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.

Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damage-associated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necrotic osteocytes in vitro and in vivo. RNA sequencing and metabolic analyses demonstrated that Mincle activation triggers osteoclastogenesis via ITAM-based calcium signaling pathways, skewing osteoclast metabolism toward oxidative phosphorylation. Deletion of Mincle in vivo effectively blocked the activation of osteoclasts after induction of osteocyte death, improved fracture repair, and attenuated inflammation-mediated bone loss. Furthermore, in patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity. Taken together, these data point to what we believe is a novel DAMP-mediated process that allows osteoclast activation and bone loss in the context of osteocyte death.

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.

Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by autoimmunity that triggers joint inflammation and tissue destruction. Traditional concepts of RA pathogenesis have strongly been focused on inflammation. However, more recent evidence suggests that autoimmunity per se modulates the disease and in particular bone destruction during the course of RA. RA-associated bone loss is caused by increased osteoclast differentiation and activity leading to rapid bone resorption. Autoimmunity in RA is based on autoantibodies such as rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPA). These autoantibodies exert effector functions on immune cells and on bone resorbing osteoclasts, thereby facilitating bone loss. This review summarizes potential pathways involved in increased destruction of bone tissue in RA, particularly focusing on the direct and indirect actions of autoantibodies on osteoclast generation and function.