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This article is part of the Research Topic

Autoantibodies

Editorial ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00484

Autoantibodies

 Rikard Holmdahl1, Falk Nimmerjahn2 and  Ralf J. Ludwig3*
  • 1Karolinska Institute (KI), Sweden
  • 2Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
  • 3Department of Dermatology, Universität zu Lübeck, Germany

Autoantibodies
Studies on autoantibodies have become a vivid research field with a constantly growing number of research reports. The increasing interest from the scientific community is also reflected by the high number of articles within this Research Topic, illustrated by an interaction map, drawn by using the keywords of all articles of this collection (Fig 1). These articles, selected from the theme of the topic, clusters around “Autoantibodies” and “Autoimmunity”. Clustering was also observed for specific diseases, namely pemphigus and pemphigoid, lupus, arthritis, as well as neuroimmunology. Theme-wise, cytokines, B cells, cell signalling and complement are in the focus of many manuscripts within the Research Topic. This clustering was the basis for the selection of the manuscripts discussed in this Editorial.

Pemphigus and pemphigoid
We received quite a number of submissions on the topic of pemphigus and pemphigoid diseases, which are characterized and caused by autoantibodies to structural proteins of the skin Schmidt and Zillikens, 2013, Hammers and Stanley, 2016, Liu et al., 2017. After binding to their target antigen these autoantibodies directly (in the case of pemphigus) or indirectly (in the case of pemphigoid) cause skin blistering, which is the common clinical denominator of these diseases. Diagnosis is based on clinical presentation, detection of autoantibodies and/or complement deposits in the skin by direct immunofluorescent (IF) microscopy, as well as serological detection of the autoantibodies Witte et al., 2018. For both pemphigus and pemphigoid systemic immunosuppression, mostly using corticosteroids, is still the backbone of treatment. Yet, lack of efficacy and/or adverse events contribute to the medical burden of these diseases, which have an overall high and unmet medical need Lamberts et al., 2018. Within the research topic “Autoantibodies”, insights into the pathogenesis, as well as novel biomarkers and treatments are presented, which are likely to improve diagnosis and treatment of pemphigus and pemphigoid.

Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a complex and multifactorial systemic autoimmune disease, affecting mostly young women. The chronic inflammatory processes triggered during the disease can affect a variety of organ systems, including the skin, blood vessels, kidneys, and joints. Loss of humoral tolerance towards nuclear antigens such as RNA, DNA, and histones is one hallmark of the disease, although the direct contribution of autoantibodies to disease pathology in humans is still discussed controversially. However, novel treatments targeting autoantibody producing plasma cells have shown promising effects in patients with refractory SLE Alexander et al., 2015. In addition, novel insights into the activation and expansion of waves of polycolonal autoreactive B cell responses during SLE in humans have emphasized the tight connection between loss of humoral tolerance and disease activity Tipton et al., 2015. More direct evidence for a critical role of autoantibodies in SLE pathology is provided by animal model systems studying lupus nephritis, which have clearly demonstrated that autoantibody dependent activation of innate immune effector cells is a major factor for kidney and lung inflammation. With respect to genetic factors involved in the loss of humoral tolerance to nuclear antigens, a loss or an impaired signalling through the inhibitory FcgRIIb has been shown to lead to an increased level of autoantibody production by B cells and a decreased threshold for activation of innate immune effector cells Bolland et al., 2002. In line with the studies in mice, a non-functional FcgRIIb variant has been shown to be a genetic risk factor for SLE development in humans Willcocks et al., 2010, Waisberg et al., 2011. It is also clear, however, that multiple factors contribute to SLE development, including defects in apoptosis or enhanced TLR signalling Yajima et al., 2003, Pisitkun et al., 2006. Within the research topic “Autoantibodies” Weissenburger and colleagues provided new insights into how mutations in the Deoxyribonuclease 1-like 3 gene lead to the massive production of autoantibodies against double stranded DNA Weisenburger et al., 2018. Moreover, Biermann et al. demonstrated that autoantibodies for secondary necrotic cells identify patients with SLE Biermann et al., 2018. On the side of the innate immune effector cells, a decreased phagocytic capacity, resulting in the prolonged presence of dying cells in the body, has also been suggested to contribute to disease development Herrmann et al., 1998. In summary, more and more pieces of the SLE puzzle are falling into place, suggesting that the loss of humoral tolerance is not only a bystander but rather an active player in the pathogenesis of SLE.

