Frontiers in Immunology has organized a series of Research Topics which aim to promote debate or to change the perspective on unsettled clinical or experimental research in various areas of the field of immunology. To provide a critical evaluation of the state of research in the field of "Complement", leading experts have been invited by our Topic Editors to contribute their thoughts and perspectives on current challenges, latest discoveries, recent advances, and future perspectives in the field. This Research Topic solicits the submission of Opinion and Perspective articles that provide editorialized analysis related to the field of "Complement" by established researchers in the field. Please note, we do not accept spontaneous submissions to this article collection. As such, please inform the Editorial Office at immunology.submissions@frontiersin.org once you are prepared to submit.

Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk

INSERM Public Health

National University of Singapore

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Frontiers in Immunology

Inflammation

Molecular Innate Immunity

Expert Opinions and Perspectives in Complement: 2022

The complement system is characterized by the numerous and abundant components which are secreted or surface-expressed to mount an effective, regulated, and non-injurious attack on microbial pathogens. By the dawn of the 21st century, the three pathways of complement activation were discovered, i.e. the classical, alternative, or lectin pathways (<a href="#B1">1</a>). Detailed interfaces between these pathways and known and emerging microbial pathogens continue to reveal new functional aspects of this complex system. In addition, growing numbers of non-microbial complement targets continue to forge new fronts of research such as aging and autoimmunity (<a href="#B2">2</a>). Intracellular complement activation is yet another new front of complement research that can have broad physiological relevance (<a href="#B3">3</a>). The complement system is a `double-edged sword’ which eliminates sterile and microbial triggers of tissue inflammation but it amplifies inflammatory damages in excess. In this topic, three major areas of complement functions are discussed.The complement system is expected to defend against COVID-19 infection but it is probably more noticeable for its contributions to the severe inflammatory tissue injuries observed in advanced patients (<a href="#B4">4</a>). In the manifestation of complement-mediated damages, the anaphylatoxins resulting from C3 and especially C5 activation, i.e. C3a and C5a, play critical roles (<a href="#B5">5</a>, <a href="#B6">6</a>). In this topic, <a href="https://doi.org/10.3389/fimmu.2020.01661">Stahel and Barnum</a> highlighted the role of complement activation in the pathophysiology of SARS-Cov-2 and other coronavirus infections and brought our attention to the successful use of the C3 inhibitor AMY-101 and the C5 inhibitor eculizumab in severely ill COVID-19 patients. Nonetheless, there is still an unmet need for the complex investigation of complement inhibition as a therapeutic target. The rationale for such studies comes from mouse models showing a milder course of disease upon C3 deficiency or treatment with an antibody that blocks the C5a receptor. Moreover, many studies suggest crosstalk between complement and coagulation cascades and its possible link to thrombotic microangiopathies reported in COVID-19 patients (<a href="#B4">4</a>). Besides acknowledged inhibitors like AMY-101 and eculizumab that have been tested, several new candidates are considered, including recombinant C1 inhibitor (conestat alpha), another C5 blocker ravulizumab, IFX-1 and advoralimab (monoclonal antibodies blocking C5a-C5aR interaction), and narsoplimab (monoclonal antibody against MASP-2). The latter agent affects the lectin complement pathway, which is the most recently discovered route of cascade activation, thus putatively hiding the most unexplored aspects. Initial components of the lectin pathway are locally produced by alveolar epithelium, a primary target for SARS-CoV-2, and their elevated levels were found in patients’ lung tissue. Colocalization of viral envelope proteins with these markers was also found in blood vessels affected by thrombosis and endotheliitis. <a href="https://doi.org/10.3389/fimmu.2020.604512">Polycarpou et&nbsp;al.</a> describe the resemblance of post-infection Multisystem Inflammatory Syndrome in Children (MIS-C) with Kawasaki disease, an illness of unknown etiology characterized by acute vasculitis in children under 5 years of age. Although the age of patients with MIS-C is typically older, the number of clinical and laboratory parameters in these two syndromes overlap. The authors pointed out that the lectin pathway of complement activation bridges MIS-C and Kawasaki disease, making this complement pathway an attractive target for therapeutic approaches.Association between the complement system and systemic autoimmune diseases involves most apparently the classical pathway. On the one hand, these autoimmune diseases are hallmarked by immune complexes which deposit in tissues and small blood vessels, and activate the complement pathway through C1q and its associated C1r/C1s proteases (<a href="#B1">1</a>). It leads to tissue inflammation and injuries which contribute to disease manifestation. Paradoxically, genetic deficiency of the classical pathway (i.e. C1q, C1r, or C1s) often causes systemic lupus erythematosus (SLE), which is a systemic autoimmune disease due to antinuclear autoantibodies (ANA) (<a href="#B7">7</a>). What causes these pathogenic antibodies remains unclear and, in the article by <a href="https://doi.org/10.3389/fimmu.2023.1196544">Wu et&nbsp;al.</a>, a comprehensive body of literature has been reviewed to evaluate the nucleolus as a potential ANA trigger and how this may be suppressed by C1q/C1r/C1s.Like microorganisms, apoptotic cells are also targeted by C1q albeit that C1q binds to apoptotic cells directly without antibodies (<a href="#B8">8</a>). C1q binds predominantly to the exposed nucleolus (<a href="#B9">9</a>), which causes C1r/C1s activation and proteolytic degradation of nucleolar autoantigens and alarmins (<a href="#B10">10</a>–<a href="#B12">12</a>). <a href="https://doi.org/10.3389/fimmu.2023.1196544">Wu et&nbsp;al.</a> divided the nucleus into three distinct regions each representing one clinical ANA staining pattern, i.e. the chromatin network (homogeneous), sites of pre-mRNA processing (speckled), and sites of pre-rRNA processing (nucleolus). They provided documented the structural and functional contexts for these three nuclear regions and discussed autoantigens and alarmins in each of them, hypothesizing that each region is potentially sufficient to induce self-reactive autoantibodies (<a href="#B12">12</a>–<a href="#B14">14</a>) and C1q/C1r/C1s dampen their immunogenicity (<a href="#B12">12</a>, <a href="#B15">15</a>).Previous studies have emphasized the role of the complement system in initiating and propagating a neuroinflammatory response after stroke (<a href="#B16">16</a>–<a href="#B18">18</a>). However, while most preclinical stroke models are performed on young healthy animals, they may not be representative of clinical cohorts. In a perspective article, <a href="https://doi.org/10.3389/fimmu.2023.1161051">Couch et&nbsp;al.</a> postulate that the inadequacy of in vivo stroke models complicates the translation of the beneficial effects observed with multiple neuroprotective agents from mouse to human. Using an in vivo model of stroke on aged mice exposed to cigarette smoke, two major co-morbidity factors, authors showed that site-specific inhibition of complement C3 activation with B4-Crry significantly ameliorates neurological deficit by reducing dendritic loss and microglial activation. This study supports that the complement system mediates, at least in part, the neuroinflammatory response in stroke, and might offer a potential alternative treatment to patients who are not eligible for endovascular intervention due to the risk of haemorrhage and oedema.JL initiated and coordinated this editorial. MO, NM and JL contributed equally to the content of this editorial. All authors contributed to the article and approved the submitted version.This work is supported by the Singapore National Medical Research Council Open-funding Individual Research Grants (NMRC/OFIRG/0013/2016; MOH-000958).The editors thank contributing authors and reviewers to this topic, and thank the editorial office staff for their supports.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.

