of psychosocial stress and major depression</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes"><name><surname>Engler-Chiurazzi</surname> <given-names>Elizabeth</given-names></name><xref ref-type="corresp" rid="c001"><sup>&#x002A;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/1624094/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/conceptualization/"/>
<role content-type="https://credit.niso.org/contributor-roles/funding-acquisition/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
</contrib-group>
<aff><institution>Department of Neurosurgery and Neurology, Clinical Neuroscience Research Center, Tulane Brain Institute, Tulane University School of Medicine</institution>, <addr-line>New Orleans, LA</addr-line>, <country>United States</country></aff>
<author-notes>
<fn fn-type="edited-by" id="fn0001">
<p>Edited by: Olga Rojas, University Health Network (UHN), Canada</p>
</fn>
<fn fn-type="edited-by" id="fn0002">
<p>Reviewed by: Ruxandra F. Sirbulescu, Massachusetts General Hospital and Harvard Medical School, United States</p>
<p>Kenji Hashimoto, Chiba University, Japan</p>
</fn>
<corresp id="c001">&#x002A;Correspondence: Elizabeth Engler-Chiurazzi, <email>eenglerchiurazzi@tulane.edu</email></corresp>
</author-notes>
<pub-date pub-type="epub">
<day>08</day>
<month>04</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>18</volume>
<elocation-id>1360242</elocation-id>
<history>
<date date-type="received">
<day>22</day>
<month>12</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>25</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024 Engler-Chiurazzi.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Engler-Chiurazzi</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>The immune system has emerged as a key regulator of central nervous system (CNS) function in health and in disease. Importantly, improved understanding of immune contributions to mood disorders has provided novel opportunities for the treatment of debilitating stress-related mental health conditions such as major depressive disorder (MDD). Yet, the impact to, and involvement of, B lymphocytes in the response to stress is not well-understood, leaving a fundamental gap in our knowledge underlying the immune theory of depression. Several emerging clinical and preclinical findings highlight pronounced consequences for B cells in stress and MDD and may indicate key roles for B cells in modulating mood. This review will describe the clinical and foundational observations implicating B cell-psychological stress interactions, discuss potential mechanisms by which B cells may impact brain function in the context of stress and mood disorders, describe research tools that support the investigation of their neurobiological impacts, and highlight remaining research questions. The goal here is for this discussion to illuminate both the scope and limitations of our current understanding regarding the role of B cells, stress, mood, and depression.</p>
</abstract>
<kwd-group>
<kwd>stress</kwd>
<kwd>major depression</kwd>
<kwd>immune system</kwd>
<kwd>B lymphocyte</kwd>
<kwd>brain</kwd>
</kwd-group>
<counts>
<fig-count count="2"/>
<table-count count="2"/>
<equation-count count="0"/>
<ref-count count="284"/>
<page-count count="21"/>
<word-count count="20922"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Non-Neuronal Cells</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="sec1"><label>1</label>
<title>Introduction</title>
<p>As appreciation for the complexity of neuroimmune interactions continues to grow, there is increasing evidence that B lymphocytes may play important roles in central nervous system (CNS) structure and function across the lifespan (<xref ref-type="bibr" rid="ref49">Dwyer et al., 2022</xref>). Indeed, pathogenic as well as protective effects of B cells have been reported in the context of neurological and spinal cord injuries (<xref ref-type="bibr" rid="ref54">Engler-Chiurazzi et al., 2020</xref>; <xref ref-type="bibr" rid="ref198">Plantone et al., 2022</xref>; <xref ref-type="bibr" rid="ref151">Maheshwari et al., 2023</xref>; <xref ref-type="bibr" rid="ref152">Malone et al., 2023</xref>), autoimmune diseases (<xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>), and brain aging, neurodegeneration, and dementia (<xref ref-type="bibr" rid="ref198">Plantone et al., 2022</xref>), to name just a few examples. Neuroinflammation is a shared feature of many of the neurological diseases in which B cells are implicated (<xref ref-type="bibr" rid="ref15">Bersano et al., 2023</xref>). And yet, while systemic and neuroinflammation is being increasingly linked to the response to psychosocial stress and the manifestation of chronic stress-related conditions (<xref ref-type="bibr" rid="ref146">Maes, 2011</xref>; <xref ref-type="bibr" rid="ref267">Wohleb et al., 2016</xref>; <xref ref-type="bibr" rid="ref87">Herkenham and Kigar, 2017</xref>; <xref ref-type="bibr" rid="ref39">Dantzer, 2018</xref>), the role of the B cell in this context is not well understood.</p>
<p>This discussion will focus on B cells in the context of psychosocial stress and the impacts these cells may have on stress disorders, including major depression (MDD). The sections below will reiterate the clinical significance posed by stress-related disorders, review B cell functional roles within the immune system, describe clinical and foundational observations implicating B cell-psychological stress interactions, discuss potential mechanisms by which B cells may impact brain function in the context of stress and mood disorders, describe research tools that support the investigation of their neurobiological impacts, and highlight remaining research questions. The goal here is that this discussion will illuminate both the scope and limitations of our current understanding regarding the role of B cells, stress, mood, and depression.</p>
</sec>
<sec id="sec2"><label>2</label>
<title>Brief background of B cell development and activation</title>
<p>The process underlying B cell development, activation, maturation, and effector functions is complex and has been extensively reviewed elsewhere (<xref ref-type="bibr" rid="ref168">Meinl et al., 2006</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). In brief here, the majority of B cell development begins in the bone marrow. There, hematopoietic stem cells differentiate into pro- and then pre-B cells, proceeding through several key developmental stages of random recombination of the B cell receptor heavy and light chains to generate lymphocytes with responsivity to a huge diversity of immunogens. Self-reactivity, determined by at least three checkpoints (immature, transitional, and activated na&#x00EF;ve B cell stages) must be lacking for survival and migration to secondary immune organs as na&#x00EF;ve B cells. Na&#x00EF;ve B1 B cells have limited B cell receptor diversity and are predominantly found in the peritoneal and pleural cavities. B2 follicular na&#x00EF;ve B cells comprise the majority of B cells in lymphoid organs, namely the spleen. Following encounters with their antigen, a subset of activated B cells migrate to germinal centers (GCs) to undergo somatic hypermutation and class switch recombination to support affinity maturation. From there, maturing B cells become memory B cells or antibody secreting cells. A separate subset of antigen activated B cells will mature into short-lived plasmablasts outside of lymphoid structures while others become long-lived plasma cells (PC). Of note, following encounter with an antigen, activation can take place in T cell-dependent or -independent cascades depending on the B cell subset. Once activated, the functions of various B cell subsets can be classified into several domains: (1) producers of antibodies that, once created and bound to antigen, promote complement signaling as well as antigen neutralization, antigen opsonization (coating with antibodies), and ultimately destruction by other immune cells, (2) antigen presenters, and (3) cytokine and trophic factor secretors, (4) immune response regulators, and (5) memory cells that enable a more rapid and specific threat response in future encounters with that specific antigen (<xref ref-type="fig" rid="fig1">Figure 1</xref>). However, it is noteworthy that there is significant overlap and redundancy among the subset populations with regards to functional roles in response to immunogenic stimuli.</p>
<fig position="float" id="fig1"><label>Figure 1</label>
<caption>
<p>Domains of B lymphocyte function in the immune system. The process governing development, activation, and maturation of B lymphocytes is multifaceted and complex. Once activated by their cognate pathogenic signal, B cell subset functions within the broader immune response include (1) antigen presentation via major histocompatibility complexes (MHC) to effector immune cells, namely CD4<sup>+</sup> or CD8<sup>+</sup> T cells, (2) antibody production, and (3) pro- or anti-inflammatory cytokine secretion. These functions coordinate and potentially amplify, restrain, or resolve the broader immune response (<xref ref-type="bibr" rid="ref54">Engler-Chiurazzi et al., 2020</xref>), and also serve as the foundation for immune memory to a given immunogen (<xref ref-type="bibr" rid="ref198">Plantone et al., 2022</xref>). IL, Interleukin; TCR, T Cell Receptor; TGF, Transforming Growth Factor; TNF, Tumor Necrosis Factor. Figure created with <ext-link xlink:href="http://BioRender.com" ext-link-type="uri">BioRender.com</ext-link>.</p>
</caption>
<graphic xlink:href="fncel-18-1360242-g001.tif"/>
</fig>
</sec>
<sec id="sec3"><label>3</label>
<title>Clinical significance of stress-related disorders</title>
<p>Mood disorders, including MDD, are a significant global health issue. Lifetime prevalence of mood disorders has been reported to be nearly 10% (<xref ref-type="bibr" rid="ref227">Steel et al., 2014</xref>; <xref ref-type="bibr" rid="ref270">World Health Organization, 2017</xref>) and it was recently estimated that more than 320 million people currently are affected by MDD worldwide (<xref ref-type="bibr" rid="ref57">Ferrari et al., 2013</xref>). Problematically, the burden of mood disorders appears to be increasing. Indeed, between 2005 and 2018 in the United States alone, the number of adults with MDD increased from 15.5 to 17.5 million patients; the annual costs associated with this condition (including direct, suicide-related, and workplace costs) are estimated at $326 billion (<xref ref-type="bibr" rid="ref76">Greenberg et al., 2021</xref>), a nearly 38% increase from previous cost estimates (<xref ref-type="bibr" rid="ref75">Greenberg et al., 2015</xref>). While treatment interventions including antidepressant drugs are available, there is significant heterogeneity with regards to latency to symptom amelioration and in their response efficacy profiles (<xref ref-type="bibr" rid="ref247">Trivedi et al., 2006</xref>; <xref ref-type="bibr" rid="ref5">Al-Harbi, 2012</xref>). These factors have coalesced to make MDD a leading cause of disability worldwide (<xref ref-type="bibr" rid="ref66">Friedrich, 2017</xref>) and a significant source of human suffering. There is, therefore, an urgent need to improve understanding of its pathogenic mechanisms and develop novel, more effective treatment interventions.</p>
</sec>
<sec id="sec4"><label>4</label>
<title>Evidence supporting a role for the B cell in stress and depression</title>
<p>Although once considered &#x201C;immune privileged,&#x201D; a compelling body of literature indicates that the CNS and the peripheral immune systems engage in bidirectional communication, profoundly influencing one another during homeostasis and in pathological/diseased neurological states (<xref ref-type="bibr" rid="ref192">Pavlov et al., 2018</xref>), including those associated with chronic stress and MDD. Indeed, it is now accepted that inflammatory cascades mediated by brain resident microglia as well as peripheral innate inflammatory and adaptive T cell-mediated arms of the immune system significantly contribute to MDD, at least in some patient subsets (<xref ref-type="bibr" rid="ref146">Maes, 2011</xref>; <xref ref-type="bibr" rid="ref267">Wohleb et al., 2016</xref>; <xref ref-type="bibr" rid="ref87">Herkenham and Kigar, 2017</xref>; <xref ref-type="bibr" rid="ref39">Dantzer, 2018</xref>). Is there evidence also implicating B cells?</p>
<sec id="sec5"><label>4.1</label>
<title>Observations among clinical populations</title>