Arthritis
Rheumatoid arthritis (RA) is one of the most common autoimmune disease of large socioeconomic importance. The role of autoantibodies, such as rheumatoid factors (RF), have been instrumental in the classification and thought on the causes and pathogenesis of the disease. More recently addition autoantibodies, such as antibodies to citrullinated proteins (ACPA) has been described. The successful treatment with antibodies targeting B cells, reviewed by Dr. Hoffmann and colleagues have been a key for the revival of the belief of a major role of B cells in RA and in several other autoimmune diseases Hofmann et al., 2018. As in most autoimmune diseases these autoantibodies appear years before the clinical inset of the disease. Dr. Sieghart and colleagues analysed the isotype distribution of the different RA autoantibodies in early and established RA and could show that both ACPA and RF of the IgG isotypes are specific but that analysis of the IgM isotype increase the sensitivity of the test Sieghart et al., 2018. RA has a high level of different antibodies and in the report is emphasised the value of analysing different specificities for the diagnosis. Dr. Bitoun and colleagues immunized Macaque monkeys with citrullinated peptides and could show that the T cell response, but not the B cell response, was mainly directed to citrulline, as has been observed in humans Bitoun et al., 2017 Bitoun et al). However, in contrast to humans, monkey with MHC class II alleles know to be associated with RA in humans, did not predispose for T cell or B cell responses to citrullinated peptides. This shows that we are still lacking an animal model that accurately reflect the autoimmune process leading to an ACPA response, known to occur in RA.

Autoimmune neurological diseases
Several articles also focused on autoimmune neurological diseases, mostly on improved diagnostics. Autoantibodies have been shown to be the cause of several neurological diseases, such as anti-NMDA receptor encephalitis Venkatesan and Adatia, 2017 or myasthenia gravis. Within this article collection, the role of autoantibodies in “classical” neurodegenerative diseases, such as Parkinson's Disease is discussed Jiang et al., 2018. This contributes to the current observations that autoantibodies to specific neuronal surface antigens are detected in a number of neuropsychiatric disorders Zong et al., 2017. Given a functional validation of these autoantibodies, this would change the landscape of treatment in a number of neuropsychiatric diseases.

Insights into pathogenesis
Animal model systems, if their limitations are considered Sundberg and Schofield, 2018, can significantly contribute to the understanding of disease pathogenesis. Within this Research Topic, two new animal models are described: Dr. Zheng and colleagues describe an immunization-based mouse model for primary Sjögren’s Syndrome Zheng et al., 2017, Yin et al., 2018. Dr. Tong and colleagues describe shared epitopes among type XI and type II collagens in mice and humans with arthritis Tong et al., 2018. Furthermore, an immunization-based arthritis model in the macaque Bitoun et al., 2017 and a model of feline limbic encephalitis Tröscher et al., 2017 are described within this Research Topic.

