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.
•Murine systems have offered paradigms by which imbalances and translocations of gut pathobionts contribute to autoimmune pathogenesis.•Commensal microbes express orthologues of SSA/Ro and β2 ...glycoprotein I that prime for the autoantigen-specific immune responses in predisposed individuals.•In several independent reports, characteristic patterns of gut dysbiosis have been identified in clinical Lupus cohorts.•Candidate pathobionts include Ruminococcus gnavus, an obligate anaerobe implicated in Lupus nephritis as well as in several other diseases.•R. gnavus strains may produce a B cell superantigen postulated to contribute to immune pathogenesis.
Throughout our lives we are immersed in, and colonized by, immense and complex microbial communities. These microbiota serve as activators and early sparring partners for the progressive construction of the layers within our immune defenses and are essential to immune homeostasis. Yet, at times imbalances within the microbiota may contribute to metabolic and immune regulatory abnormalities that underlie the development of inflammatory and autoimmune diseases. Here, we review recent progress in investigations of the microbiome, with emphasis on the gut microbiota associated with systemic autoimmunity. In particular, these studies are beginning to illuminate aspects of the pathogenesis of Systemic Lupus Erythematosus, and may suggest that interconnections with specific disease-associated patterns of dysbiosis within gut communities are bidirectional and mutually reinforcing.
For more than a century, certain bacterial infections that can breach the skin and mucosal barriers have been implicated as common triggers of autoimmune syndromes, especially post-infection ...autoimmune diseases that include rheumatic fever and post-streptococcal glomerulonephritis. However, only in the past few years has the importance of imbalances within our own commensal microbiota communities, and within the gut, in the absence of infection, in promoting autoimmune pathogenesis become fully appreciated. A diversity of species and mechanisms have been implicated, including disruption of the gut barrier. Emerging data suggest that expansions (or blooms) of pathobiont species are involved in autoimmune pathogenesis and stimulate clonal expansion of T cells and B cells that recognize microbial antigens. This Review discusses the relationship between the gut microbiome and the immune system, and the potential consequence of disrupting the community balance in terms of autoimmune development, focusing on systemic lupus erythematosus. Notably, inter-relationships between expansions of certain members within gut microbiota communities and concurrent autoimmune responses bear features reminiscent of classical post-infection autoimmune disease. From such insights, new therapeutic opportunities are being considered to restore the balance within microbiota communities or re-establishing the gut-barrier integrity to reinforce immune homeostasis in the host.
Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, ...disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias.
Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome.
110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients.
Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity.
Yet >60% of all patients display primary resistance to ICI treatment, which has been linked to a number of factors intrinsic to the tumor (i.e., low mutational burden and poor antigenicity of tumor ...cells), to the host immune response (i.e., defective antigen presentation or exhaustion of the tumor-infiltrating lymphocytes), or arising from their functional interactions (i.e., local immunosuppression by extracellular metabolites).1 Following a 2015 report on clinical responses in patients receiving anti-CTLA-4 ICI,2 in early 2018 a flurry of reports has further highlighted the influences of a previously unsuspected internal universe on ICI responsiveness. Clinical improvement was correlated with enhanced in vitro T-cell response to individual candidate bacterial species4 and, in another report,7 with decreased frequency of peripherally derived colonic Tregs, increased frequencies of dendritic cell subsets associated with antitumor immune responses, and greater responses from T helper cell (Th1) and/or CD8+ T-cell subsets. ...as experimental monocolonization by an individual species does not have a physiological analogue, the experimental focus is now shifting to transfers of mixed commensal communities and to defining the molecular mechanisms by which microbes may affect the efficacy of ICI treatments.6 In summary, the current state of the art suggests that the clinical miracles imparted by ICI agents to some patients with malignancy may be directly or indirectly linked to the influence of pathobionts within the gut microbiome.
The X chromosome, hemizygous in males, contains numerous genes important to immunological and hormonal function. Alterations in X-linked gene dosage are suspected to contribute to female predominance ...in autoimmunity. A powerful example of X-linked dosage involvement comes from the BXSB murine lupus model, where the duplication of the X-linked Toll-Like Receptor 7 (Tlr7) gene aggravates autoimmunity in male mice. Such alterations are possible in men with autoimmune diseases. Here we showed that a quarter to a third of men with rheumatoid arthritis (RA) had significantly increased copy numbers (CN) of TLR7 gene and its paralog TLR8. Patients with high CN had an upregulated pro-inflammatory JNK/p38 signaling pathway. By fluorescence in situ hybridization, we further demonstrated that the increase in X-linked genes CN was due to the presence of an extra X chromosome in some cells. Men with RA had a significant cellular mosaicism of female (46,XX) and/or Klinefelter (47,XXY) cells among male (46,XY) cells, reaching up to 1.4% in peripheral blood. Our results present a new potential trigger for RA in men and opens a new field of investigation particularly relevant for gender-biased autoimmune diseases.
ObjectiveWhereas genetic susceptibility for Systemic Lupus Erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between ...microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities.MethodsIn an observational study, taxonomic analyses, including multivariate analysis of b- diversity, assessed time-dependent alterations in fecal communities from patients and healthy controls. From blooms, strains were isolated with genomes and associated glycans analyzed.ResultsMultivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common amongst in SLE patients, with transient intestinal growth spikes of several pathogenic species. Expansions of only the anaerobic commensal, Blautia (Ruminococcus) gnavus (RG) occurred at times of high-disease activity, and was detected in almost half of patients during lupus nephritis (LN) disease flares. Bulk RNA sequencing, from blood Paxgene tubes, demonstrated that patients with active LN and concurrent RG gut blooms have pathways of platelet activation, first documented in patients with sepsis. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature for strains found during Lupus flares was the common expression of a novel type of cell wall-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic- determinants, recognized by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares.1Gut colonization with RG strains from LN patients induce high levels of IgG antibodies to lipoglycan and lupus autoantibodies in non autoimmune prone C57BL/6 mice, while RG strains from heathy donors do not.ConclusionsOur findings rationalize how blooms of the RG pathobiont may be common .drivers of clinical flares of often remitting-relapsing Lupus disease, by pathways that may be different from other forms of LN, and highlight the potential pathogenic properties and clinical impact of specific strains isolated from active Lupus nephritis patients. An antibody biomarker assay for the novel RG strain-associated lipoglycan could aid to earlier diagnosis of LN risk, and better therapeutic decision-making, whereas therapeutic targeting of pathobiont strains could provide a means to treat LN flares without the immunosuppression inherent to all current treatments.ReferenceAzzouz D, et al. Ann Rheum Dis 2023 (in press).
Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy ...women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal
polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and
polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight
5'URR/3'UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL,
< 0.0001), independently of clinical subtypes, autoantibody profiles, disease duration, or treatments. Moreover, sHLA-G levels were inversely correlated to FMc quantities (Spearman correlation,
< 0.01). Finally, women with SSc had lower sHLA-G independently of the eight
5'URR/3'UTR polymorphisms, although they were statistically more often homozygous than heterozygous for
polymorphism genotypes -716 (G/T), -201 (G/A), 14 bp (ins/del), and +3,142 (G/A) than healthy women. In conclusion, women with SSc display less sHLA-G expression independently of the eight
polymorphisms tested. This decreased production correlates with higher quantities of persisting FMc commonly observed in blood from SSc women. These results shed some lights on the contribution of the maternal HLA-G protein to long-term persistent fetal Mc and initiate new perspectives in this field.
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