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Background/PurposeTo search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.MethodsIn a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.ResultsCompared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.ConclusionThese findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.

Natural IgM are highly represented in the circulation at birth, and these often autoreactive antibodies have been postulated to have innate-like properties and play crucial roles in apoptotic cell clearance, tissue homeostasis, and immune modulation. This review summarizes the known properties of these IgM autoantibodies, and the evidence that these anti-apoptotic cell IgM natural antibodies can regulate inflammatory responses through ancient pathways of the innate immune system that first arose long before the initial emergence of the adaptive immune system. While the regulatory contributions of these natural IgM autoantibodies are certainly not an essential and fundamental component of host defenses, these provide an additional layer to further protect the host. More importantly, these IgM antibody responses are highly inducible and their up-regulation can be a powerful means for the host to survive in a setting of chronic inflammation. The observed beneficial clinical associations for cardiovascular disease and autoimmunity, as well as opportunities for potential therapeutic implications are discussed.

Antibodies are a vital part of the armamentarium of the adaptive immune system for the fine-tuning of the recognition and response to foreign threats. However, in health there are some types of antibodies that instead recognize self-antigens and these contribute to the enhancement of primitive innate functions. This repertoire of natural IgM antibodies is postulated to have been selected during immune evolution for their contributions to critical immunoregulatory and housekeeping properties. The clearance of dying cells is one of the most essential responsibilities of the immune system, which is required to prevent uncontrolled inflammation and autoimmunity. In the murine immune system, natural IgM antibodies that recognize apoptotic cells have been shown to enhance the phagocytic clearance of dead and dying cells and to suppress innate immune signaling pathways. In the mouse, natural IgM are often the products of B-1 cell clones that arise during immune development without an absolute requirement for exogenous antigenic stimulation. In patients with systemic lupus erythematosus, IgM autoantibodies, which bind to neo-epitopes on apoptotic cells, have been demonstrated to be present at significantly higher levels in patients with lower disease activity and with less severe organ damage. While certain specificities of IgM autoantibodies correlate with protection from lupus renal disease, others may convey protective properties from lupus-associated atherosclerotic cardiovascular disease. New and unexpected insights into the functional roles of IgM antibodies are still emerging, especially regarding the functions of natural antibodies. Herein, we review recent progress in our understanding of the potential roles of natural IgM autoantibodies in the regulation of immune homeostasis and for protection from autoimmune and inflammatory diseases.

Imbalances in the gut microbiome are suspected contributors to the pathogenesis of Systemic Lupus Erythematosus, and our studies and others have documented that patients with active Lupus nephritis have expansions of the obligate anaerobe, Blautia (Ruminococcus) gnavus (RG). To investigate whether the RG strains in Lupus patients have in vivo pathogenic properties in a gnotobiotic system, we colonized C57BL/6 mice with individual RG strains from healthy adults or those from Lupus patients. These strains were similar in their capacity for murine intestinal colonization of antibiotic-preconditioned specific-pathogen-free, as well as of germ-free adults and of their neonatally colonized litters. Lupus-derived RG strains induced high levels of intestinal permeability that was significantly greater in female than male mice, whereas the RG species-type strain (ATCC29149/VPI C7-1) from a healthy donor had little or no effects. These Lupus RG strain-induced functional alterations were associated with RG translocation to mesenteric lymph nodes, and raised serum levels of zonulin, a regulator of tight junction formation between cells that form the gut barrier. Notably, the level of Lupus RG-induced intestinal permeability was significantly correlated with serum IgG anti RG cell-wall lipoglycan antibodies, and with anti-native DNA autoantibodies that are a biomarker for SLE. Strikingly, gut permeability was completely reversed by oral treatment with larazotide acetate, an octapeptide that is a specific molecular antagonist of zonulin. Taken together, these studies document a pathway by which RG strains from Lupus patients contribute to a leaky gut and features of autoimmunity implicated in the pathogenesis of flares of clinical Lupus disease.

T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca 2+ influx via Ca 2+ release-activated Ca 2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca 2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca 2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells. Regulatory T (Treg) cells are important for maintaining immune homeostasis. Here the authors show that STIM1 and STIM2, which activate the Ca 2+ channel ORAI1, are essential for the differentiation of peripheral Treg cells into tissue-resident and follicular Treg cells and their ability to limit autoimmunity in mice.