Large scale genetic analysis, such as genome wide association studies, have provided detailed insights in the underlying genetic association in autoimmune diseases, with the HLA locus a major risk allele Vodo et al., 2018, Sajda et al., 2016, Kim et al., 2017, Ghodke-Puranik and Niewold, 2015. Work within this Research Topic demonstrates a clustering of autoimmune diseases, namely pemphigus and thyroid autoimmunity. Interestingly, the increased prevalence of anti-TPO autoantibodies was associated with the absence of certain HLA alleles and with the presence on non-desmoglein antibodies Seiffert-Sinha et al., 2018. Clustering on the mRNA expression level are also prevalent in different autoimmune diseases, specifically between pemphigus and systemic lupus erythematosus (SLE) Sezin et al., 2017. These comparative approaches may be useful to identify novel therapeutic targets, that are either specific to one certain autoimmune disease, or maybe even effective at a specific cluster of autoimmune diseases. Examples of newly identified and validated risk alleles for SLE are described within this Research Topic: Gene expression from B cells from quiescent SLE patients identified an increased expression of TRIB1. To elute the functional relevance of this gene for SLE pathogenesis, transgenic mice with a B-cell-specific overexpression of Trib1 were generated in the C57Bl/6 genetic background. Trib1 overexpression in B cells led to lower IgG1 concentrations under normal conditions. Immunization of mice with a T cell-dependent antigen, also led to lower antigen-specific IgG titers, and basal or forced anti-dsDNA IgM titers were lower in mice overexpressing Trib1. Collectively, these data point towards a regulatory role of Trib1 in autoantibody production in health, as well as in disease Simoni et al., 2018. Based on the recent discovery of rare null-alleles for the deoxyribonuclease 1 like 3 (DNASE1L3) and the Fc gamma receptor IIB (FCGR2B) in SLE patients and genetic mouse models, Dr. Weisenburger and colleagues investigated the functional impact on these 2 genes in mice. For this purpose, mice deficient in both, Dnase1l3- and FcgR2b were generated in the C57BL/6 genetic background. In these mice, already at the age of 10 weeks, high levels of anti-DNA IgG were observed. Autoantibody titers in these mice exceeded those observed in 9-month old NZB/W mice. In conclusion, both genes synergize to promote IgG anti-DNA autoantibody production by B cells Weisenburger et al., 2018. For the organ-specific autoimmune disease pemphigus, novel associations with complement genes Bumiller-Bini et al., 2018 and within the neonatal Fc receptor are described within the Research Topic Recke et al., 2018.

Yet, the genetic does only partially explain disease susceptibility, and (at least in mice) genetically determined disease susceptibility can be overcome by changing daily habits Aqel et al., 2017. Indeed, autoantibody production is modulated by environmental factors, such as the diet and the microbiota Petta et al., 2018, Edwards et al., 2018. Furthermore, gender may have a greater impact on autoantibody production that previously appreciated Edwards et al., 2018. Within this Research Topic, several manuscripts addressed the contribution of environmental factors on the generation of autoantibodies and/or autoimmune disease: In their study Dr. Issac and colleagues showed that mice unable to clear a Salmonella infection spontaneously develop anti-dsDNA autoantibodies. This was associated with an increased CD25 expression on both, CD4+ and CD8+ T cells. This effect was specific to Salmonella infection, as infections with other bacteria did not induce autoantibody production Issac et al., 2018. Two articles demonstrate that pemphigoid diseases can be induced by treatment with gliptins or physical triggers, such as burns Gaudin et al., 2018, Mai et al., 2018.

Once autoantibodies are bound to their target antigen, they may induce disease through a variety of mechanisms Ludwig et al., 2017. These are either direct, Fab-mediated effects, such as induction of aberrant signalling - or alternatively, Fc-mediated events, such as activation of complement and engagement of activating Fc-receptors, drives tissue damage.