<p>Interest in interrogating immune underpinnings of mood began in the late-1980s/early 1990s, when initial pioneering studies revealed distinct patterns of peripheral immune cell profiles among patients with MDD and mentally healthy controls (<xref ref-type="bibr" rid="ref146">Maes, 2011</xref>; <xref ref-type="bibr" rid="ref267">Wohleb et al., 2016</xref>). Indeed, <xref ref-type="bibr" rid="ref147">Maes et al. (1990)</xref> noted that MDD patients displayed elevated levels of cluster of differentiation (CD)-4<sup>+</sup> T cells, higher circulating soluble interleukin (IL)-2 receptor levels, and higher percentages of cells expressing CD25 (IL-2 receptor). As well, elevated levels of circulating cytokines, principally tumor necrosis factor (TNF)-&#x03B1;, IL-1&#x03B2; and IL-6, have been consistently reported among some subsets of depressed populations (<xref ref-type="bibr" rid="ref47">Dowlati et al., 2010</xref>; <xref ref-type="bibr" rid="ref114">K&#x00F6;hler-Forsberg et al., 2017</xref>). Depression-associated profiles of some immune cell populations and proinflammatory cytokines also normalized among patients responsive to pharmacological therapeutic intervention (<xref ref-type="bibr" rid="ref211">Roumestan et al., 2007</xref>; <xref ref-type="bibr" rid="ref9">Arteaga-Henr&#x00ED;quez et al., 2019</xref>). Antidepressant treatment with co-administration of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs, statins, or cytokine inhibitors, improved depressive symptoms and MDD remission rates (<xref ref-type="bibr" rid="ref115">K&#x00F6;hler&#x2010;Forsberg et al., 2019</xref>). However, high levels of inflammatory biomarkers are also often associated with poor responsiveness to serotonin (5-HT) targeting interventions (<xref ref-type="bibr" rid="ref9">Arteaga-Henr&#x00ED;quez et al., 2019</xref>), possibly accounting for the large heterogeneity in antidepressant efficacy for symptom remission in this population (<xref ref-type="bibr" rid="ref247">Trivedi et al., 2006</xref>; <xref ref-type="bibr" rid="ref5">Al-Harbi, 2012</xref>; <xref ref-type="bibr" rid="ref4">Akil et al., 2018</xref>). Finally, observations that autoimmune patients prescribed inflammatory interventions developed rapid and profound depressed mood provided strong empirical support for immune-MDD associations (<xref ref-type="bibr" rid="ref202">Pryce and Fontana, 2017</xref>).</p>
<p>At least initially, available evidence suggested that B lymphocytes were not consistently impacted by MDD. For instance, studies have reported both an increase or a decrease in B lymphocyte counts among students experiencing exam stress (<xref ref-type="bibr" rid="ref149">Maes et al., 1999</xref>; <xref ref-type="bibr" rid="ref162">McGregor et al., 2008</xref>). Some studies found no difference in B cell counts between MDD patients and controls (<xref ref-type="bibr" rid="ref40">Darko et al., 1988</xref>) while others reported increased total or subset B cell counts (<xref ref-type="bibr" rid="ref148">Maes et al., 1992</xref>) and still others showed reduced numbers (<xref ref-type="bibr" rid="ref193">Pav&#x00F3;n et al., 2006</xref>). Later, <xref ref-type="bibr" rid="ref3">Ahmetspahic et al. (2018)</xref> identified that while numbers of total B cells were not altered among MDD patients relative to healthy controls, there were reduced counts of IgD<sup>+</sup>CD27<sup>&#x2212;</sup> na&#x00EF;ve, CD1d<sup>+</sup>CD5<sup>+</sup> regulatory-like, and CD24<sup>+</sup>CD38<sup>hi</sup> B cell populations. However, these early studies were limited by a number of factors, including a highly heterogenous patient population, small sample sizes, and a focus on circulating immune cell profiles identified with lineage markers and immune cell phenotyping tools available at the time. Interestingly, a recent meta-analysis revealed elevated B cell counts in MDD patients (<xref ref-type="bibr" rid="ref63">Foley et al., 2023</xref>). These findings are summarized in <xref ref-type="table" rid="tab1">Table 1</xref>.</p>
<table-wrap position="float" id="tab1"><label>Table 1</label>
<caption>
<p>Summary of clinical data regarding B cell changes in stress and depression.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Domain</th>
<th align="left" valign="top">Study population</th>
<th align="left" valign="top">Impact to circulating B cells profiles</th>
<th align="left" valign="top">Citation</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="2">Psychological stress</td>
<td align="left" valign="top">University students (<italic>N</italic> =&#x2009;38) weeks before, immediately prior to, and weeks after examination periods; classified as stress reactors or non-reactors based on Perceived Stress Scale scores</td>
<td align="left" valign="top">In stress reactive students, CD19<sup>+</sup> B cells were increased relative to their baseline counts</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref149">Maes et al. (1999)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top">Doctoral trainees 3&#x2009;days following qualifying exams and matched community controls (<italic>N</italic> =&#x2009;10/group)</td>
<td align="left" valign="top">Mean CD19<sup>+</sup> lymphocyte percentage was reduced</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref162">McGregor et al. (2008)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="5">MDD</td>
<td align="left" valign="top">Patients with MDD and age-, sex-, and race-matched controls (<italic>N</italic> =&#x2009;11/group)</td>
<td align="left" valign="top">B cells not changed</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref40">Darko et al. (1988)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top">Minor (<italic>N</italic> =&#x2009;14), simple major (<italic>N</italic> =&#x2009;12), and melancholic (<italic>N</italic> =&#x2009;12) depressed patients (<italic>N</italic> =&#x2009;38) and normal controls (<italic>N</italic> =&#x2009;10)</td>
<td align="left" valign="top">Pan (CD19<sup>+</sup>) B cells increased in melancholic patients</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref148">Maes et al. (1992)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top">MDD outpatients (<italic>N</italic> =&#x2009;33) and non-depressed controls (<italic>N</italic> =&#x2009;33) matched for age, ethnicity, and demographic characteristics</td>
<td align="left" valign="top">CD3<sup>&#x2212;</sup>CD19<sup>+</sup> B cells were reduced</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref193">Pav&#x00F3;n et al. (2006)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top">MDD patients (<italic>N</italic> =&#x2009;37) before and 6&#x2009;weeks after mood-modulating intervention (antidepressants, benzodiazepines, mood stabilizers, and/or antipsychotics) and healthy donors (<italic>N</italic> =&#x2009;27)</td>
<td align="left" valign="top">Prior to treatment, frequencies of B cells (CD19<sup>+</sup>) were not altered compared to controls but IgD<sup>+</sup>CD27<sup>&#x2212;</sup> B cell proportions were reduced<break/>CD24<sup>+</sup>CD38<sup>hi</sup> immature transitional B cells were reduced<break/>CD38<sup>hi</sup>IgD<sup>+</sup> Bm2 B cells were reduced<break/>CD1d<sup>+</sup>CD5<sup>+</sup> B cells were reduced<break/>CD5 expression increased on B cells in treatment responsive patients</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref3">Ahmetspahic et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="left" valign="top">Depressed patients before (<italic>N</italic> =&#x2009;31) and after (<italic>N</italic> =&#x2009;10) 52&#x2009;weeks of antidepressant treatment (various selective serotonin reuptake inhibitors), and healthy controls (<italic>N</italic> =&#x2009;22)</td>
<td align="left" valign="top">No differences in B cells prior to treatment between patients and controls<break/>B cell counts increased with treatment relative to their own baseline values and those of healthy controls</td>
<td align="left" valign="top">
<xref ref-type="bibr" rid="ref117">Kolan et al. (2019)</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="sec6"><label>4.2</label>
<title>Preclinical associations between B lymphocytes and the response to stress: focus on glucocorticoid signaling through the hypothalamic&#x2013;pituitary&#x2013;adrenal axis</title>
<sec id="sec7"><label>4.2.1</label>
<title>Shifts in B cell number and functional profiles with pharmacological and behavioral stress exposure</title>
<p>The response to psychological stress is generally considered to be mediated by engagement of the hormones involved in the hypothalamic&#x2013;pituitary&#x2013;adrenal axis (HPA; namely glucocorticoids), the sympathetic nervous system via catecholamines (discussed below), and more recently cytokines and immune cells. While glucocorticoids were historically considered immunosuppressive, collective evidence now indicates that stress-immune interactions, including those pertaining to B cells, are dynamic and complex (<xref ref-type="bibr" rid="ref121">Kovacs, 2014</xref>). Indeed, like T cells, B cells of virtually all developmental stages express the cellular machinery [namely glucocorticoid (GR) and mineralocorticoid (MR) receptors] to respond to stress signals (<xref ref-type="bibr" rid="ref77">Gruver-Yates et al., 2014</xref>) and studies have evaluated the effects of stress exposure on the number and function of B cells in key immune- and stress-related tissues. For instance, findings from several <italic>in vitro</italic> studies indicate that B cells, and particularly immature B cells, are susceptible to apoptotic consequences with exposure to high levels of corticosteroids (<xref ref-type="bibr" rid="ref69">Garvy and Fraker, 1991</xref>; <xref ref-type="bibr" rid="ref136">Lill-Elghanian et al., 2002</xref>; <xref ref-type="bibr" rid="ref96">Igarashi et al., 2005</xref>). Further, in long-term cultured B lymphoblastoids collected from MDD patients or healthy controls, basal GR expression was elevated in depressed patients but showed a larger expression reduction when exposed hydrocortisone stimulation (<xref ref-type="bibr" rid="ref86">Henning et al., 2005</xref>). <italic>In vivo,</italic> circulating B lymphocyte counts are reduced with administration of exogenous corticosterone (<xref ref-type="bibr" rid="ref43">Dhabhar et al., 2012</xref>; <xref ref-type="bibr" rid="ref77">Gruver-Yates et al., 2014</xref>) and tablet implant-based elevations in corticosterone levels in young adult male mice resulted in profound loss of bone marrow B cell subsets (<xref ref-type="bibr" rid="ref69">Garvy and Fraker, 1991</xref>).</p>
<p>Behaviorally-induced glucocorticoid signaling has been shown to have a profound impact on B cells. For example, in adult male Sprague&#x2013;Dawley rats, circulating B cell numbers initially increased in the minutes following a single acute restraint stress exposure; numbers then decreased over 2&#x2009;h to below baseline levels, which the authors considered indicative of lymphocyte trafficking into tissues (<xref ref-type="bibr" rid="ref43">Dhabhar et al., 2012</xref>). <xref ref-type="bibr" rid="ref228">Stefanski and Engler (1998)</xref> noted reduced circulating B cell numbers with exposure to 2&#x2009;h of social defeat stress in Long Evans rats, suggesting similar lymphocyte consequences in other stress conditions. B cell changes have also been reported in the context of chronic stress paradigms in a tissue-dependent manner. Although splenic and bone marrow B cell counts remained steady, 14&#x2009;days of restraint for 2, 3, or 5&#x2009;h/day significantly reduced B cell numbers in blood and thymus (<xref ref-type="bibr" rid="ref45">Dom&#x00ED;nguez-Gerpe and Rey-M&#x00E9;ndez, 2001</xref>). Leveraging a nine-week chronic variable stress paradigm, Gurfein and colleagues noted that stress exposure increased the frequency of immature and marginal zone, but decreased the frequency of follicular, B cells; interestingly total B cell counts were not altered (<xref ref-type="bibr" rid="ref79">Gurfein et al., 2014</xref>, <xref ref-type="bibr" rid="ref80">2017</xref>). Notably, many of these effects are altered by environmental enrichment, an intervention known to attenuate the negative effects of stress paradigms (<xref ref-type="bibr" rid="ref64">Fox et al., 2006</xref>). Corticotrophin releasing hormone (CRH)-transgenic mice, a well-established genetic model of stress in which persistent activation of the HPA axis is associated with increased corticosterone production and avoidance behaviors seen in chronically stressed organisms (<xref ref-type="bibr" rid="ref230">Stenzel-Poore et al., 1992</xref>, <xref ref-type="bibr" rid="ref231">1994</xref>), display fewer total splenic, circulating, and bone marrow B cell counts (<xref ref-type="bibr" rid="ref175">Murray et al., 2001</xref>). More specifically, B cell profiles tended to be skewed, with transgenic animals having higher proportions of immature cells within the tissues assayed. Finally, functional capacity of B cells may be affected by stress as chronic restraint also impaired GC responses including immunoglobulin (Ig)G1 antibody production, an effect which was prevented by GR blockade (<xref ref-type="bibr" rid="ref236">Sun et al., 2019</xref>).</p>
