Background/Purpose: Production of antinuclear autoantibodies (ANAs) is one of the major characteristics of the systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), but the mechanisms of their production are not known. Past studies showed athymic nude BALB/c mice developed spontaneous ANAs and lupus-like autoimmunity, and lymphopenic transfer model mice, in which CD4⁺CD25^– cells were transferred into nude mice, produced various autoantibodies including ANAs and anti-parietal cells antibodies, and organ specific autoimmune diseases. Here, using these mouse models, we investigated the mechanisms of the ANA production, in terms of the differentiation of transferred T cells into follicular helper T (T_FH) cells via lymphopenia-induced homeostatic proliferation (LIP). Moreover, by depleting intestinal microbiota by antibiotics administration, we elucidated the role of intestinal microbiota in this system.

Methods: CD4⁺T cell subsets from wild-type BALB/c mice were adoptively injected into athymic BALB/c nude mice, with or without depleting recipient mice of their intestinal microbiota by orally administering broad-spectrum antibiotics in drinking water. Immunoprecipitation, immunofluorescent staining, and ELISA were performed to detect ANAs. Flowcytometry and immunostaining were performed to detect germinal center formation, and differentiation of transferred T cells. 

Results: This lymphopenic mouse transfer model induced high titer IgG-type ANA production early and at high rates. Clinically important autoantibodies in SLE, such as anti- double strand-DNA, Sm, U1-RNP antibodies, were also detected by ELISA. Class switching and ANA production were enhanced when regulatory T cells-depleted CD4⁺ T cells were transferred into. We identified IL-21-producing PD-1⁺ T_FHcells which develop from conventional T cells during LIP and drive germinal center reactions with aberrant B cell responses. Depletion of intestinal microbiota resulted in significant reduction of both spontaneously occurring ANAs in nude mice and enhanced ANAs in lymphopenic transfer model. LIP and differentiation into TFH cells of transferred conventional T cells were also substantially impaired by microbiota depletion.

Conclusion: This study reveals that ANA production by nude mice is enhanced by LIP-T_FH cells. The novel insight that intestinal microbiota plays a critical role in both spontaneous and induced ANA production, would help to understand the immunopathogenesis of systemic autoimmune diseases. Moreover, the further investigation into the crosstalk between intestinal microbiota and the innate and adaptive immune systems may lead to a new therapeutic approach to systemic autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intestinal-microbiota-plays-a-critical-role-in-the-production-of-antinuclear-antibodies-in-lymphopenia-induced-autoimmunity/