Editorial: Expert opinions and perspectives in complement: 2022

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins.

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins.

The axis of complement C1 and nucleolus in antinuclear autoimmunity

Multiple neuroprotective agents have shown beneficial effects in rodent models of stroke, but they have failed to translate in the clinic. In this perspective, we consider that a likely explanation for this failure, at least in part, is that there has been inadequate assessment of functional outcomes in preclinical stroke models, as well the use of young healthy animals that are not representative of clinical cohorts. Although the impact of older age and cigarette smoking comorbidities on stroke outcomes is well documented clinically, the impact of these (and other) stroke comorbidities on the neuroinflammatory response after stroke, as well as the response to neuroprotective agents, remains largely unexplored. We have shown that a complement inhibitor (B4Crry), that targets specifically to the ischemic penumbra and inhibits complement activation, reduces neuroinflammation and improves outcomes following murine ischemic stroke. For this perspective, we discuss the impact of age and smoking comorbidities on outcomes after stroke, and we experimentally assess whether increased complement activation contributes to worsened acute outcomes with these comorbidities. We found that the pro-inflammatory effects of aging and smoking contribute to worse stroke outcomes, and these effects are mitigated by complement inhibition.

Multiple neuroprotective agents have shown beneficial effects in rodent models of stroke, but they have failed to translate in the clinic. In this perspective, we consider that a likely explanation for this failure, at least in part, is that there has been inadequate assessment of functional outcomes in preclinical stroke models, as well the use of young healthy animals that are not representative of clinical cohorts. Although the impact of older age and cigarette smoking comorbidities on stroke outcomes is well documented clinically, the impact of these (and other) stroke comorbidities on the neuroinflammatory response after stroke, as well as the response to neuroprotective agents, remains largely unexplored. We have shown that a complement inhibitor (B4Crry), that targets specifically to the ischemic penumbra and inhibits complement activation, reduces neuroinflammation and improves outcomes following murine ischemic stroke. For this perspective, we discuss the impact of age and smoking comorbidities on outcomes after stroke, and we experimentally assess whether increased complement activation contributes to worsened acute outcomes with these comorbidities. We found that the pro-inflammatory effects of aging and smoking contribute to worse stroke outcomes, and these effects are mitigated by complement inhibition.