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 (T_FH) 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 T_FH 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