In pemphigus, autoantibodies to the desmosomal proteins desmoglein (Dsg) 3 and (often also) Dsg 1 cause intraepidermal blistering in the skin and mucous membranes Kasperkiewicz et al., 2017. In addition to Dsg 1/3, a wide range of autoantibodies has been identified in pemphigus patients Amber et al., 2018. The pathogenic relevance of these autoantibodies is not as firmly established as for anti-Dsg1/3. However, injection of IgG from a patient with Dsg 3-, but not Dsg 1-reactivity, into Dsg 3 deficient mice, led to the induction of intraepidermal blistering Vu et al., 1998. Recently, a model how Dsg- and non-Dsg autoantibodies leading to intraepidermal blistering has been proposed: In brief, this model proposes that depending on the pathogenic activity of all autoantibodies towards structures on keratinocytes they are either capable to induce disease alone or in combination with other autoantibodies Sinha and Sajda, 2018. The precise mechanisms how autoantibodies in pemphigus lead to desmosome dysfunction remains to be fully elucidated Spindler and Waschke, 2018: Steric hindrance, i.e. blockade of homophilic Dsg-interactions within the desmosome, through autoantibody binding is believed to be one cause of blistering in pemphigus. Furthermore, Dsg3 is internalized after binding of anti-Dg3 autoantibodies Schlögl et al., 2018, a process that required p38MAPK activation Vielmuth et al., 2018, Cipolla et al., 2017. In addition to Dsg3 internalization, keratin retraction, induced by pemphigus autoantibodies, has recently been demonstrated to be of importance in mediating autoantibody-induced cell dissociation Schlögl et al., 2018

Novel diagnostics / biomarkers
Precise molecular diagnosis, paired with predictive biomarkers form the basis of diagnosis, as well as the selection of the appropriate treatment for each individual patient. Hence, almost 20% of the articles within the Research Topic “Autoantibodies” focused on this topic.

Serological detection of autoantibodies is the basis of the diagnosis of many autoimmune diseases Ludwig et al., 2017. Anti-nuclear antibodies (ANA) are among the most-known autoantibodies. ANA are associated with several rheumatic diseases, for example systemic lupus erythematosus and systemic sclerosis. However, low titres of ANA are also present in healthy individuals Prussmann et al., 2014. The gold-standard for their detection is by indirect immunofluorescent microscopy, incubating patient serum with Hep-2 cells Meroni and Schur, 2010. Conventional ANA testing, however, requires time, is laborious, and requires microscopy expertise. To overcome these limitations and to standardize and automate ANA indirect IF testing, a fully automated system including pattern recognition of staining was recently developed Voigt et al., 2012. The workflow and performance characteristics of a fully automated ANA IIF system was compared to manual ANA testing by Dr. Ricchiuti and colleagues Ricchiuti et al., 2018. Use of the fully automated ANA determination has significant labour savings and good concordance with manual ANA readings.

As mentioned above, ANA are also found in quite a proportion of healthy individuals, ranging from 5% to 30% depending on the population and method used Tan et al., 1997, Prussmann et al., 2014, Satoh et al., 2012, Semchuk et al., 2007. This by far exceeds the prevalence of ANA-associated rheumatic diseases. If the target antigen is identified, autoantibodies to DFS70 are often found Interestingly, isolated anti-DFS70 reactivity, which was observed in over 500 serum samples, was not associated with rheumatic disease. Hence, if the dense fine speckled nuclear pattern, which corresponds to anti-DFS70 reactivity, is observed in Hep cells in ANA testing, and anti-DFS70 reactivity is confirmed, presence of rheumatic disease is very unlikely Carter et al., 2018. In contrast, detection of anti-cN-1A autoantibodies, which are found in 12% of patients with primary Sjögren’s Syndrome and in 10% of SLE patients, is associated with the presence of other autoimmune diseases Rietveld et al., 2018.

If an autoimmune disease is suspected but no autoantibodies can be detected by routine methods, these may be identified by applying novel techniques such as determination of specific isotypes of autoantibodies in suspected rheumatoid arthritis Sieghart et al., 2018 or by use of a keratinocyte binding assay in suspected pemphigus Giurdanella et al., 2018. In addition, autoantibodies are also found in diseases, which, so far are just beginning to be considered to be mediated by autoantibodies. These include neurological conditions Scharf et al., 2018, chronic obstructive pulmonary disease Wen et al., 2018, as well as cardiovascular diseases Basavalingappa et al., 2017, Meier and Binstadt, 2018, Ernst et al., 2017. However, with few exceptions, such as anti-NMDA receptor autoantibodies Planagumà et al., 2015, the pathogenic relevance of these autoantibodies needs to be determined.