Systemic lupus erythematosus (SLE), the embodiment of a multi-organ autoimmune disease, results from hyperactivation of host-defence pathways and immune recognition of the most fundamental building blocks of life. In 2018, key advances have placed intestinal immunity and dysregulated expansions of candidate pathobionts at the forefront of SLE pathogenesis.

We suggest that the exuberant blood clotting and immune hyper-reaction seen in patients with COVID-19 may be exacerbated by depletion of the same regulator. This agent is protein S, which is both an anticoagulant in the blood coagulation cascade and an activating ligand for the immunosuppressive TAM family of receptor tyrosine kinases.In this Comment, Greg Lemke and Gregg Silverman propose that the excessive blood clotting and immune activation seen in severe COVID-19 may be mechanistically linked through protein S, a ligand for the immunosuppressive TAM receptor family.

A correction has been made to theMaterials and methods, Statistical analyses of genetic SNP (Section 2.5), second paragraph Error: “Additionally, among the significantly overrepresented SNPs (Fisher’s exact test, p < 0.005) with a positive mean allele frequency in ERs compared to NRs, we identified 317 SNPs of interest that had a mean allele frequency of for NRs but an allele frequency of at least 2 in ERs (Supplementary Table S2).” Corrected sentence: “Additionally, among the significantly overrepresented SNPs (Fisher’s exact test, p < 0.005) with a positive mean allele frequency in ERs compared to NRs, we identified 317 SNPs of interest that had a mean allele frequency for NRs but an allele frequency of at least 2 in ERs (Supplementary Table S2).” A correction has been made to theDiscussion, fifth paragraph (after heading “4 Discussion”) Error: “In our patients, we observed an appropriate reciprocal decrease in serum BAFF levels concurrent with the period of peripheral B cell replenishment. In MS patients, the differences in BAFF levels in ER and NR thus appear to be a conseque” Corrected sentence: “In our patients, we observed an appropriate reciprocal decrease in serum BAFF levels concurrent with the period of peripheral B cell replenishment.

Recent investigations have identified patients of African ancestry (AA) with Multiple Sclerosis (MS), who display more rapid B-cell repopulation after standard semi-annual infusions with an anti-CD20 monoclonal antibody for B cell depletion. In this study, we explored the immunologic and genetic factors, with, serum drug monitoring that may contribute to a faster rate of B-cell repletion that follows during recovery from treatment with anti-CD20 antibody. In AA MS patients treated with an anti-CD20 antibody that had early repopulation of peripheral blood B cells, we assessed for extrinsic factors, including the presence of anti-drug antibodies against ocrelizumab, which may contribute to early repletion. We also documented the associated serum drug levels. In addition, we examined for inheritance of intrinsic gene polymorphisms associated with B cell survival and immune function. Our findings identified a subset of AA patients with early B cell repletion after anti-CD20 treatment associated with anti-drug antibodies and an absence of detectable drug. Furthermore, a separate set of AA patients with the early B cell repletion phenotype without anti-drug antibodies had significant over-representation of genetic polymorphisms that map to genes for the B cell survival factor, BAFF, to antibody-dependent cytotoxicity, and to pathways involved in inflammation, leukocyte activation and B cell differentiation. In AA patients with MS, after anti-CD20 antibody treatment we found an unexpected high occurrence of early B cell replenishment. This was associated with the presence of anti-drug antibodies and/or specific genetic polymorphisms. Larger studies are now needed to determine whether these factors may lead to impaired therapeutic benefits of B cell targeted therapy and clinical progression, and these findings may be useful to guide future optimized personalized therapeutic strategies.

[...]they summarize several animal models including humanized mice, that are currently being used to study the role of EBV in autoimmunity. In the current study, Munroe et al. demonstrate that lymphocytes from mCD40-LMP1 mice injected with EBNA-1 develop significantly greater cellular and humoral immune responses to EBNA-1 and to Sm B than lymphocytes from wild type mice and have elevated ANAs and anti-dsDNA antibodies due to epitope spreading to DNA protein complexes. In their review article,Wu et al.discuss how microbial dysbiosis in the gut and disturbances in several pathways that affect the interaction of gut microbes with the host, may play a role in disease pathogenesis in SLE, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), MS, and type I diabetes (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786055/). [...]an original and a review article in this Research Topic examines the role of the gut microbiome in ankylosing spondyloarthropathies.