<p>Appreciation for the importance of brain-spleen interactions in CNS health and disease is growing (<xref ref-type="bibr" rid="ref262">Wei et al., 2022</xref>). Splenic changes associated with stress/inflammatory exposure include altered gross morphology, shifts in profiles of distinct immune cells, and changes in cytokine secretion patterns (<xref ref-type="bibr" rid="ref262">Wei et al., 2022</xref>). For instance, repeated social defeat stress increases spleen weights, promotes hematopoietic stem cell progenitor release from bone marrow and recruitment to spleen, and induces splenomegaly with significant increases in CD11b+, natural killer, and granulocyte cell populations observed among stress-susceptible mice (<xref ref-type="bibr" rid="ref164">McKim et al., 2018</xref>; <xref ref-type="bibr" rid="ref278">Zhang et al., 2021</xref>). Similarly, systemic inflammation, like that induced by the bacterial infection mimic and well-established model of sickness behavior, lipopolysaccharide (LPS) (<xref ref-type="bibr" rid="ref39">Dantzer, 2018</xref>), can profoundly alter splenic morphology and levels of circulating proinflammatory cytokines (<xref ref-type="bibr" rid="ref277">Zhang et al., 2020</xref>). Stress exposure prior to LPS administration primes inflammatory responses in systemic and central macrophages (<xref ref-type="bibr" rid="ref104">Johnson et al., 2002</xref>; <xref ref-type="bibr" rid="ref65">Frank et al., 2007</xref>). It is noteworthy that stress and inflammation influences on splenic immune populations can vary by cell type and even cell subtype (<xref ref-type="bibr" rid="ref79">Gurfein et al., 2014</xref>, <xref ref-type="bibr" rid="ref80">2017</xref>). Moreover, LPS is associated with inducing sickness and depressive-like behaviors and these behaviors appear to be mediated by activation of indoleamine 2,3-dioxygenase and other components of the kynurenine pathway (<xref ref-type="bibr" rid="ref19">Bluth&#x00E9; et al., 1992</xref>; <xref ref-type="bibr" rid="ref185">O'Connor et al., 2009</xref>; <xref ref-type="bibr" rid="ref206">Remus and Dantzer, 2016</xref>).</p>
<p>Yet, while brain-spleen innervation patterns have been known for some time, and include some notable stress-related regions (e.g., locus coeruleus, central amygdala, and hypothalamic nuclei) (<xref ref-type="bibr" rid="ref24">Cano et al., 2001</xref>), until recently very few studies have investigated the convergence of stress exposure, splenic B cells and the brain. In an elegant series of experiments, <xref ref-type="bibr" rid="ref275">Zhang et al. (2020)</xref> found that CRH expressing neurons in the central amygdala and paraventricular nucleus (PVN) of the hypothalamus signal though the splenic nerve to impact B cell maturation. Activation of these neurons when mice were exposed to a chronic regimen of daily brief elevated platform stress increased numbers of splenic PCs, a finding that was later replicated by <xref ref-type="bibr" rid="ref144">Lynall et al. (2021)</xref> using a chronic social defeat stress paradigm. PVN CRH-expressing neurons were also found to control acute restraint stress-induced shifts in peripheral lymphocyte pools (<xref ref-type="bibr" rid="ref199">Poller et al., 2022</xref>). Indeed, stress exposure was associated with transiently reduced circulating splenic, and lymph node, B cells that homed to bone marrow. Excitingly, these findings demonstrate top-down brain control of peripheral adaptive immunity in response to certain types of psychosocial stress and lay mechanistic foundations for the continued exploration of these associations.</p>
<p>In addition to glucocorticoids, mineralocorticoids impact the stress response and MDD (<xref ref-type="bibr" rid="ref41">de Kloet et al., 2016</xref>). Although aldosterone (a key MR ligand) has been reported to increase B cell activation and recruitment, the consequences of MR expression and binding on B cell function, especially in the context of stress, has been largely unexplored (<xref ref-type="bibr" rid="ref11">Bene et al., 2014</xref>; <xref ref-type="bibr" rid="ref58">Ferreira et al., 2021</xref>). Emerging data suggests that activation of MRs may play critical roles in modulating stress response resolution and promoting resilience (<xref ref-type="bibr" rid="ref241">ter Heegde et al., 2015</xref>). Thus, future interrogation of the interplay between B cell and MR signaling will be key to discerning the full scope of stress-B cell interactions.</p>
</sec>
<sec id="sec8"><label>4.2.2</label>
<title>Genetic modification of immune function alters stress responsivity</title>
<p>Further support for a role for lymphocytes in the response to stress comes from findings leveraging mouse models genetically modified to capture specific immune phenotypes. Studies in lymphocyte-deficient mice (nude, scid, or Rag &#x2212;/&#x2212; mice) have noted deficits in adaptability to stress; reconstitution of various lymphocyte populations in these mice generally implicated the absence of T cells in mediating these deficits (<xref ref-type="bibr" rid="ref36">Cohen et al., 2006</xref>; <xref ref-type="bibr" rid="ref16">Beurel et al., 2013</xref>; <xref ref-type="bibr" rid="ref204">Rattazzi et al., 2013</xref>; <xref ref-type="bibr" rid="ref34">Clark et al., 2014</xref>; <xref ref-type="bibr" rid="ref21">Brachman et al., 2015</xref>). Importantly, (primarily T) lymphocytes from stress-exposed mice can modify the behavioral response to stress when adoptively transferred into lymphocyte deficient subjects (<xref ref-type="bibr" rid="ref21">Brachman et al., 2015</xref>; <xref ref-type="bibr" rid="ref216">Scheinert et al., 2016</xref>).</p>
<p>However, some evidence may support an association between the absence in B cells and pro-stress susceptible phenotype. Along with CD38, CD157, also known as bone marrow stromal cell antigen-1 (aka bone marrow stromal cell antigen-1), plays an important role in nicotinamide adenine dinucleotide metabolism and cell signaling cascades (<xref ref-type="bibr" rid="ref141">Lopatina et al., 2020</xref>). CD157 is expressed on a number of cell types, including central and peripheral immune cells but also many nestin-positive neural cells (<xref ref-type="bibr" rid="ref90">Higashida et al., 2017</xref>). Interestingly, CD157&#x2212;/&#x2212; mice displayed pronounced maladaptive responses to forced swim stress, leading authors to conclude that CD157 may play an important role in anxiety and social avoidance (<xref ref-type="bibr" rid="ref142">Lopatina et al., 2014</xref>). Notably, B cell development in these mice is impaired as is the B cell-driven antibody response to infection (<xref ref-type="bibr" rid="ref100">Itoh et al., 1998</xref>). This suggests that B cell deficiency may be at least partially involved with maladaptive stress responses and social interactions.</p>
</sec>
</sec>
<sec id="sec9"><label>4.3</label>
<title>Evidence for B cell presence in CNS sites in stress and depression</title>
<p>The presence of peripheral immune cells in healthy brain parenchyma is rare (<xref ref-type="bibr" rid="ref120">Korin et al., 2017</xref>) though robust immune cell recruitment to CNS can take place in times of neuroinflammatory challenge (<xref ref-type="bibr" rid="ref140">Londo&#x00F1;o and Mora, 2018</xref>), such as stress and MDD (<xref ref-type="bibr" rid="ref166">Medina-Rodriguez et al., 2023</xref>). The neurobiology of stress and MDD is complex, and potentially injurious changes to brain structure and function have been reported when the stress response becomes dysregulated. Indeed, while these cascades have been extensively discussed elsewhere (<xref ref-type="bibr" rid="ref160">McEwen, 2017</xref>; <xref ref-type="bibr" rid="ref71">Godoy et al., 2018</xref>; <xref ref-type="bibr" rid="ref161">McEwen and Karatsoreos, 2020</xref>), some stress-related consequences include reductions in brain volume (<xref ref-type="bibr" rid="ref118">Koolschijn et al., 2009</xref>), region-specific changes in neuronal excitability leading to hypertrophy or atrophy (<xref ref-type="bibr" rid="ref30">Chaudhury et al., 2015</xref>), tract-specific white matter disruptions and demyelination (<xref ref-type="bibr" rid="ref22">Breit et al., 2023</xref>), blood&#x2013;brain barrier (BBB) disruption and increased permeability (<xref ref-type="bibr" rid="ref167">Medina-Rodriguez et al., 2023</xref>), and impaired hippocampal neurogenesis (<xref ref-type="bibr" rid="ref219">Schoenfeld and Cameron, 2015</xref>). These highlight just a few examples of the numerous CNS impacts reported in both acute and chronic stress conditions among human and preclinical populations. A key question to address here is Do B cells accumulate in brain or brain-adjacent tissues during stress or depression, and if so, what role do they play? Do they promote chronic stress cascades, support resilience to the negative consequences of stress, or both?</p>
<p>Much of our understanding of B cell accumulation in CNS comes from neurological aging, injury or disease models such as stroke, or autoimmunity. Indeed, in multiple sclerosis (MS), gut origin IgA<sup>+</sup> PCs that mediate mucosal immunity represent at least some of the B cell subsets that are recruited to CNS border sites and accumulate at lesions (<xref ref-type="bibr" rid="ref61">Fitzpatrick et al., 2020</xref>; <xref ref-type="bibr" rid="ref201">Pr&#x00F6;bstel et al., 2020</xref>). Immunosenescence is associated with a profound shift in the B cell compartment and the emergence of innate-like age-associated B cells that accumulate in meninges (<xref ref-type="bibr" rid="ref23">Brioschi et al., 2021</xref>). During stroke, B cells traffic to brain and accumulate both in the infarcted tissue and also at sites distal to stroke damage (<xref ref-type="bibr" rid="ref187">Ortega et al., 2020</xref>). The functional significance of this accumulation is still being interrogated given that several reports note neuroprotective and neurorestorative actions of B cells (<xref ref-type="bibr" rid="ref207">Ren et al., 2011</xref>; <xref ref-type="bibr" rid="ref187">Ortega et al., 2020</xref>) while others suggest that autoreactive B cells may promote long-term poststroke cognitive deficits (<xref ref-type="bibr" rid="ref48">Doyle et al., 2015</xref>).</p>
<p>There is limited but emerging support for brain-B cell interactions in the context of stress and MDD. For instance, in a few small cohort studies evaluating post-mortem brain tissues of schizophrenic, mood disorder, MDD, or bipolar disorder patients, a subset of subjects from each diagnosis condition displayed elevated brain lymphocyte profiles (<xref ref-type="bibr" rid="ref20">Bogerts et al., 2017</xref>; <xref ref-type="bibr" rid="ref217">Schlaaff et al., 2020</xref>). More specifically, in mood disorders, T and B cells were elevated relative to non-psychiatric patient controls. Interestingly, B cells appeared to accumulate in hippocampus/parahippocampal region, pre/peri/postcentral gyrus area, central white matter, and entorhinal and inferior temporal regions. Finally, B cells accumulated in hippocampi of mice exposed to a prolonged (but not acute) foot shock-induced learned helplessness or chronic restraint relative to non-stress exposed mice (<xref ref-type="bibr" rid="ref17">Beurel et al., 2018</xref>). Surprisingly, chronic restraint stress did not result in similar T cell elevations, suggesting that stressor type may influence immune cell type recruitment patterns.</p>
<p>In addition to blood or organ-derived B cells, recent data identifying local CNS/CNS-adjacent originating B cells could suggest an additional mechanism by which B cells respond to neuroinflammatory states. Indeed, <xref ref-type="bibr" rid="ref23">Brioschi et al. (2021)</xref> identified that B cells represent approximately 30% of CD45<sup>+</sup> cells in the meninges. In addition, they identified a population of CNS antigen educated B cells that are derived from a bone marrow niche in the skull and reach meninges through vascular channels from the calvaria. Schafflick et al. further identified the dura as a site of progenitor B cell residence (<xref ref-type="bibr" rid="ref215">Schafflick et al., 2021</xref>). Interestingly, while chronic learned helplessness increased hippocampal B cell numbers, splenic total B cell counts were not affected (<xref ref-type="bibr" rid="ref17">Beurel et al., 2018</xref>). This observation, while considering that meningeal B cells were reduced in mice exposed to chronic social defeat (<xref ref-type="bibr" rid="ref144">Lynall et al., 2021</xref>), may implicate meningeal or other local CNS-adjacent lymphocyte pools as the source of these parenchymal infiltrating cells.</p>
<p>In addition to trafficking to secondary lymphoid organs, leukocytes including B cells influence the local immune response by migrating to inflamed non-lymphoid tissues and forming ectopic or tertiary lymphoid structures (ELS) (<xref ref-type="bibr" rid="ref140">Londo&#x00F1;o and Mora, 2018</xref>; <xref ref-type="bibr" rid="ref84">Harrer et al., 2022</xref>). ELSs in the CNS were first discovered in meninges close to inflammatory lesions in the context of MS (<xref ref-type="bibr" rid="ref177">Negron et al., 2020</xref>), where the trafficking of B cells via key chemokine ligand-receptor interactions (discussed below) was shown to potentiate disease progression (<xref ref-type="bibr" rid="ref150">Magliozzi et al., 2007</xref>). Additional studies have since identified B cell aggregating ELS in neuropsychiatric lupus (<xref ref-type="bibr" rid="ref232">Stock et al., 2019</xref>), stroke (<xref ref-type="bibr" rid="ref48">Doyle et al., 2015</xref>), and acute or chronic spinal cord damage (<xref ref-type="bibr" rid="ref35">Cohen et al., 2021</xref>), to name a few examples. Importantly, research regarding development of local CNS ELS is in its infancy. Whether such structures form in response to the neuroinflammatory state produced by stress and MDD is not yet known though one study in a mouse model of lupus, a model in which depressive-like phenotypes have been well-established (<xref ref-type="bibr" rid="ref68">Gao et al., 2009</xref>), found evidence for ELS in choroid plexus (<xref ref-type="bibr" rid="ref232">Stock et al., 2019</xref>).</p>