Bullous pemphigoid (BP) is the most frequent pemphigoid disease Hübner et al., 2016. BP responds well to systemic of (whole body) topical steroid treatment Joly et al., 2002. After stopping steroid treatment relapse occurs in 30-40% of the patients Joly et al., 2009. Hence, biomarkers allowing to predict relapse would allow to select patients in which steroid treatment can be stopped, or which patients require prolonged steroid and/or adjuvant treatment. In a retrospective analysis of BP patients, Dr. Koga and colleagues demonstrated that high BP180 autoantibody levels were associated with future relapse. In contrast, age, BP230 antibodies or total IgE had no predictive value Koga et al., 2018. Colleagues from France describe elevated anti-type VII collagen autoantibodies, which are the cause of epidermolysis bullosa acquisita Koga et al., 2018 in almost half of the BP patients at the time of relapse Giusti et al., 2018. This, again is a retrospective chart analysis with a limited number of patients. Both studies, however, imply the possibility that predictive biomarkers for BP relapse can be identified. The steps towards this is a joint analysis of retrospective patient cohorts from several departments, as well as a prospective diagnostic study.

Novel treatments
Based on the understanding of disease pathogenesis, novel treatment targets or therapeutic approaches for autoantibody-mediated diseases have emerged. Within the Research Topic “Autoantibodies” several articles focused on new treatments.

The anti-CD20 antibody rituximab has dramatically improved the treatment of several autoantibody-mediated diseases, most recently demonstrated in a phase III clinical trial in pemphigus patients Joly et al., 2017. Of note, the response to rituximab is not uniform across all autoantibody-mediated diseases as demonstrated by the lower efficacy of anti-CD20 treatment in pemphigoid patients, when compared to pemphigus patients Lamberts et al., 2018. Rituximab and emerging treatments to modulate B and plasma cells were the topic of three reviews within the research topic Hofmann et al., 2018, Musette and Bouaziz, 2018, Malkiel et al., 2018. In this Research Topic, Dr. Roders and colleagues also identified SYK as a regulator of B cell activation. Thus, targeting SYK not only affects the effector functions (see below), but possibly also the generation of autoantibodies Roders et al., 2018. A different approach to modulate autoantibody concentrations may be to enhance their turnover by inhibiting the neonatal Fc receptor Lee et al., 2018, or by selective immunoadsorption using recombinant antigens to specifically elute autoantibodies Hofrichter et al., 2018

Blockade of autoantibody functions, either by targeting the Fab- or the Fc-portion, is another highly interesting treatment approach for autoantibody-mediated diseases. High doses of intravenous immunoglobulins (IVIG) are an effective second- or third-line treatment for a number of autoimmune diseases Iwata et al., 2018, Ishii et al., 2010, Amagai et al., 2009. How IVIG mediates the therapeutic effects, is controversially discussed Schwab and Nimmerjahn, 2013: One school of thought claims that all therapeutic effects of IVIG are mediated through inhibition of the neonatal Fc receptor (FcRn) Li et al., 2005. By administering excess IgG, the FcRn becomes saturated and thus all IgG molecules (including the autoantibodies) are more rapidly cleared. Others provide compelling evidence that the anti-inflammatory effect of IVIG is mediated by regulating the activation threshold in myeloid effector cells by changing the ratio of activating versus inhibitory FcR expression Kaneko et al., 2006. This effect required both terminal sialic acid residues at the Fc portion of the IgG, as well as expression of the inhibitory FcRIIB Schwab et al., 2014. Lastly, presence of anti-idiotypic antibodies had been reported. Specifically, the presence of anti-anti-Dsg 3 autoantibodies in IVIG preparations Mimouni et al., 2010, Mimouni et al., 2005. In this Research Topic, Dr. Kamaguchi and colleagues isolated anti-idiotypic antibodies against type XVII collagen, the major autoantigen in bullous pemphigoid Liu et al., 2017, and demonstrated a significant inhibitory activity of these antibodies against the pathogenic effects of BP patients’ autoantibodies Kamaguchi et al., 2017.

