Background: Alcohol consumption has emerged as consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown.
Objectives: To understand the anti-arthritogenic effect of alcohol
Methods: The immune-regulatory properties of alcohol consumption in vivo were tested in the collagen-induced arthritis (CIA) and serum-induced arthritis (SIA) model as well as after immunization with T cell- dependent (NP-CGG) and independent (TNP-FICOLL) antigens. Additional experiments in vivo experiments in these models were done with acetate- the metabolite of ethanol. The models were analysed for T- cell lineage and plasma cell differentiation, germinal centre formation and IgG levels and sialylation. Molecular expression of T follicular helper cell (TFH) activation such as IL-21, Bcl-6 and PD-1, as well as TFH: B cell conjugates were also assessed. Furthermore, TFH cells were generated in vitro, exposed to ethanol or acetate and tested for IL-21 production, PD1 expression and conjugate formation with B cells.
Results: Ethanol exposure significantly inhibited arthritis in the active adaptive immunity-driven model of arthritis (CIA) but not in the passive innate immunity-driven model (STA) suggesting that the immune suppressive effect of alcohol is based on interference of T- and B- cell activation. In line ethanol and even more its metabolite acetate, suppressed T cell dependent antibody formation after NP-CGG immunization, while T cell independent antibody formation after TNP-FICOLL immunization was not suppressed. Ethanol, as well as its metabolite acetate, specifically altered the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice showed reduced Bcl6 and PD-1 expression as well as interleukin (IL)-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH: B cell conjugates in the germinal centre. This effect of alcohol on TFH cells was associated with impaired autoantibody formation, higher sialylation of autoantibodies and less arthritis. In accordance, overexpression of IL-21 in vivo completely reversed the immune regulatory effects of alcohol.
Conclusion: In summary, these data provide a new mechanistic explanation for the immune regulatory and tolerance-inducing effect of alcohol consumption in arthritis.
Acknowledgments: Funden by DFG-FOR2886, DFG–CRC1181, Staedtler foundation, Johannes und Frieda Marohn-Stiftung, Else Kröner-Fresenius foundation, Interdisciplinary Centre for Clinical Research, Erlangen, BMBF-MASCARA, IMI funded project RTCure.
Disclosure of Interests: Vugar Azizov: None declared, Maria V Sokolova: None declared, Kerstin Sarter: None declared, Vladimir Temchura: None declared, Ulrike Steffen (née Harre): None declared, Martin Herrmann: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Mario Zaiss: None declared
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