</sec>
</sec>
<sec id="sec10"><label>5</label>
<title>Mechanisms by which B cells migrate to, access, and remain at sites of inflammation</title>
<p>To address the role of B cells in the stressed brain, it is important to determine the extent to which B cell recruitment, trafficking, and survival signals are engaged during the experience of stressful life events, and to discern whether these signals become dysregulated in chronic stress.</p>
<sec id="sec11"><label>5.1</label>
<title>B cell recruitment and trafficking signals</title>
<p>Central to an effective immune response to challenge is the tightly regulated movement of immune cells within lymphoid organs and to sites of inflammation. This process is governed by chemokines (<xref ref-type="bibr" rid="ref229">Stein and Nombela-Arrieta, 2005</xref>; <xref ref-type="bibr" rid="ref31">Chen et al., 2018</xref>). Several chemokines are implicated in the recruitment of B cells to key organs and sites, including C-X-C motif ligand (CXCL)12 (and cognate receptors CXCR4/7), CXCL13 (CXCR5), CC chemokine ligand (CCL)19 (CCR7), and CCL21 (CCR7) (<xref ref-type="bibr" rid="ref99">Irani, 2016</xref>; <xref ref-type="bibr" rid="ref84">Harrer et al., 2022</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). These chemokines can be homeostatic (e.g., CXCL13, CCL21), regulating cellular trafficking during immune surveillance or inflammation-induced (e.g., CXCL9, CXCL10). They can support development (e.g., CXCL12), and can modulate migration through primary (CXCL12) and secondary lymphoid organs (e.g., CXCL13, CCL19, CCL21). Some chemokines (CXCL12, CCL19, CCL21) are considered to have key brain homing functions. Importantly, some chemokines regulate the movement of several immune cell subtypes, including T cells (e.g., CCL19, CCL21, CXCL10).</p>
<p>B cell trafficking chemokines play diverse roles in the CNS. CXCL12, CCL19, and CCL21 are constitutively expressed in CNS at low levels namely by neurons, glial cells, and vascular endothelial cells (<xref ref-type="bibr" rid="ref134">Li and Ransohoff, 2008</xref>; <xref ref-type="bibr" rid="ref127">Lalor and Segal, 2010</xref>; <xref ref-type="bibr" rid="ref172">Milenkovic et al., 2019</xref>) while these in addition to CXCL13 may be inducible in neural cell types in a disease state-dependent fashion (<xref ref-type="bibr" rid="ref124">Krumbholz et al., 2007</xref>; <xref ref-type="bibr" rid="ref99">Irani, 2016</xref>). Indeed, spinal cord neurons produce CXCL13 in a preclinical ligation model of neuropathic pain (<xref ref-type="bibr" rid="ref103">Jiang et al., 2016</xref>) but not in viral encephalomyelitis where microglia show upregulated <italic>Cxcl13</italic> gene expression (<xref ref-type="bibr" rid="ref55">Esen et al., 2014</xref>). Various CNS cell populations are responsive to chemokine signals but regional distribution of chemokine receptors is varied and suggests distinct functional roles for each ligand-receptor system (<xref ref-type="bibr" rid="ref249">Turbic et al., 2011</xref>). For example, CXCR4, and CXCR7 to a lesser extent, is expressed on a wide variety of CNS cell types (such as astrocytes, microglia, and neurons and neural progenitor cells) in the hippocampus and subventricular zone. Thus, it is perhaps unsurprising that the CXCL12-CXCR4/7 system facilitates proliferation and migration of neural progenitor cells during development and adulthood (<xref ref-type="bibr" rid="ref220">Sch&#x00F6;nemeier et al., 2008</xref>; <xref ref-type="bibr" rid="ref213">S&#x00E1;nchez-Alca&#x00F1;iz et al., 2011</xref>). CXCL12 can also act directly on cells as it has been shown to induce GABAergic activity in diverse neuronal populations (<xref ref-type="bibr" rid="ref81">Guyon, 2014</xref>). CXCR5 expression is not well represented regionally in CNS tissues though other findings suggest that this receptor is expressed by most CNS cell types (<xref ref-type="bibr" rid="ref249">Turbic et al., 2011</xref>; <xref ref-type="bibr" rid="ref233">Stuart et al., 2015</xref>). CXCL13 expression was upregulated in neurospheres exposed to inflammatory cytokine challenge (<xref ref-type="bibr" rid="ref249">Turbic et al., 2011</xref>) and other cellular sources of CXCL13 produced during inflammatory conditions include microglia (<xref ref-type="bibr" rid="ref99">Irani, 2016</xref>; <xref ref-type="bibr" rid="ref140">Londo&#x00F1;o and Mora, 2018</xref>) and astrocytes (<xref ref-type="bibr" rid="ref237">Szpakowski et al., 2022</xref>). Several investigations regarding CXCL13 and the brain center on its contributions to autoimmunity, with converging findings suggests that CXCL13-mediated recruitment of B cells is associated with disease severity, progression, and poor prognosis (<xref ref-type="bibr" rid="ref140">Londo&#x00F1;o and Mora, 2018</xref>). CXCL13 neutralization in systemic lupus prone mice improved object recognition cognitive function and attenuated forced swim depressive-like behavior (<xref ref-type="bibr" rid="ref95">Huang et al., 2021</xref>). However, in stroke, CXCL13 levels support trafficking of B cells to brain where they may mediate neuroprotective effects (<xref ref-type="bibr" rid="ref173">Monson et al., 2014</xref>; <xref ref-type="bibr" rid="ref187">Ortega et al., 2020</xref>). Increased CXCL13 and CXCR5 in anterior cingulate cortex facilitated conditioned place aversion in a rodent model of neuropathic pain, suggesting that these cascades, and possibly B cells themselves may benefit aversive learning and memory under physical stress conditions on the water maze (<xref ref-type="bibr" rid="ref272">Wu et al., 2019</xref>). However, B cell deficiency did not impact memory performance (<xref ref-type="bibr" rid="ref268">Wolf et al., 2009</xref>). CXCR5<sup>&#x2212;/&#x2212;</sup> knockout mice displayed enhanced adult dentate gyrus neurogenesis and possible anxiolytic effects as indicated by increased movement in general and in the inner zone of the open field (<xref ref-type="bibr" rid="ref233">Stuart et al., 2015</xref>). CCL21 may also impact adult neuronal differentiation given the high expression of CCR7 in the subventricular zone and on astrocytes, microglia, and neurons (<xref ref-type="bibr" rid="ref249">Turbic et al., 2011</xref>; <xref ref-type="bibr" rid="ref183">Noor and Wilson, 2012</xref>). This position adjacent to the CSF-filled lateral ventricle may also poise this chemokine-receptor system to engage in T and B immune cell recruitment. Indeed, CCL21 is expressed on the surface of choroid plexus epithelium and on endothelial venules only during inflammation and may mediate T or other CXCR7 expressing cell transit through brain-CSF and BBB routes (<xref ref-type="bibr" rid="ref7">Alt et al., 2002</xref>; <xref ref-type="bibr" rid="ref113">Kivis&#x00E4;kk et al., 2004</xref>).</p>
<p>Levels of chemokines have been investigated in the context of stress and MDD (<xref ref-type="bibr" rid="ref172">Milenkovic et al., 2019</xref>). The majority of the published clinical studies reveal consistent circulating or CSF expression elevations in CCL2 and CXCL8 chemokines in depressed patients (<xref ref-type="bibr" rid="ref56">Eyre et al., 2016</xref>). Of note, <italic>in vitro</italic> evidence suggests that these chemokines along with CCL20 may also support B cell trafficking and possible entry into CNS (<xref ref-type="bibr" rid="ref8">Alter et al., 2003</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). Some clinical studies noted higher CXCL12 in depressed men and women in comparison with controls (<xref ref-type="bibr" rid="ref186">Og&#x0142;odek et al., 2014</xref>; <xref ref-type="bibr" rid="ref210">Romero-Sanchiz et al., 2020</xref>). Similarly, one study in rats exposed to prenatal stress (dam received gestational bright light exposure) revealed that CXCL12 was upregulated in the hippocampus and prefrontal cortex (<xref ref-type="bibr" rid="ref225">&#x015A;lusarczyk et al., 2015</xref>) and microglial CXCR4 expression was reduced with prenatal stress (<xref ref-type="bibr" rid="ref225">&#x015A;lusarczyk et al., 2015</xref>). Stress exposure may also modulate expression of recruitment signal receptors on B cells. <xref ref-type="bibr" rid="ref199">Poller et al. (2022)</xref> demonstrated that bone marrow homing restraint stress-exposed B and T cells unregulated expression of CXCR4. Further, <xref ref-type="bibr" rid="ref144">Lynall et al. (2021)</xref> noted that meningeal B cells from chronic social defeat exposed mice showed trends toward increased expression of CXCL13 genes. Other generalized immune cell recruitment signals may support B cell trafficking to CNS. Indeed, pathogen challenge increased brain chemokine expression and facilitated B cell recruitment in a CXCL9- and&#x2009;&#x2212;&#x2009;10-dependent manner (<xref ref-type="bibr" rid="ref139">Lokensgard et al., 2016</xref>); these chemokines have been found to be elevated in patients with high levels of anxiety and MDD (<xref ref-type="bibr" rid="ref130">Leighton et al., 2018</xref>). Finally, a thorough investigation of B cell recruitment signaling in CSF is still outstanding but may warrant further direct interrogation given that under normal conditions, levels of chemokines in CSF are low but increase manifold with inflammatory challenge (<xref ref-type="bibr" rid="ref197">Pilz et al., 2020</xref>; <xref ref-type="bibr" rid="ref44">DiSano et al., 2021</xref>).</p>
</sec>
<sec id="sec12"><label>5.2</label>
<title>Mechanisms modulating B cell access to brain</title>
<p>The mechanisms regulating immune cell migration across tissues, namely the BBB, are complex and has been extensively discussed elsewhere (<xref ref-type="bibr" rid="ref154">Marchetti and Engelhardt, 2020</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). In brief here, several primary factors appear to regulate B cell movement across the BBB. First, activated leukocyte cell adhesion molecule (ALCAM) expressed on the surface of the activated proinflammatory B cells as well as on endothelial cells supports B cell diapedesis across the BBB (<xref ref-type="bibr" rid="ref171">Michel et al., 2019</xref>). Leukocyte function-associated antigen-1 (LFA-1) on the surface of B cells binds its ligand intracellular adhesion molecule-1 (ICAM1). Very late antigen-4 (VLA4) expressed on activated B cells has been well studied in autoimmune diseases. Further, in autoimmune models, B cells appear to be recruited to CNS in an antigen-independent manner (<xref ref-type="bibr" rid="ref242">Tesfagiorgis et al., 2017</xref>) and do not take up residence in sites of inflammation. L-selectin (aka CD62L) and vascular cell adhesion molecule-1 do not appear to play a robust role in B cell movement across membranes (<xref ref-type="bibr" rid="ref8">Alter et al., 2003</xref>). While mechanisms regulating immune cell trafficking across BBB were extensively reviewed, whether B cells engaged these mechanisms in times of immune surveillance was not discussed (<xref ref-type="bibr" rid="ref154">Marchetti and Engelhardt, 2020</xref>).</p>
<p>Studies on the effects of stress exposure, and stress-associated hormonal signaling, on leukocyte adhesion mechanisms have yielded interesting observations (<xref ref-type="bibr" rid="ref98">Ince et al., 2018</xref>). Following 12&#x2009;days of chronic unpredictable stress, RNAseq data in prefrontal cortex revealed increased gene expression of <italic>Alcam</italic> in non-neuronal cell clusters as well as several types of inhibitory and excitatory neuronal populations (<xref ref-type="bibr" rid="ref126">Kwon et al., 2022</xref>). Fifteen minutes of forced public speaking resulted in elevated LFA-1 on mixed lymphocytes, no impact to ICAM1 density, and a decrease in L-selectin on T cells (<xref ref-type="bibr" rid="ref72">Goebel and Mills, 2000</xref>). Similarly, VLA-4, CD44, and LFA-1 expression in T cells was altered by a single 16&#x2013;18&#x2009;h restraint stress exposure (<xref ref-type="bibr" rid="ref240">Tarcic et al., 1995</xref>). With the exception of (<xref ref-type="bibr" rid="ref43">Dhabhar et al., 2012</xref>), in which acute restraint stress reduced circulating B cell numbers and induced a biphasic decrease in L-selectin expression on B cells in the 2&#x2009;h following stress cessation, the impact of stress exposure on adhesion mechanisms specifically in B cells were not measured in these studies. Interestingly, administration of norepinephrine (NE, aka noradrenaline), the receptors for which are expressed on B cells, decreased the number of L-selectin (CD62L) positive B cells but increased circulating B cells negative for this cell adhesion marker without impacting overall B cell L-selectin expression.</p>
