Biology subjects

Silverman, G. J.

Publications and source records attributed to Silverman, G. J..

7 recordsLinked to original sources

bioRxiv2026

Autoantibodies Drive Fc Gamma Receptor-Dependent Colon Inflammation During Immune Checkpoint Blockade

Immune checkpoint inhibitor (ICI)-associated colitis limits effective cancer immunotherapy, yet host determinants of severe toxicity remain undefined. We investigated whether humoral immunity is associated with subsequent severe immune-related colitis (irC). In melanoma patients, baseline serum autoantibody (AAb) profiling identified a composite antigen signature - a signature-level association rather than validated functional specificities - associated with severe irC, marked by retained reactivity to tumor-associated antigens and relative depletion of antibodies recognizing immune- and mucosal-regulatory proteins. To assess functional relevance, we transferred polyclonal IgG from severe- or non-severe-irC patients into wild-type or humanized Fc{gamma} receptor (hFc{gamma}R) mice treated with anti-PD-1 or anti-CTLA-4. IgG alone did not induce inflammation; however, severe-irC IgG amplified checkpoint-driven colonic inflammation in hFc{gamma}R mice, but not in wild-type mice, with checkpoint-specific remodeling of myeloid, lymphoid, and innate lymphoid compartments. These findings suggest that pretreatment humoral immunity conditions susceptibility to irC via the IgG-Fc{gamma}R axis.

cancer biology↗

bioRxiv2025

Persistent Classical and Atypical Memory B Cells Underlie Heterogeneous Vaccine Responses in Ocrelizumab-Treated Multiple Sclerosis

Background and ObjectivesPatients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR), a B-cell-depleting therapy, exhibit heterogeneous humoral responses to SARS-CoV-2 mRNA vaccination. The mechanisms underlying this variability remain incompletely understood. We performed a longitudinal analysis of B-cell subset dynamics and antigen-specific T cell responses in OCR-treated pwMS and healthy controls to determine how immune cell composition, timing of OCR infusion, and lymphocyte dynamics influence humoral response outcomes. MethodsBased on post-vaccination anti-Spike IgG titers measured by multiplex bead immunoassay, pwMS were categorized as super-responders (SR), responders (R), or non-responders (NR). A 35-marker spectral flow cytometry panel was used to characterize T- and B-cell subsets longitudinally, at baseline and following stimulation with a SARS-CoV-2 peptide pool. ResultsCD4+ and CD8+ T cell populations were preserved across OCR-treated pwMS, and SARS-CoV-2-specific T cells remained detectable for more than 6 months after vaccination. In contrast, residual B-cell subset composition distinguished responders from non-responders. DN2-like B cells (CD19+CD27-IgD-T-bet+CD11c+CXCR5-) persisted despite repeated OCR infusions and were enriched in SR compared with NR. Repletion of mature naive B cells in peripheral blood correlated with time since last OCR infusion and with stronger humoral immune responses. ConclusionsB-cell subsets that resist OCR-mediated depletion may contribute to vaccine responsiveness in OCR-treated pwMS. Altered repletion kinetics of naive B cell subsets in non-responders suggest that specific B-cell populations may serve as predictive biomarkers of vaccine-induced humoral immunity, despite preserved T-cell responses.

immunology↗

bioRxiv2025

Pathogenic strains of a gut commensal drive systemic platelet activation and thromboinflammation in lupus nephritis

Imbalances in the gut microbiome have been linked to increased intestinal permeability and disease flares in systemic lupus erythematosus (SLE). Our study revealed that patients with flares of lupus nephritis (LN) and intestinal expansions of the anaerobic commensal, Ruminococcus gnavus (RG), displayed whole blood transcriptome profiles indicative of platelet, neutrophil, and myeloid cell activation, a profile reminiscent of sepsis. Serum analysis confirmed elevated serum levels of Platelet Factor 4 and neutrophil extracellular traps, which significantly correlated with levels of IgG-antibody to a novel lipoglycan (LG) produced by pathogenic RG strains, which was also documented in an independent LN cohort. To test for causality, in vivo mouse models further demonstrated that gut colonization with LG-producing RG strains, as well as a single intraperitoneal challenge with an LG preparation, caused platelet activation and megakaryocytosis in bone marrow and spleen. Mice colonized with RG strains that produce LG developed cellular infiltration of the kidneys by neutrophils and monocytes. Hence, RG expansions during renal flares may identify a specific LN flare endotype driven by thromboinflammatory mechanisms. Antibodies that arise from immune exposure to the RG lipoglycan may serve as a surrogate biomarker, helping to elucidate the impact of the relationship between gut microbiota communities and clinical outcomes in patients afflicted by LN. [208] Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/641288v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@1239f8eorg.highwire.dtl.DTLVardef@1c062caorg.highwire.dtl.DTLVardef@195ece2org.highwire.dtl.DTLVardef@1f3123f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation

