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Natural autoantibodies (natAAbs) react with evolutionarily conserved antigens but they do not lead to pathological tissue destruction, contrary to pathological autoantibodies (pathAAbs). NatAAbs usually belong to the IgM isotype, and their network, also known as the "immunological homunculus", is thought to play a role in immunological tolerance. NatAAbs are produced by B1 cells found mostly on the serosa surfaces or the spleen. The exact relation between natAAbs and pathAAbs is still not completely understood. The recombinant human proteoglycan (PG) aggrecan G1 domain (rhG1)-induced arthritis (GIA) is an excellent mouse model for rheumatoid arthritis because it represents most of the clinical, immunological and laboratory parameters of the corresponding human pathology. Recently, we studied the role of the spleen in GIA, and found that a splenectomy modified the development of autoimmunity. To further characterize the possible role of the nAAb levels in tolerance and autoimmunity, in the present study, we set out to measure the nat- and pathAAb levels in GIA. We analyzed the natAAb levels in the serum against cartilage PG aggrecan, Hsp60 and Hsp70, and the mitochondrial citrate synthase (CS) antigens in healthy control and arthritic mice. Furthermore, we studied whether the splenectomy influenced the production of nat- and pathAAbs in mice with GIA. Our results show that the natAAb levels against PG aggrecan, Hsp60, Hsp70 and CS showed age-related variations in healthy BALB/c mice. The induction of autoimmune arthritis did not change the levels of the measured natAAbs significantly. Splenectomy, on the other hand, clearly decreased the levels of all the measured natAAbs. Interestingly, the levels of the pathAAbs showed the opposite change: they were higher in the splenectomized group than in the control arthritic mice. Based on these results, we conclude that the spleen plays a role in setting the balance between nat- and pathAAbs in autoimmune arthritis. [ABSTRACT FROM AUTHOR]

Autoantibody production is a hallmark of systemic sclerosis (SSc) and the most extensively studied role of B cells in the pathogenesis of the disease. However, the potential involvement of innate immune molecules in B-cell dysfunction in SSc is less understood. B-cell activation is an early event in the pathogenesis of SSc and is influenced by complement receptors (CRs) and Toll-like receptors (TLRs), shaping antibody responses. CR2 and CR1 modulate B-cell activation, and the roles of CR3 and CR4 are associated with autoimmune conditions. We investigated the expression of CRs in B cells from patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and the effect of TLR CD180 ligation on their expression. We found no significant difference in the basal expression of CD21 and CD11c in B cells between dcSSc and healthy controls (HCs). However, reduced basal CD11b expression in B cells in dcSSc compared to HCs, accompanied by a decrease in CD35 and an increase in CD11c expression following CD180 ligation may promote plasma cell formation and autoantibody production. Additionally, we searched for correlations between dcSSc-associated anti-DNA topoisomerase I (Scl-70) autoantibody, anti-citrate synthase (CS) natural autoantibody and complement component 3 (C3) levels and found a negative correlation between C3 and anti-CS autoantibody in dcSSc but not in HCs, supporting the hypothesis that natural autoantibodies could activate the complement system contributing to tissue injury in SSc. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN-I) signaling has been shown to be upregulated in systemic sclerosis (SSc). Dysregulated B-cell functions, including antigen presentation, as well as antibody and cytokine production, all of which may be affected by IFN-I signaling, play an important role in the pathogenesis of the disease. We investigated the IFN-I signature in 71 patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and 33 healthy controls (HCs). Activation via Toll-like receptors (TLRs) can influence the IFN-I signaling cascade; thus, we analyzed the effects of the TLR homologue CD180 ligation on the IFN-I signature in B cells. CD180 stimulation augmented the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in dcSSc B cells (p = 0.0123). The expression of IFN-I receptor (IFNAR1) in non-switched memory B cells producing natural autoantibodies was elevated in dcSSc (p = 0.0109), which was enhanced following anti-CD180 antibody treatment (p = 0.0125). Autoantibodies to IFN-Is (IFN-alpha and omega) correlated (dcSSc p = 0.0003, HC p = 0.0192) and were present at similar levels in B cells from dcSSc and HC, suggesting their regulatory role as natural autoantibodies. It can be concluded that factors other than IFN-alpha may contribute to the elevated IFN-I signature of dcSSc B cells, and one possible candidate is B-cell activation via CD180. [ABSTRACT FROM AUTHOR]

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