<p>It is noteworthy that the BBB is not the only barrier impacted by stress. Several studies have found that intestinal barriers are leaky among patients with psychiatric disease (<xref ref-type="bibr" rid="ref261">Wasiak and Gawlik-Kotelnicka, 2023</xref>). Immune cells are critically involved in the extent of intestinal barrier integrity. Indeed, B cells support intestinal homeostasis through production of IgA and IgM antibodies, immune regulatory functions, and cytokine secretion; whether they play a protective, pathogenic, or mixed role in intestinal inflammatory conditions is the subject of intense investigation (<xref ref-type="bibr" rid="ref282">Zogorean and Wirtz, 2023</xref>). Gut microbiota composition is closely related to intestinal permeability status, and shifts in microbiome taxa composition have been reported in MDD (<xref ref-type="bibr" rid="ref33">Cheung et al., 2019</xref>). As appreciation for gut-brain-immune interactions in the context of stress and MDD continues to increase, novel interventions such as psychobiotics or fecal microbiome transfers may prove beneficial (<xref ref-type="bibr" rid="ref248">Trzeciak and Herbet, 2021</xref>).</p>
</sec>
<sec id="sec13"><label>5.3</label>
<title>B cell survival and retention in CNS or CNS-adjacent sites</title>
<p>If cells are recruited to sites of inflammation, such as the stressed brain, another question remains: is there sufficient support for B cells to survive and remain there to enact their cellular functions?</p>
<sec id="sec14"><label>5.3.1</label>
<title>BAFF and APRIL</title>
<p>Two principal B cell survival signals are well described in the immunology literature (<xref ref-type="bibr" rid="ref256">Vincent et al., 2013</xref>). B cell activating factor (BAFF; aka B lymphocyte stimulator, TNF&#x03B1; APOL-related leukocyte expressed ligand, and CD257), is a cytokine belonging to the TNF&#x03B1; ligand family. It is expressed by a variety of immune cell types and acts to activate B cells as well as to induce their proliferation and differentiation. Receptors for BAFF include BAFF-R, BCMA, and TACI, in order of ligand affinity. BAFF-R is expressed on immature B cells, while TACI is principally expressed on innate like B1 cells. Inadequate BAFF fails to activate B cells to mature and go on to produce antibody or enact other effector functions; excessive BAFF levels limit B cell apoptosis and may cause overproduction of antibodies, potentially leading to autoimmunity.</p>
<p>A proliferation-inducing ligand (APRIL, aka TNFSF13) is another B cell survival signal (<xref ref-type="bibr" rid="ref256">Vincent et al., 2013</xref>). APRIL acts as a co-stimulator for B and T cell proliferation and acts via TACI and BCMA receptors. APRIL also promotes IL-10 production and regulatory functions of B cells (<xref ref-type="bibr" rid="ref94">Hua et al., 2016</xref>). Within CNS, APRIL is expressed by astrocytes in postmortem MS patient brains (<xref ref-type="bibr" rid="ref243">Thangarajh et al., 2007</xref>) and facilitated axon growth of hippocampal pyramidal and midbrain and striatal dopaminergic neurons during embryonic development (<xref ref-type="bibr" rid="ref188">Os&#x00F3;rio et al., 2014</xref>; <xref ref-type="bibr" rid="ref165">McWilliams et al., 2017</xref>). Expression of BAFF/APRIL receptors in the brain is unclear (<xref ref-type="bibr" rid="ref155">Marella et al., 2022</xref>) though a recently identified BAFF receptor Noggo-66 was found to be expressed on neurons and possibly glial cells, and may be a negative regulator of cell function (<xref ref-type="bibr" rid="ref281">Zhang et al., 2009</xref>).</p>
<p>BAFF and APRIL may play a role in stress. Indeed, increased anxiety-like behaviors (open field, elevated plus maze, novelty suppressed feeding), evidence of neuroinflammation (reactive astrocytes, activated microglia), impaired hippocampal neurogenesis, and disrupted long-term potentiation were found in BAFF overexpressing transgenic mice, a common preclinical model of autoimmunity (<xref ref-type="bibr" rid="ref38">Crupi et al., 2010</xref>). In humans, one small cohort study reported reduced circulating BAFF in MDD patients; levels were elevated with antidepressant intervention (<xref ref-type="bibr" rid="ref218">Schmidt et al., 2019</xref>). However, in a larger study of 3,221 subjects, plasma levels of BAFF were not significantly different between healthy control subjects and patients with schizophrenia or MDD, though BAFF levels were elevated among bipolar patients (<xref ref-type="bibr" rid="ref52">Engh et al., 2022</xref>). Plasma levels of APRIL were lower in psychosis patients compared to healthy controls and significantly correlated with higher psychotic symptom load, though other studies have not found APRIL levels to differ (<xref ref-type="bibr" rid="ref38">Crupi et al., 2010</xref>; <xref ref-type="bibr" rid="ref218">Schmidt et al., 2019</xref>).</p>
<p>While CNS levels of BAFF and APRIL have not been well studied in the stress exposed brain, <xref ref-type="bibr" rid="ref144">Lynall et al. (2021)</xref> noted that meningeal B cells from chronic social defeat exposed mice were lower in number but showed trends toward increased expression of BAFF genes. As the stressed brain represents a state of neuroinflammation (<xref ref-type="bibr" rid="ref137">Liu et al., 2017</xref>) and collective evidence suggests that the inflamed CNS provides a pro-survival microenvironment for leukocytes including B cells (<xref ref-type="bibr" rid="ref168">Meinl et al., 2006</xref>), perspectives gleaned from other neuroinflammatory conditions can inform our understanding of B cell interactions with stress and MDD. For example, following experimental stroke, BAFF expression is elevated in microglia (<xref ref-type="bibr" rid="ref135">Li et al., 2017</xref>) and CD11b<sup>high</sup> B cells recruited to brain after injury are known to regulate microglia activation, increasing their phagocytic capacity (<xref ref-type="bibr" rid="ref119">Korf et al., 2022</xref>). BAFF ligand-receptor interactions have been found to support neuronal survival and impart neuroprotection in an animal model of amyotrophic lateral sclerosis, an effect that may be independent of B cells (<xref ref-type="bibr" rid="ref238">Tada et al., 2013</xref>). Astrocytes also express BAFF and promote B cell activation in response to viral infection (<xref ref-type="bibr" rid="ref139">Lokensgard et al., 2016</xref>) or in MS (<xref ref-type="bibr" rid="ref123">Krumbholz et al., 2005</xref>). Interestingly, in animals exposed to experimental autoimmune encephalomyelitis (animal model of MS) and in MS patients, disease attenuating anti-CD20 treatment increased BAFF levels in serum, CSF, and leptomeninges (<xref ref-type="bibr" rid="ref259">Wang et al., 2024</xref>). Further, the beneficial effects for gray matter and microgliosis were reversed when anti-BAFF treatment was given in conjunction with B cell depletion, suggesting that BAFF plays a neuroprotective role in MS (<xref ref-type="bibr" rid="ref259">Wang et al., 2024</xref>). Whether other CNS cell types produce BAFF and support B cell survival, especially in the context of psychosocial stress or MDD, is not known and represents an important question to be answered.</p>
</sec>
<sec id="sec15"><label>5.3.2</label>
<title>Growth factors</title>
<p>Neurotrophins, such as brain derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), and nerve growth factor (NGF), play important roles in development, survival, and function of a wide variety of CNS and immune cell types. Of relevance here, evidence suggests that B cells express neurotrophin receptors p75TR, TrkA, TrkB, and TrkC in a subtype-specific pattern (<xref ref-type="bibr" rid="ref91">Hillis et al., 2016</xref>). Neurotrophins have complementary and sometimes redundant impacts to B cells. BDNF supports bone marrow B cell maturation as well as mature B cell survival (<xref ref-type="bibr" rid="ref46">D'Onofrio et al., 2000</xref>), while NGF, and NT3 to a lesser extent, facilitate proliferation, survival, differentiation, antibody production, and CD40 T cell co-stimulatory expression (<xref ref-type="bibr" rid="ref91">Hillis et al., 2016</xref>). Importantly, B lymphocytes can also secrete neurotrophins and this may have neuroprotective effects against inflammatory insults (<xref ref-type="bibr" rid="ref108">Kerschensteiner et al., 1999</xref>).</p>
<p>A large body of evidence has implicated growth factors in mood disorders and/or the response to antidepressants (<xref ref-type="bibr" rid="ref276">Zhang et al., 2015</xref>; <xref ref-type="bibr" rid="ref28">Ceci et al., 2021</xref>). For instance, BDNF and TrkB levels are reduced in hippocampi of depressed patients (<xref ref-type="bibr" rid="ref276">Zhang et al., 2015</xref>) and BDNF knock out mice display increased depressive-like behaviors and also have fewer B cells (<xref ref-type="bibr" rid="ref221">Schuhmann et al., 2005</xref>). NGF, a potent survival factor for memory B cells (<xref ref-type="bibr" rid="ref91">Hillis et al., 2016</xref>), is increased in inflamed tissues and has been shown to be elevated in blood in response to acute stress (<xref ref-type="bibr" rid="ref28">Ceci et al., 2021</xref>). However, chronic stress and depressed mood conditions are often (though not always) associated with downregulation of NGF. Like other growth factors, NT3 is highly expressed in brain regions implicated in MDD, such as hippocampus, and is often elevated in MDD brains (<xref ref-type="bibr" rid="ref276">Zhang et al., 2015</xref>). Known to regulate BDNF expression, one study reported reduced NT3 mRNA expression in peripheral white blood cells of MDD patients (<xref ref-type="bibr" rid="ref189">Otsuki et al., 2008</xref>). While these associations are interesting, the paucity of work directly addressing the convergence of stress/depression, growth factors, and B cells leaves several remaining questions as to the extent to which these three factors interact to influence mood. Moreover, still more work is needed to address how B cells engage with other growth factors, including insulin-like growth factor, platelet derived growth factor, and glial derived growth factor, in these contexts.</p>
</sec>
<sec id="sec16"><label>5.3.3</label>
<title>Interactions with T cells</title>
<p>Interactions with CD4<sup>+</sup> T helper cells support survival and differentiation of B cells as well as GC formation, B cell isotype switching and somatic hypermutation, and formation of long-lived antibody-secreting PC (<xref ref-type="bibr" rid="ref6">Aloulou and Fazilleau, 2019</xref>). The classic mechanism by which these interactions take place is via CD40 binding with CD40 ligand (CD40L) expressed by CD4 T and B cells (among other cell types) under inflammatory conditions. Importantly, a number of studies have identified important roles for CD4 T cells in CNS, namely in modulating neurological function in the healthy, stressed, injured, or diseased brain (<xref ref-type="bibr" rid="ref62">Fletcher et al., 2010</xref>; <xref ref-type="bibr" rid="ref60">Filiano et al., 2017</xref>; <xref ref-type="bibr" rid="ref87">Herkenham and Kigar, 2017</xref>; <xref ref-type="bibr" rid="ref205">Rayasam et al., 2018</xref>). In fact, one of the most consistently reported immune compartment alterations in depressed patient populations is an elevated circulating CD4<sup>+</sup>/CD8<sup>+</sup> ratio (<xref ref-type="bibr" rid="ref146">Maes, 2011</xref>; <xref ref-type="bibr" rid="ref87">Herkenham and Kigar, 2017</xref>; <xref ref-type="bibr" rid="ref110">Khedri et al., 2020</xref>). Further, preclinical studies in lymphocyte-deficient mice (nude, scid or Rag &#x2212;/&#x2212; mice) have noted deficits in adaptability to stress; reconstitution of various lymphocyte populations in these mice generally implicates the absence of T cells in mediating these deficits (<xref ref-type="bibr" rid="ref36">Cohen et al., 2006</xref>; <xref ref-type="bibr" rid="ref16">Beurel et al., 2013</xref>; <xref ref-type="bibr" rid="ref204">Rattazzi et al., 2013</xref>; <xref ref-type="bibr" rid="ref34">Clark et al., 2014</xref>; <xref ref-type="bibr" rid="ref21">Brachman et al., 2015</xref>). A variety of T cell subsets have been found in brain parenchyma following acute and chronic stress, including CD4<sup>+</sup> T cells (<xref ref-type="bibr" rid="ref16">Beurel et al., 2013</xref>; <xref ref-type="bibr" rid="ref195">Peng et al., 2022</xref>; <xref ref-type="bibr" rid="ref167">Medina-Rodriguez et al., 2023</xref>). T cells also robustly respond to glutamatergic signaling (<xref ref-type="bibr" rid="ref67">Ganor and Levite, 2014</xref>), a neurotransmitter system that is emerging as a key contributor to MDD and a principal target for novel, fast acting antidepressants (<xref ref-type="bibr" rid="ref260">Wang et al., 2021</xref>).</p>