In addition to modulation of the Fab function of autoantibodies, their function can also be manipulated by changing the conserved N-linked Fc-glycan attached to the asparagine at position 297 in the constant region of the Fc heavy chain domains Dekkers et al., 2018. Indeed, treatment of mice with endo-β-N-acetylglucosaminidase (EndoS), that hydrolyses the β-1,4-di-N-acetylchitobiose core of the N-linked complex type glycan on the asparagine 297 Collin and Olsen, 2001, suppressed induction of experimental arthritis Nandakumar et al., 2018, which was associated with the inhibition of the formation of large immune complexes, and independent of changes in complement- or antigen-binding. The modulation of the conserved IgG’s N-glycosylation site may, however, have implications beyond the mere effector functions as reported by Dr. Bartsch and colleagues Bartsch et al., 2018: In their work they demonstrate that antigen-specific sialylated autoantibodies, but not unspecific sialylated IgG, attenuates disease manifestation in experimental lupus and arthritis. The antigen-specific sialylated autoantibodies modulated B- and T cell functions rather than modulating the effector functions of the autoantibodies.

In several autoimmune diseases, such as arthritis and pemphigoid disease, activation of complement and binding of immune cells to the immune complexes, as well as the subsequent intracellular signalling events are critical for pathogenesis Ludwig et al., 2017. Generalized inhibition of the complement inhibition, which is for example achieved by the anti-C5 antibody eculizumab Zuber et al., 2012, is, however associated with the risk of potentially life-threatening infections Benamu and Montoya, 2016. These adverse effects could be reduced by restricting the complement inhibition at the site of complement activation, or even more ideally at the site of pathologic tissue damage. By coupling a cyclic-RGD peptide to a function blocking C5 antibody, with directs the construct to sites of damaged endothelial cells. Thus, C5 inhibition preferentially occurs where endothelial damage is present Durigutto et al., 2017. In addition to targeted delivery of C5-inhibitry compounds, selectivity may also be achieved by certain complement pathways, which are upregulated in specific diseases. Dissection of the individual contribution of complement activation cascades in the pemphigoid disease epidermolysis bullosa acquisita Mihai et al., 2007, Mihai et al., 2018, demonstrated a predominant role of the alternative complement activation and no contribution of the membrane attack complex. Thus, selective targeting of C1q had therapeutic effects in an animal model of epidermolysis bullosa acquisita Mihai et al., 2018.

In addition to complement anaphylatoxins, cytokines recruit leukocytes to sites of autoantibody-induced pathology. Thus, their inhibition has become a well-established therapeutic principle for several chronic inflammatory diseases Reichert, 2012. So far, however, each of the licenced biologics targets one single cytokine. To enhance the anti-inflammatory activity, Dr. Abraham and colleagues used phage display to identify promiscuous chemokine-binding peptides. These bind a number of pro-inflammatory chemokines, such as CCL2, CCL5, as well as CXCL9-11. Use of their selected lead compounds in models auf autoimmune diseases, ameliorated clinical disease manifestation Abraham et al., 2017. This approach may be applicable in endemic pemphigus foliaceus, where alterations in cytokine and chemokine serum concentrations have previously been noted Timóteo et al., 2017.