Tryptophan modulates disease activity and the composition of microbiota in the B6.Sle1.Sle2.Sle3 (TC) mouse model of lupus. To directly test the effect of tryptophan on the gut microbiome, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated non-autoimmune B6 mice that were fed with a high or low tryptophan diet. The recipient mice with TC microbiota and high tryptophan diet had higher levels of immune activation, autoantibody production and intestinal inflammation. A bloom of Ruminococcus gnavus (Rg), a bacterium associated with disease flares in lupus patients, only emerged in the recipients of TC microbiota fed with high tryptophan. Rg depletion in TC mice decreased autoantibody production and increased the frequency of regulatory T cells. Conversely, TC mice colonized with Rg showed higher autoimmune activation. Overall, these results suggest that the interplay of genetic and tryptophan can influence the pathogenesis of lupus through the gut microbiota.

immunology↗

bioRxiv2022

Lupus disease flares are concordant with immune responses to blooms of lipoglycan-expressing Ruminococcus blautia gnavus strains arising from unstable gut microbiota communities

Whereas genetic susceptibility for Systemic Lupus Erythematosus has been well explored, the precipitants for clinical disease flares remain a mystery. To investigate for dynamic-relationships between gut-microbial communities and Lupus disease activity, we performed taxonomic surveys of fecal 16S rRNA gene amplicon-libraries from Lupus patients and healthy volunteers, obtained at serial timepoints over many months to several years. Individual Lupus patients commonly displayed imbalances in alpha and beta microbiota-diversity, which were uniquely different from healthy individuals as well as from other Lupus patients. Moreover, multivariate analysis of sequential Lupus libraries documented community-wide ecological microbiota instability overtime, most pronounced in patients with Lupus Nephritis LN), a severe form associated with worse prognosis. Lupus gut communities displayed transient spikes of pathogenic bacterial species, with by far the most prevalent being blooms of Ruminococcus blautia gnavus (RG), occurring in nearly half of LN patients often concordant with disease activity flares. RG strains isolated during disease flares, but not those isolated from healthy individuals or patients with inflammatory bowel disease, commonly expressed a novel, highly immunogenic cell wall-associated lipoglycan with conserved structural features that include a diacyl glycerol anchor. Cross-reactive antigenic determinants on these lipoglycans were recognized by murine monoclonal antibodies, and by spontaneously arising Lupus serum IgG antibodies with peak serum antibody responses also concordant with RG blooms. As SLE is frequently characterized by remitting-relapsing disease, despite appropriate treatment, we speculate that gut blooms of pathogenic bacteria, that impair gut barrier function and stoke systemic inflammation, directly contribute to immunopathogenesis.

immunology↗

bioRxiv2021

Lupus Gut Microbiota Transplants Cause Autoimmunity and Inflammation

BackgroundThe etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free mice. ResultsCompared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to germ free (GF) C57BL/6 mice caused GF mice to develop a series of lupus-like phenotyptic features, which including an increased serum autoimmune antibodies, and imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. ConclusionsOverall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.

immunology↗

bioRxiv2021

Sex-dependent Lupus Ruminococcus blautia gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity

Imbalances in the gut microbiome are suspected as 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, Ruminococcus blautia gnavus (RG). To investigate whether the RG strains in Lupus patients have in vivo pathogenic properties, we colonized C57BL/6 mice with individual RG strains from healthy adults or those from Lupus patients. These strains had a similar capacity for murine intestinal colonization, in antibiotic-preconditioned specific-pathogen-free, as well as germ-free adults, and 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. Lupus RG strain-induced functional alterations were associated dysregulated occluden transcript production in the ileal wall as well as 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 to 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 molecular pathway by which RG strains from Lupus patients induce a leaky gut and autoimmunity that have been implicated in the pathogenesis of flares of clinical Lupus disease.

microbiology↗