<p>There is evidence that co-stimulatory pathways involved with T-B cell interactions are impacted in stress and depression. Basal platelet CD40 expression is higher in patients with MDD (<xref ref-type="bibr" rid="ref179">Neubauer et al., 2013</xref>). As well, circulating soluble CD40L levels were elevated in first episode unmedicated MDD patients and these levels were reduced when antidepressant interventions were administered (<xref ref-type="bibr" rid="ref131">Leo et al., 2006</xref>; <xref ref-type="bibr" rid="ref176">Myung et al., 2016</xref>), though another study reported reduced CD40L serum levels in MDD patients (<xref ref-type="bibr" rid="ref274">Zhang et al., 2023</xref>). CD40 activation induces sickness behavior and depressive-like phenotypes in mice, as revealed by reduced saccharine preference and impaired fear learning (<xref ref-type="bibr" rid="ref27">Cathomas et al., 2015</xref>). Thus, while T cells in the stressed brain may exert their own effector functions, their presence may serve to facilitate stress-responsive actions of B cells, or vice versa- B cells may facilitate the CNS effector functions of T cells.</p>
<p>One potential though controversial action of B cells is that they can regulate the development and activation of subsets of T cells via OX40-OX40 ligand or inducible T cell co-stimulator (ICOS)-ICOS ligand interactions (<xref ref-type="bibr" rid="ref196">Petersone et al., 2018</xref>). While mice exposed to a single 12&#x2009;h session of restraint did not show differences in splenic OX40 protein expression (<xref ref-type="bibr" rid="ref2">Ahmad et al., 2015</xref>), hippocampal ICOS mRNA expression was elevated in mice exposed to footshock induced learned helplessness (<xref ref-type="bibr" rid="ref17">Beurel et al., 2018</xref>). B cells may be a potential source of both OX40 or ICOS ligands (<xref ref-type="bibr" rid="ref196">Petersone et al., 2018</xref>), yet there is little known as to how either ligands are impacted by stress or depression. Of note, though ICOS ligand is the exclusive binding partner for ICOS, it can be produced by most antigen presenting cells (<xref ref-type="bibr" rid="ref266">Wikenheiser and Stumhofer, 2016</xref>) and some barrier cell types. Whether B cells are a significant source of ICOS ligand production in response to stress is currently unknown.</p>
</sec>
</sec>
<sec id="sec17"><label>5.4</label>
<title>B cell-neurotransmitter interactions</title>
<sec id="sec18"><label>5.4.1</label>
<title>Serotonin</title>
<p>B cells express receptors for a wide variety of neurotransmitters and this may have important implications in stress and depression. The serotonergic (5HT) system has been historically implicated in chronic stress disorders and functioned as targets of antidepressant action, though that association is not without controversy (<xref ref-type="bibr" rid="ref102">Jauhar et al., 2023</xref>). B cells express 5HT receptors 1A, 2A, 3 and 7 along with the 5HT transporter (SERT) (<xref ref-type="bibr" rid="ref89">Herr et al., 2017</xref>). 5HT stimulation of B cells appears to induce proliferation, likely in a 5HT-1A receptor dependent mechanism (<xref ref-type="bibr" rid="ref97">Iken et al., 1995</xref>) that requires inflammatory gene transcription (<xref ref-type="bibr" rid="ref1">Abdouh et al., 2001</xref>). Some evidence in B cell and lymphoma lines suggests that SERT expression increases in activated B cells enabling them to take up 5HT (<xref ref-type="bibr" rid="ref169">Meredith et al., 2005</xref>) and transport it, potentially long distances. However, B cell-derived lymphoma cells failed to proliferate with 5HT stimulation and showed increased apoptosis with 5HT uptake (<xref ref-type="bibr" rid="ref222">Serafeim et al., 2002</xref>; <xref ref-type="bibr" rid="ref117">Kolan et al., 2019</xref>). Interestingly, antidepressant intervention restores some B cell population numbers in MDD (<xref ref-type="bibr" rid="ref88">Hernandez et al., 2010</xref>; <xref ref-type="bibr" rid="ref3">Ahmetspahic et al., 2018</xref>). Lacking expression of tryptophan hydroxylase 1, B cells do not appear to be able to synthesize 5HT like T cells (<xref ref-type="bibr" rid="ref89">Herr et al., 2017</xref>). MDD patients consistently show reduced expression of SERT on peripheral lymphocytes that can be ameliorated at least in part with administration of one of several classes of antidepressant intervention (<xref ref-type="bibr" rid="ref252">Urbina et al., 1999</xref>; <xref ref-type="bibr" rid="ref194">Pe&#x00F1;a et al., 2005</xref>). As 5HT can also be synthesized in both the brain and the periphery via distinct mechanisms, this should be considered when trying to discern the convergence of 5HT, B cells, and stress (<xref ref-type="bibr" rid="ref89">Herr et al., 2017</xref>).</p>
</sec>
<sec id="sec19"><label>5.4.2</label>
<title>Norepinephrine/noradrenaline</title>
<p>In addition to regulating the immune response via stress signaling through the HPA axis, the brain leverages the sympathetic nervous system innervation of primary and secondary immune organs principally through release of NE (<xref ref-type="bibr" rid="ref112">Kin and Sanders, 2006</xref>; <xref ref-type="bibr" rid="ref87">Herkenham and Kigar, 2017</xref>; <xref ref-type="bibr" rid="ref29">Chan et al., 2023</xref>). Antigen-mediated immune activation resulted in increased NE release and turnover in lymphoid organs, an effect that was partially blocked when NE signaling from brain to periphery was inhibited (<xref ref-type="bibr" rid="ref116">Kohm et al., 2000</xref>). Immune cells located in these organs express NE receptors, specifically &#x03B2;2 adrenergic receptors (<xref ref-type="bibr" rid="ref107">Kerage et al., 2019</xref>); moreover, this receptor is expressed much more highly on B cells than T cells (<xref ref-type="bibr" rid="ref112">Kin and Sanders, 2006</xref>). Lymphocytes express the NE transporter (<xref ref-type="bibr" rid="ref157">Mata et al., 2005</xref>), and dopamine (DA)-&#x03B2; hydroxylase, a key enzyme governing the conversion of DA to NE, is also found in B cells (<xref ref-type="bibr" rid="ref191">Papa et al., 2017</xref>). This suggests that B cells can take up and also synthesize NE <italic>de novo</italic>.</p>
<p>In the context of public speaking stress, which elevated circulating NE levels, there was a trend toward elevated peripheral B cell counts but also a tendency toward less IgM produced in response to mitogen stimulation <italic>in vitro</italic> when compared with B cells collected pre-stress (<xref ref-type="bibr" rid="ref159">Matthews et al., 1995</xref>). Retrograde viral tracing revealed that several stress/reward-associated brain regions, such as hypothalamus, hippocampus, amygdala, ventral tegmental area, and locus coeruleus, innervate bone marrow, a site of NE release (<xref ref-type="bibr" rid="ref42">D&#x00E9;nes et al., 2005</xref>). Similar regions were reflected in brain-spleen innervation patterns (<xref ref-type="bibr" rid="ref24">Cano et al., 2001</xref>), further supporting an association between NE, B cell immunity, and stress. In MDD patients, while NE levels were not altered, lymphocyte NE transporter expression was reduced (<xref ref-type="bibr" rid="ref157">Mata et al., 2005</xref>). It may be that stress effects on at least some immune cells are mediated by both corticosterone and catecholaminergic stimulation as noted that adrenalectomy or catecholamine receptor antagonism prevent at least some stress-associated circulating leukocyte shifts (<xref ref-type="bibr" rid="ref53">Engler et al., 2004</xref>). Interestingly, epinephrine (adrenaline), but not NE administration, reduced total B lymphocytes in circulation, suggesting these cells were trafficked into tissues (<xref ref-type="bibr" rid="ref43">Dhabhar et al., 2012</xref>).</p>
</sec>
<sec id="sec20"><label>5.4.3</label>
<title>Dopamine</title>
<p>DA, a key mediator of reward circuits known to be dysregulated in MDD (<xref ref-type="bibr" rid="ref212">Russo and Nestler, 2013</xref>), is now appreciated to have potent immunomodulatory actions (<xref ref-type="bibr" rid="ref255">Vidal and Pacheco, 2020</xref>). Relative to other immune cell types, B cells displayed the most robust expression of DA receptors (DRDs); DRDs 2&#x2013;5 were expressed on B cells, with DRD3 expressed at the highest levels (<xref ref-type="bibr" rid="ref163">McKenna et al., 2002</xref>). Stimulation of unique DRDs can exert distinct and sometimes competing effects within the immune system. For example, B cell DRD1 stimulation by CD4<sup>+</sup> T follicular cells, found to be potent secretors of DA, reorganizes expression of co-stimulator machinery, facilitates GC synapses, and promotes B cell maturation (<xref ref-type="bibr" rid="ref191">Papa et al., 2017</xref>). In a small cohort study of patients with rheumatoid arthritis, B cell DRD expression was lower than that of healthy controls, B cell DRD2 stimulation is negatively correlated with disease activity (<xref ref-type="bibr" rid="ref263">Wei et al., 2015</xref>), and DRD2 and&#x2009;&#x2212;&#x2009;3 expression levels were increased among patients treated for 3&#x2009;months with an anti-rheumatic disease modifying drug (<xref ref-type="bibr" rid="ref264">Wieber et al., 2022</xref>). However, in female rheumatoid arthritis patients, B cells were shown to express DRD1, the frequency of DRD1 was correlated with severity of disease, and stimulation of these cells increased expression of proinflammatory factors, suggesting sex-specific effects with regard to DA-B cell interactions in this disease. Further, the consequences of DAergic stimulation of B cells may be disease context-specific, as MOG-induced mouse models of MS promoted CNS infiltration of DRD3 expressing B cells with regulatory/immunosuppressive and antigen presenting phenotypes (<xref ref-type="bibr" rid="ref200">Prado et al., 2021</xref>). Expression of the DA transporter is found on lymphocytes and mice in which it is lacking show exaggerated memory B cell responses (<xref ref-type="bibr" rid="ref74">Gopinath et al., 2023</xref>). Further, DA transporter expression on resting lymphocytes was reduced in schizophrenic and bipolar psychosis patients (<xref ref-type="bibr" rid="ref153">Marazziti et al., 2010</xref>). Chronic stress can induce hyperexcitability in certain DAergic neuronal populations, namely in stress- and mood-related brain areas in which DA expression is high (including hippocampus, paraventricular nucleus, and striatum) (<xref ref-type="bibr" rid="ref212">Russo and Nestler, 2013</xref>). Whether these stress-related consequences in DAergic signaling impact the number and function of B cells that are present in or trafficked to these regions and what that means for stress susceptibility or resolution is worthy of further exploration. However, evidence suggests this potential as designer receptors activated only by designer drug-induced activation of the ventral tegmental area increased IgM<sup>+</sup> B cells and potentiated IgM antibody secretion with <italic>E. coli</italic> immune challenge relative to mice who did not receive neuronal activation (<xref ref-type="bibr" rid="ref13">Ben-Shaanan et al., 2016</xref>).</p>
</sec>
<sec id="sec21"><label>5.4.4</label>
<title>Glutamate and GABA</title>
<p>Dysfunction in the glutamatergic system, representing the major excitatory neurotransmitter of the CNS, has emerged as a key component of MDD development and potential novel target for fast-acting depressive symptom amelioration (<xref ref-type="bibr" rid="ref214">Sarawagi et al., 2021</xref>). Indeed postmortem assessments of MDD patient brains revealed reduced size of the glutamatergic neuronal layer VI (<xref ref-type="bibr" rid="ref37">Cotter et al., 2002</xref>) as well as reduced expression of glutamatergic receptor machinery in prefrontal cortex (<xref ref-type="bibr" rid="ref59">Feyissa et al., 2009</xref>). Similarly, in MDD, size and density of various GABAergic interneurons are reduced in this and other regions implicated including the anterior cingulate and amygdala (<xref ref-type="bibr" rid="ref203">Rajkowska et al., 2007</xref>; <xref ref-type="bibr" rid="ref246">Tripp et al., 2011</xref>; <xref ref-type="bibr" rid="ref78">Guilloux et al., 2012</xref>). Imaging studies of a variety of modalities have confirmed disruption in these neurotransmitter systems (<xref ref-type="bibr" rid="ref214">Sarawagi et al., 2021</xref>) and recent meta-analyses revealed decreased levels of glutamate+glutamine in the anterior cingulate and medial frontal cortex as well as decreased GABA in occipital and prefrontal cortex of MDD patients (<xref ref-type="bibr" rid="ref143">Luykx et al., 2012</xref>; <xref ref-type="bibr" rid="ref209">Romeo et al., 2018</xref>; <xref ref-type="bibr" rid="ref174">Moriguchi et al., 2019</xref>).</p>
<p>Emerging evidence suggests that B cells can be impacted by glutamatergic receptor ligands. Indeed, human B cells expressed GRIK2, &#x2212;3, &#x2212;4, and&#x2009;&#x2212;&#x2009;5 kainate receptor genes and activation of these receptors resulted in increased proliferation and IgE release (<xref ref-type="bibr" rid="ref234">Sturgill et al., 2011</xref>). B cells may also express metabotropic glutamate receptors and ligand binding may mediate apoptotic cascades (<xref ref-type="bibr" rid="ref145">Ma et al., 2015</xref>). Finally, B cells may express functional N-methyl-D-aspartate receptors (NMDA; GluN2A and B) (<xref ref-type="bibr" rid="ref244">Torres et al., 2021</xref>). The functional significance of which is not currently well studied though one recent report noted that non-competitive antagonists impaired B cell migration, proliferation and Ig production but increased numbers of IL-10 secreting B cells (<xref ref-type="bibr" rid="ref224">Simma et al., 2014</xref>). Further interrogation of these complex interactions will be important considering the recent regulatory approvals for glutamatergic modulation in patients with refractory MDD (<xref ref-type="bibr" rid="ref214">Sarawagi et al., 2021</xref>).</p>