Once bound to the immune complexes, a complex signalling cascade is triggered in the leukocytes, which ultimately leads to their activation, and subsequent inflammation and tissue damage Ludwig , 2017. Contrasting mRNA expression between inflamed and healthy skin in experimental pemphigoid disease, several hub-genes that potentially contribute to tissue damage in pemphigoid were identified. The spleen tyrosine kinase was among the identified hub-genes. Both, LysM-specific SYK knock-out mice, and mice treated with a small molecule SYK inhibitor were completely protected from induction of experimental pemphigoid disease by autoantibody transfer Samavedam et al., 2018, Németh et al., 2017. Corresponding findings were made in a mouse model of arthritis Németh et al., 2018. Taken together, this suggests that targeting SYK is a potential therapeutic approach for a number of autoantibody-mediated diseases. Furthermore, in the pemphigoid mouse model, inhibition of PI3K also prevented disease onset. Furthermore, pharmacological PI3K inhibition improved clinical disease manifestation when applied in therapeutic experimental settings Koga et al., 2018. In addition to these signalling pathways, others also contribute to the pathogenesis of pemphigoid disease, which have recently been reviewed elsewhere Ludwig , 2017.

In pemphigus, in addition to the above-described alterations in cell signalling, several lines of evidence suggest that apoptosis contributes to the loss of keratinocyte adhesion, and consequently intraepidermal blistering Schmidt and Waschke, 2009. Initially, the contribution of apoptosis was suggested by an increased expression of molecules involved in this process, i.e. different caspases, Fas, as well as FasL Pacheco-Tovar et al., 2009. Following this concept, inhibition of the Fas-FasL interaction by a function blocking anti-FasL antibody, pemphigus IgG-induced pathology can be inhibited in vitro. Furthermore, mice lacking expression of the secreted soluble FasL, do not develop intraepidermal blistering when injected with pemphigus patient IgG Lotti et al., 2018.

All of the above-mentioned treatments focused on targeting IgG-mediated autoimmunity. In addition to IgG-mediated autoimmunity, IgA autoantibodies have also relatively long been recognised as pathogenic. However, only recently attention has been attributed to IgE-mediated autoimmunity Maurer et al., 2018. Despite their presence at high frequencies in many autoimmune diseases, the pathogenic relevance of IgE autoantibodies has so far not been in the focus. In atopic dermatitis, a common, chronic inflammatory skin disease Leung and Bieber, 2003, removal of immunoglobulins by immunoadsorption, and even selective removal of IgE has therapeutic effects Kasperkiewicz et al., 2018, Wegner et al., 2017, Kasperkiewicz et al., 2018, which are comparable to that of biological atopic dermatitis treatment Beck et al., 2014. However, immunoadsorption is a very specialized procedure. In addition, especially in the S. aureus colonized skin of atopic dermatitis patient, central intravenous lines may lead to severe infectious complications.

Concluding remarks
“Autoantibodies” are a hot research topic, as reflected by the articles of this Research Topic. Based on enhanced understanding of disease pathogenesis, as well as the advancement of technology, we are at the verge of developing specific treatments for autoantibody-mediated diseases, that may even be able to induce a cure. This development, is for example reflected by the use of chimeric autoantigen receptor T cells in the treatment of experimental pemphigus Ellebrecht et al., 2016. In addition, novel developments in diagnostics now allow to better diagnose patients, as well as understand the autoimmune nature of diseases, which had not been thought of to be caused by an underlying autoimmune mechanism Scharf et al., 2018. So even, if causal treatment is not possible, we still may be able to carefully select treatments that are tailored to each patient’s need based on the detected biomarkers.

Keywords: Autoantibody, Pemphigus, Pemphigoid, Arthritis, Systemic lupu erythematosus, autoimmune neurological disease, Pathogenesis, biomarker, Diagnos, Treatment

Received: 24 Jan 2019; Accepted: 22 Feb 2019.

Edited by:

Herman Waldmann, University of Oxford, United Kingdom

Copyright: © 2019 Holmdahl, Nimmerjahn and Ludwig. 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.

* Correspondence: Prof. Ralf J. Ludwig, Universität zu Lübeck, Department of Dermatology, Lübeck, 23562, Germany, ralf.ludwig@uksh.de