Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.

Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA (“seropositive”) in general display a different etiology and disease course compared to so-called “seronegative” patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.

Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut–joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis. Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites. RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days. Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation. We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention. Furthermore, patient-related outcomes of RA improved. Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies.

Objective: To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA).Methods: We conducted a prospective cohort study of psoriasis patients without clinical evidence of musculoskeletal involvement who underwent baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intraarticular sites by high‐resolution peripheral quantitative computed tomography. Adjusted relative risks of developing PsA associated with baseline vBMD and the presence of structural entheseal lesions were calculated using multivariable Cox regression models.Results: The cohort included 114 psoriasis patients (72 men and 42 women) with a mean ± SD follow‐up duration of 28.2 ± 17.7 months, during which 24 patients developed PsA (9.7 per 100 patient‐years [95% confidence interval (95% CI) 6.2–14.5]). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4 per 100 patient‐years [95% CI 12.5–34.3]; hazard ratio [HR] 5.10 [95% CI 1.53–16.99], P = 0.008). With respect to vBMD, a 1‐SD increase in entheseal, but not intraarticular, vBMD was associated with an ~30% reduced risk of progression to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per 1 SD [95% CI 0.14–0.71]), and the association remained robust after multiple imputation of missing data (HR 0.64 [95% CI 0.42–0.98]).Conclusion: The presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.

Alcohol consumption is a 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. Here we show that alcohol and its metabolite acetate alter 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 have reduced Bcl6 and PD-1 expression as well as IL-21 production by T_FHcells, preventing proper spatial organization of T_FHcells to form T_FH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.

Objective: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS–CoV‐2 in patients with B cell depletion and controls who are B cell–competent.Methods: Antibody responses (tested using enzyme‐linked immunosorbent assay) and T cell responses (tested using interferon‐γ enzyme‐linked immunospot assay) against the SARS–CoV‐2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls.Results: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS–CoV‐2 spike S1 were found after both infection and vaccination. A SARS–CoV‐2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS–CoV‐2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls.Conclusion: These data show that B cell depletion completely blocks humoral but not T cell SARS–CoV‐2 vaccination response. Furthermore, limited humoral immune responses are found after SARS–CoV‐2 infection in patients with B cell depletion.