<p>B cells may also interact with the GABA system, the key inhibitory neurotransmitter of the CNS (<xref ref-type="bibr" rid="ref214">Sarawagi et al., 2021</xref>). Indeed, B cells can take up glutamine and process it to produce glutamate or GABA; CD8<sup>+</sup> T cell or macrophage proinflammatory antitumor responses were dampened as a result (<xref ref-type="bibr" rid="ref279">Zhang et al., 2021</xref>). Importantly, GABA deficiency has long been considered an important component of disordered mood (<xref ref-type="bibr" rid="ref214">Sarawagi et al., 2021</xref>). Whether B cells in the CNS of behavioral stress-exposed or depressed organisms also secrete GABA and exert anti-inflammatory effects or neuromodulatory effects that regulate immune cascades present in stress/MDD-implicated brain regions is yet to be determined. For both glutamate and GABA, an informed understanding of B cell impacts will need to include the observation of B cell production of autoantibodies against these receptors must also be considered (<xref ref-type="bibr" rid="ref235">Sun et al., 2020</xref>) (see below).</p>
</sec>
</sec>
<sec id="sec22"><label>5.5</label>
<title>Potential CNS-directed effector functions of B cells</title>
<p>The next question to be answered is what might B cells be doing in the stressed CNS? The answer may be condition specific as B cells appear to be pathogenic drivers in autoimmunity and Alzheimer&#x2019;s-like dementia whereas they may be neurorestorative in acute brain or spinal cord injury (<xref ref-type="bibr" rid="ref54">Engler-Chiurazzi et al., 2020</xref>; <xref ref-type="bibr" rid="ref198">Plantone et al., 2022</xref>; <xref ref-type="bibr" rid="ref151">Maheshwari et al., 2023</xref>; <xref ref-type="bibr" rid="ref152">Malone et al., 2023</xref>).</p>
<sec id="sec23"><label>5.5.1</label>
<title>B cell antibody production</title>
<p>A key effector function of B cells is their capacity to produce antibodies, including IgA, IgD, IgE, IgG, and IgM. Antibody production ability of B cells can have important functional consequences for CNS. For instance, B cells, and their production of IgM, may play a critical role in myelin development, a tightly regulated process dependent on local microenvironment signaling (<xref ref-type="bibr" rid="ref181">Nishiyama et al., 2021</xref>). <xref ref-type="bibr" rid="ref239">Tanabe and Yamashita (2018)</xref> identified that B cells, specifically B1a B cells, are recruited to choroid plexus and meningeal spaces via CXCL13 and supported oligodendrocyte proliferation via IgM secretion. Importantly, antibody titers may be altered by stress and in stress-related disease (<xref ref-type="bibr" rid="ref122">Kronfol and House, 1989</xref>; <xref ref-type="bibr" rid="ref105">Joyce et al., 1992</xref>; <xref ref-type="bibr" rid="ref226">Song et al., 1994</xref>; <xref ref-type="bibr" rid="ref73">Gold et al., 2012</xref>). Relative to mentally healthy control subjects, <xref ref-type="bibr" rid="ref73">Gold et al. (2012)</xref> noted that depressed populations displayed reductions in serum IgA, but not IgM or IgG levels. However, <xref ref-type="bibr" rid="ref105">Joyce et al. (1992)</xref> reported increased IgA in MDD patients. Exam and occupational stress was associated with elevated IgA, IgG, and IgM levels (<xref ref-type="bibr" rid="ref149">Maes et al., 1999</xref>; <xref ref-type="bibr" rid="ref158">Matos-Gomes et al., 2010</xref>). Methodological differences between sample populations and measurement approaches may account for some of the discrepancy between these studies, though recent meta-analyses confirmed that acute stress elevated Ig levels while chronically stressed humans showed age-related increased IgA or decreased IgM (<xref ref-type="bibr" rid="ref109">Khan et al., 2021</xref>; <xref ref-type="bibr" rid="ref26">Castro-Quintas et al., 2023</xref>). Mainly implicated in response to allergens, serum IgE levels are elevated in MDD patients (<xref ref-type="bibr" rid="ref50">El-Ansary, 2022</xref>) and hydrocortisone increased IgE levels in IL-4 stimulated human lymphocytes (<xref ref-type="bibr" rid="ref273">Wu et al., 1991</xref>). Though one study noted elevated IgD levels among MDD patients (<xref ref-type="bibr" rid="ref50">El-Ansary, 2022</xref>), very little is known about how psychosocial stress or MDD impact IgD, likely due to its very low level of basal expression (<xref ref-type="bibr" rid="ref257">Vladutiu, 2000</xref>). In mice, elevated platform stress-induced B cell profile shifts corresponded to an increase in IgG antibody titers in blood in the weeks following the stress exposure (<xref ref-type="bibr" rid="ref275">Zhang et al., 2020</xref>). The functional consequences of these stress-induced shifts in Ig secretion for immunity are conflicting and may be Ig subtype specific. Shifted B cell profiles among CRH overexpressing transgenic mice were associated with less robust IgM and IgG antibody responses to a thymus-dependent, bacterial-like antigen immunization, yet there were no differences in survival when mice were exposed to gram-positive <italic>S. pneumoniae</italic> bacterial immune challenge (<xref ref-type="bibr" rid="ref175">Murray et al., 2001</xref>). This suggests that stress-induced changes in B cell responsivity may not negatively impact overall immune response to at least some pathogenic challenges. Yet, speech making stress exposure increased the magnitude of allergen skin prick test wheal responses among allergic rhinitis (<xref ref-type="bibr" rid="ref111">Kiecolt-Glaser et al., 2009</xref>).</p>
<p>Beyond classic immunological roles for immunoglobulins, clinical observations have noted that B cell-derived autoantibodies against CNS targets, namely glutamatergic but also GABAergic receptors, are implicated in several neurological disorders (<xref ref-type="bibr" rid="ref235">Sun et al., 2020</xref>). For instance, NMDA receptor antibody encephalitis is associated with modest CNS perivascular and meningeal CD20<sup>+</sup> B cells while CD138<sup>+</sup> plasma cells have been observed in the CNS (<xref ref-type="bibr" rid="ref250">T&#x00FC;z&#x00FC;n et al., 2009</xref>; <xref ref-type="bibr" rid="ref156">Martinez-Hernandez et al., 2011</xref>), an effect supported by the observation of elevated CSF levels of CXCL13 observed in these patients (<xref ref-type="bibr" rid="ref132">Leypoldt et al., 2015</xref>). Several reports note that patients with anti-NMDA encephalitis report poor psychosocial function (<xref ref-type="bibr" rid="ref18">Blum et al., 2020</xref>; <xref ref-type="bibr" rid="ref180">Nguyen et al., 2020</xref>) and humans (migrants) or mice with chronic life stress experience display serum NMDAR1-antibody (IgA) (<xref ref-type="bibr" rid="ref190">Pan et al., 2021</xref>). As well, neuronal surface autoantibody expression has been implicated in a number of neuropsychiatric conditions, MDD included (<xref ref-type="bibr" rid="ref283">Zong et al., 2017</xref>). Though the process governing immune tolerant B cell development is complex (<xref ref-type="bibr" rid="ref235">Sun et al., 2020</xref>), two key sources of self-reactive autoantibodies have been identified: antibody-secreting plasmablasts from GCs in secondary lymphoid organs and bone marrow resident long-lived PCs (<xref ref-type="bibr" rid="ref83">Hansen, 2022</xref>). This is important given the recent findings noting increased splenic PCs with acute and chronic stress in rodents (<xref ref-type="bibr" rid="ref275">Zhang et al., 2020</xref>; <xref ref-type="bibr" rid="ref144">Lynall et al., 2021</xref>), linking the possibility for B cells to play a significant role in stress exposure-induced CNS reactive autoantibody generation mechanisms. As to where these cells are located, the BBB disruption reported in stress and MDD provides a promising mechanism by which Igs (autoreactive or not), expressed at very low levels under normal conditions (<xref ref-type="bibr" rid="ref283">Zong et al., 2017</xref>), are able to access the CNS. Intrathecal synthesis by PCs is another possibility that has yet to be fully discerned. It is worth noting that understanding in this field is still being developed and remains controversial (<xref ref-type="bibr" rid="ref254">Vahabi et al., 2021</xref>), thus added clarity is likely to emerge with additional investigations in the coming years.</p>
</sec>
<sec id="sec24"><label>5.5.2</label>
<title>B cell interactions with T cells</title>
<p>In addition to supporting activation and survival (above), B-T cell interactions take place within the context of antigen presentation via major histocompatibility complexes (MHC) (<xref ref-type="bibr" rid="ref32">Chen and Jensen, 2008</xref>). Indeed, after internalization via pinocytosis or B cell receptor-mediated endocytosis, B cells display antigenic peptide via MHCs to the T cell receptor of their antigen-cognate T cell. This interaction serves discrete functions, dependent on MHC class. MHCI molecules are ubiquitously expressed on all nucleated cell types, including B cells (<xref ref-type="bibr" rid="ref208">Rock et al., 2016</xref>) as well as neurons and glial cells in brain regions underlying mood and cognition (<xref ref-type="bibr" rid="ref51">Elmer and McAllister, 2012</xref>). MHCI displays critical non-immune roles in cortical development, neurite outgrowth, synaptic regulation, and learning and memory (<xref ref-type="bibr" rid="ref223">Shatz, 2009</xref>; <xref ref-type="bibr" rid="ref51">Elmer and McAllister, 2012</xref>; <xref ref-type="bibr" rid="ref178">Nelson et al., 2013</xref>). Further, MHCI expression on neurons is altered by cytokines, an important observation given that stress exposure induces proinflammatory shifts in cytokine profiles. When activated B cells present antigen via MHCI, CD8<sup>+</sup> cytotoxic T cells are activated (<xref ref-type="bibr" rid="ref265">Wieczorek et al., 2017</xref>) or in some cases tolerized (<xref ref-type="bibr" rid="ref12">Bennett et al., 1998</xref>; <xref ref-type="bibr" rid="ref25">Castiglioni et al., 2005</xref>). Like other professional antigen presenting cells, B cells constitutively express modest levels of MHCII surface molecules, though expression is substantially increased following cell activation or cytokine stimulation (<xref ref-type="bibr" rid="ref208">Rock et al., 2016</xref>). Given the strong evidence for critical roles for T cells in MDD, namely the elevated ratio of CD4<sup>+</sup>/CD8<sup>+</sup> T cells in MDD patients (<xref ref-type="bibr" rid="ref147">Maes et al., 1990</xref>) and that T cell deficiency in mice increases maladaptive stress response behaviors which are ameliorated by T cell adoptive transfer (<xref ref-type="bibr" rid="ref36">Cohen et al., 2006</xref>), antigen presentation and subsequent co-stimulation of T and B cells could have critical impacts on the stress response. Several genome wide association studies have revealed variants in expression of MHC-related genes among MDD patient populations (<xref ref-type="bibr" rid="ref269">Woo et al., 2018</xref>; <xref ref-type="bibr" rid="ref271">Wray et al., 2018</xref>; <xref ref-type="bibr" rid="ref133">Li et al., 2019</xref>). <xref ref-type="bibr" rid="ref148">Maes et al. (1992)</xref> also identified increased expression of MHC-II on the surface of T cells collected from blood of depressed patients. MHC expression has also been found altered in rodent models of stress. The percent of peritoneal macrophages displaying MHCII surface molecules was reduced in adult male mice exposed to a single session of 12&#x2013;18&#x2009;h of restraint stress (<xref ref-type="bibr" rid="ref284">Zwilling et al., 1990</xref>). This effect appears to be mediated by glucocorticoid signaling as <italic>in vitro</italic>, MHCII expression in B cells exposed to corticosterone is reduced (<xref ref-type="bibr" rid="ref184">Nugent et al., 2011</xref>). Whether similar changes are occurring on B cells in response to behavioral stress is not known.</p>
</sec>
<sec id="sec25"><label>5.5.3</label>
<title>B cell cytokine production</title>
