Background/Purpose: Obesity is a major public health concern in the United States, affecting over 100 million individuals. While its detrimental effects on multiple organ systems are well documented, the impact of obesity on immune responses remains incompletely understood. In this study, we address this knowledge gap by identifying obesity-driven B cell dysfunction that exacerbates autoimmunity in a diet-induced obesity mouse model.

Methods: We developed a diet-induced obesity model in C57BL/6 mice and monitored B cell development and differentiation under both steady-state conditions and following immune challenges, including LCMV and Plasmodium infections, NP-CGG immunizations, and topical imiquimod (a TLR7 ligand) application to induce a lupus-like autoimmune setting. We assessed:changes in B cell activation markers;alterations in cellular metabolism using state-of-the-art fluorescence lifetime imaging microscopy and extracellular flux assays;the frequency of self-reactive B cell clones using our novel nuclear antigen staining strategy coupled with flow cytometry; andtranscriptional changes via single-cell RNA sequencing.Additionally, we conducted a thorough clinical comparison between obese and lean mice in both TLR7-induced and genetic (NZM) lupus models.

Results: . IntInterestingly, obese mice developed spontaneous germinal centers (GCs), yet paradoxically exhibited reduced responsiveness to NP-CGG immunization and infection, indicating disrupted B cell development and differentiation. Using our novel nuclear antigen staining strategy, we found that these spontaneous GCs in obese animals were predominantly composed of nuclear antigen-specific clones, suggesting a heightened propensity for autoimmunity.Adoptive transfer experiments demonstrated that obesity-induced B cell dysregulation is cell-intrinsic, as the dysfunction persisted even after transferring B cells from obese donors into lean recipients. Further cellular and metabolic analyses revealed extensive remodeling in B cells from obese mice, including altered surface marker expression, a metabolic shift toward increased fatty acid utilization, and enhanced sensitivity to leptin receptor signaling. Single-cell RNA sequencing uncovered distinct transcriptional profiles in B cells from obese mice, both at baseline and following infection.In lupus-like autoimmune models, obese mice exhibited a more severe and rapidly progressing disease course, characterized by skewed antibody responses, an increased frequency of autoreactive B cell clones, and accelerated mortality.

Conclusion: Collectively, these findings provide novel mechanistic insights into how obesity alters humoral immune responses and establish a direct link between obesity and heightened autoimmune risk.

B cells in obese mice has higher tendency towards oxidative phosphorylation and lower tendency towards glycolysis as compared to their lean counterparts. a,b) Seahorse extracellular flux assay, c,d) Fluorescence life time imaging microscopy

B cells in obese mice have distinct transcriptional remodeling as compared to B cells in lean mice both at rest and upon infection.

Novel strategy to detect nuclear antigen specific (self reactive) B cell clones

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/obesity-exacerbates-autoimmunity-by-dysregulating-b-cell-behavior/