<p>B cells represent a heterogenous cell population with the capacity to secrete a variety of cytokines in response to immune stimulation and these secretion patterns can have fundamentally distinct consequences for immunity and for CNS (<xref ref-type="bibr" rid="ref92">Hoffman et al., 2016</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). As elegantly depicted in 6, B cell-derived cytokines can promote macrophage activation (granulocyte-macrophage colony stimulating factor), support PC differentiation and survival (IL-6), regulate T cell differentiation, proliferation and inflammatory function (IL-6; transforming growth factor-&#x03B2;, and IL-35), facilitate formation of follicle-like structures (lymphotoxin-&#x03B1;) and modulate microglial cell activation (TNF&#x03B1;; interferon-&#x03B3;). Indeed, proinflammatory B cells regulated microglia and macrophage proinflammatory cytokine expression in MS (<xref ref-type="bibr" rid="ref245">Touil et al., 2018</xref>). In contrast, B regulatory cells have been recently been recognized to down-modulate inflammation, predominantly by restraining the inflammatory immune response via interleukin (IL)-10 secretion (<xref ref-type="bibr" rid="ref92">Hoffman et al., 2016</xref>; <xref ref-type="bibr" rid="ref101">Jain and Yong, 2022</xref>). This cytokine plays a protective role in various brain inflammatory conditions (<xref ref-type="bibr" rid="ref138">Lobo-Silva et al., 2016</xref>), systemic levels are altered in MDD, and converging data support its critical role in mediating stress susceptibility (<xref ref-type="bibr" rid="ref170">Mesquita et al., 2008</xref>; <xref ref-type="bibr" rid="ref70">Gazal et al., 2015</xref>; <xref ref-type="bibr" rid="ref128">Laumet et al., 2018</xref>). Importantly, in MS IL10-expressing B cells upregulated quiescence associated molecules (<xref ref-type="bibr" rid="ref245">Touil et al., 2018</xref>). Such cell-to-cell interactions may exert important functional consequences considering the complex roles played by microglia in regulated CNS function under normal and MDD conditions (<xref ref-type="bibr" rid="ref258">Wang et al., 2022</xref>).</p>
</sec>
</sec>
</sec>
<sec id="sec26"><label>6</label>
<title>Research tools</title>
<p>The pioneering insights gleaned from B cell interactions with CNS in other neurological conditions coupled with the availability of numerous B cell-modulating immunology research tools (<xref ref-type="bibr" rid="ref129">Lee et al., 2021</xref>; <xref ref-type="bibr" rid="ref253">Utset et al., 2021</xref>) poises the neuroscience field to rigorously interrogate mechanisms by which these cells may impact the response to stress. For instance, recent advances in spectral flow cytometry allow for more robust and comprehensive phenotyping of immune and resident cell panels in distinct tissues (<xref ref-type="bibr" rid="ref182">Nolan, 2022</xref>). Administration of fluorescently labeled immune cells permits tracking of immune cell migration with a high degree of spatial specificity. Adoptive transfer techniques can be used to reconstitute transgenic animals lacking in distinct leukocyte populations (e.g., B cells absent in &#x03BC;MT) with distinct immune cell populations (e.g., B regulatory cells) or with cells which lack certain functional capabilities (e.g., IL-6 vs. IL-10 secreting capacity). Further monoclonal antibody (mAb)-mediated strategies to deplete distinct B cell populations, cytokines, or survival signals <italic>in vivo</italic> can differentiate functional impacts during adulthood from those during some critical developmental window. Some of the many available approaches including anti-CD19 or -CD20 mAbs (e.g., Inebilizumab; Rituximab; Ocrelizumab) are in trials or approved for use in autoimmune SLE or MS (<xref ref-type="bibr" rid="ref280">Zhang et al., 2023</xref>). Moreover, various BAFF B cell survival signal inhibitors (e.g., Belimumab) are being developed or are currently deployed in clinical populations. Treatments developed for other therapeutic applications that are directed against other central [e.g., microglial depletion with colony stimulating factor 1 receptor inhibitors (PLX3397) (<xref ref-type="bibr" rid="ref10">Basilico et al., 2022</xref>)] or systemic [e.g., anti-CD3 muromonab (<xref ref-type="bibr" rid="ref125">Kuhn and Weiner, 2016</xref>)] immune cell populations can be used for discerning the extent to which interactions with other cells types is an important mechanism by which B cells influence the response to stress. MAbs directed against distinct cytokines are also available. A thorough understanding of the strengths and weaknesses of each approach is necessary to properly interpret results using these various research tools. For example, &#x03BC;MT mice exhibit reduced T cell numbers and functionality (<xref ref-type="bibr" rid="ref93">Homann et al., 1998</xref>; <xref ref-type="bibr" rid="ref14">Bergmann et al., 2001</xref>). Anti-CD20 B cell depletion (Rituximab) spares T cells (<xref ref-type="bibr" rid="ref251">Uchida et al., 2004</xref>), innate-like T cell&#x2013;independent B1 cells (<xref ref-type="bibr" rid="ref82">Hamaguchi et al., 2005</xref>) and plasma cells (<xref ref-type="bibr" rid="ref85">Hauser et al., 2008</xref>) while BAFF receptor targeting with TACI-IgG (Atacicept) robustly depletes the plasma cell compartment (<xref ref-type="bibr" rid="ref106">Kappos et al., 2014</xref>). As appreciation for the role these cells play in orchestrating immune and neurological function during homeostasis and stress grows, this understanding should better inform our current and future interventions to support mental health and wellbeing.</p>
</sec>
<sec sec-type="conclusions" id="sec27"><label>7</label>
<title>Conclusion</title>
<p>Taken together, evidence above supports complex B cell-stress-brain interactions (<xref ref-type="fig" rid="fig2">Figure 2</xref>). Psychosocial stress exerts robust effects on B cells; these effects can vary on a number of factors including the nature of the stressor, the tissue, and the B cell subtype being assayed. Brain control of peripheral immune cell compartments suggest complex regulatory cascades are engaged to control this response. Perturbation of B cell systems may be associated with alterations to hedonic state that could render an organism susceptible to a depressive-like phenotype. Multifaceted signaling and trafficking systems are engaged with stress exposure, some of which may result in B cell migration through blood or CSF to CNS target sites such as meningeal ELS, circumventricular organs, or even parenchyma itself. Finally, given their ability to engage with key neurotransmitter systems, B cells may impact the stressed brain in functionally meaningful ways that will continue to be revealed as research in this area progresses in the coming years.</p>
<fig position="float" id="fig2"><label>Figure 2</label>
<caption>
<p>Proposed schema of mechanisms governing B lymphocyte impacts to the psychosocial stressed brain. Stress exposure initiates shifts in secondary lymphoid organs that reorganize the peripheral B cell compartment and alter number and function in a subtype-specific manner. This can have important morphological consequences for immune organs. Stress modifies expression of cellular surface machinery components that impact B cell development/survival, cell&#x2013;cell interaction capacity, and migration. B cell trafficking signals govern the movement of cells to sites of inflammation in target organs, in this case the CNS. Stress exposure may render CNS protective barriers leaky, permitting infiltration of B cell secretory products (such as pro- and anti-inflammatory cytokines or antibodies) or cells themselves into brain parenchyma, where activation states and functional phenotypes of local resident CNS and/or immune cells have been altered. Cell survival signals may modulate the lifespan with which infiltrated cells have to carry out their effector functions on the stressed CNS. With repeated stress exposure, this cascade becomes dysregulated, leading to chronic stress disorders such as MDD. Figure created with <ext-link xlink:href="http://BioRender.com" ext-link-type="uri">BioRender.com</ext-link>.</p>
</caption>
<graphic xlink:href="fncel-18-1360242-g002.tif"/>
</fig>
</sec>
<sec sec-type="author-contributions" id="sec28">
<title>Author contributions</title>
<p>EE-C: Conceptualization, Funding acquisition, Writing &#x2013; original draft, Writing &#x2013; review &#x0026; editing.</p>
</sec>
</body>
<back>
<sec sec-type="funding-information" id="sec30">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by funds awarded to EE-C including NIH K01 MH117343, NIH P20 GM109036, the Tulane Brain Institute Research Fund Award, A Studio in the Woods, and start-up funds provided by the Tulane University.</p>
</sec>
<sec sec-type="COI-statement" id="sec31">
<title>Conflict of interest</title>
<p>The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
<p>The reviewer, RS, declared a past co-authorship with the author EE-C to the handling Editor.</p>
<p>The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.</p>
</sec>
<sec id="sec100" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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</ref-list>
<sec id="sec29">
<title>Glossary</title>
<table-wrap position="anchor" id="tab2">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left" valign="top">5-HT</td>
<td align="left" valign="top">serotonin</td>
</tr>
<tr>
<td align="left" valign="top">ALCAM</td>
<td align="left" valign="top">activated leukocyte cell adhesion molecule</td>
</tr>
<tr>
<td align="left" valign="top">APRIL</td>
<td align="left" valign="top">a proliferation-inducing ligand</td>
</tr>
<tr>
<td align="left" valign="top">BAFF</td>
<td align="left" valign="top">B cell activating factor</td>
</tr>
<tr>
<td align="left" valign="top">BBB</td>
<td align="left" valign="top">blood&#x2013;brain barrier</td>
</tr>
<tr>
<td align="left" valign="top">BDNF</td>
<td align="left" valign="top">brain derived neurotrophic factor</td>
</tr>
<tr>
<td align="left" valign="top">BMCA</td>
<td align="left" valign="top">B cell maturation antigen</td>
</tr>
<tr>
<td align="left" valign="top">CCL</td>
<td align="left" valign="top">CC chemokine ligand</td>
</tr>
<tr>
<td align="left" valign="top">CD</td>
<td align="left" valign="top">cluster of differentiation</td>
</tr>
<tr>
<td align="left" valign="top">CD40L</td>
<td align="left" valign="top">CD40 ligand</td>
</tr>
<tr>
<td align="left" valign="top">CNS</td>
<td align="left" valign="top">central nervous system</td>
</tr>
<tr>
<td align="left" valign="top">CRH</td>
<td align="left" valign="top">corticotrophin releasing hormone</td>
</tr>
<tr>
<td align="left" valign="top">CSF</td>
<td align="left" valign="top">cerebrospinal fluid</td>
</tr>
<tr>
<td align="left" valign="top">CXCL</td>
<td align="left" valign="top">C-X-C motif ligand</td>
</tr>
<tr>
<td align="left" valign="top">DA</td>
<td align="left" valign="top">dopamine</td>
</tr>
<tr>
<td align="left" valign="top">DRD</td>
<td align="left" valign="top">dopamine receptor</td>
</tr>
<tr>
<td align="left" valign="top">ELS</td>
<td align="left" valign="top">ectopic lymphoid structures</td>
</tr>
<tr>
<td align="left" valign="top">GABA</td>
<td align="left" valign="top">gamma aminobutyric acid</td>
</tr>
<tr>
<td align="left" valign="top">GC</td>
<td align="left" valign="top">germinal center</td>
</tr>
<tr>
<td align="left" valign="top">GR</td>
<td align="left" valign="top">glucocorticoid receptor</td>
</tr>
<tr>
<td align="left" valign="top">HPA</td>
<td align="left" valign="top">hypothalamic pituitary axis</td>
</tr>
<tr>
<td align="left" valign="top">ICAM</td>
<td align="left" valign="top">intracellular adhesion molecule</td>
</tr>
<tr>
<td align="left" valign="top">ICOS</td>
<td align="left" valign="top">inducible T cell co-stimulator</td>
</tr>
<tr>
<td align="left" valign="top">Ig</td>
<td align="left" valign="top">immunoglobulin</td>
</tr>
<tr>
<td align="left" valign="top">IL</td>
<td align="left" valign="top">interleukin</td>
</tr>
<tr>
<td align="left" valign="top">LFA</td>
<td align="left" valign="top">lymphocyte function associated antigen</td>
</tr>
<tr>
<td align="left" valign="top">LPS</td>
<td align="left" valign="top">lipopolysaccharide</td>
</tr>
<tr>
<td align="left" valign="top">mAb</td>
<td align="left" valign="top">monoclonal antibody</td>
</tr>
<tr>
<td align="left" valign="top">MDD</td>
<td align="left" valign="top">major depressive disorder</td>
</tr>
<tr>
<td align="left" valign="top">MHC</td>
<td align="left" valign="top">major histocompatibility complex</td>
</tr>
<tr>
<td align="left" valign="top">NE</td>
<td align="left" valign="top">norepinephrine</td>
</tr>
<tr>
<td align="left" valign="top">NGF</td>
<td align="left" valign="top">nerve growth factor</td>
</tr>
<tr>
<td align="left" valign="top">MR</td>
<td align="left" valign="top">mineralcorticoid receptor</td>
</tr>
<tr>
<td align="left" valign="top">MS</td>
<td align="left" valign="top">multiple sclerosis</td>
</tr>
<tr>
<td align="left" valign="top">NMDA</td>
<td align="left" valign="top">N-methyl-D-aspartate</td>
</tr>
<tr>
<td align="left" valign="top">NT3</td>
<td align="left" valign="top">neurotrophic factor 3</td>
</tr>
<tr>
<td align="left" valign="top">PC</td>
<td align="left" valign="top">plasma cell</td>
</tr>
<tr>
<td align="left" valign="top">PVN</td>
<td align="left" valign="top">paraventricular nucleus</td>
</tr>
<tr>
<td align="left" valign="top">SERT</td>
<td align="left" valign="top">serotonin transporter</td>
</tr>
<tr>
<td align="left" valign="top">TACI</td>
<td align="left" valign="top">transmembrane activator and calcium-modulator and cyclophilin ligand interactor</td>
</tr>
<tr>
<td align="left" valign="top">TNF</td>
<td align="left" valign="top">tumor necrosis factor</td>
</tr>
<tr>
<td align="left" valign="top">VLA</td>
<td align="left" valign="top">very late antigen</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</back>
</article>