Abstract
B cells play a crucial role in the pathogenesis of rheumatoid arthritis. In Nkx2-3-deficient mice (Nkx2-3−/−) the spleen’s histological structure is fundamentally changed; therefore, B cell homeostasis is seriously disturbed. Based on this, we were curious, whether autoimmune arthritis could be induced in Nkx2-3−/− mice and how B cell activation and function were affected. We induced arthritis with immunization of recombinant human proteoglycan aggrecan G1 domain in Nkx2-3−/− and control BALB/c mice. We followed the clinical picture, characterized the radiological changes, the immune response, and intracellular Ca2+ signaling of B cells. Incidence of the autoimmune arthritis was lower, and the disease severity was milder in Nkx2-3−/− mice than in control BALB/c mice. The radiological changes were in line with the clinical picture. In Nkx2-3−/− mice, we measured decreased antigen-induced proliferation and cytokine production in spleen cell cultures; in the sera, we found less anti-CCP-IgG2a, IL-17 and IFNγ, but more IL-1β, IL-4 and IL-6. B cells isolated from the lymph nodes of Nkx2-3−/− mice showed decreased intracellular Ca2+ signaling compared to those isolated from BALB/c mice. Our findings show that the transcription factor Nkx2-3 might regulate the development of autoimmune arthritis most likely through modifying B cell activation.
Highlights
Rheumatoid arthritis (RA) is the most frequent systemic autoimmune disease in the Western-European and North-American countries [1]
Those models are beneficial, which share many features of RA, like proteoglycan-aggrecan-induced arthritis (PGIA) [4] and its refined version, recombinant human G1 domain-induced arthritis (GIA) [5]. (P)GIA is similar to RA in many respect: (i) clinical picture [4,5], (ii) histological changes [4,5], (iii) radiological changes [4,6], (iv) autoreactive T cell activation [7], (v) Th1 and Th17 differentiation [8], (vi) production of autoantibodies [5] and (vii) proinflammatory cytokines was described [5]
Recombinant human G1-induced arthritis is provoked by repeated intraperitoneal injections of the aggrecan G1 domain in the dimethyl-dioctadecyl-ammonium (DDA) adjuvant
Summary
Rheumatoid arthritis (RA) is the most frequent systemic autoimmune disease in the Western-European and North-American countries [1]. Finding the potential pathogenic factors and mechanisms in the background of RA is of utmost importance because they might provide a basis for future therapies In this regard, mouse models of RA are extremely useful because several aspects of the disease can be studied more efficiently than in humans [3]. The development of autoreactive T cells and starting of autoantibody production might be the key elements of this preclinical/latent phase of RA [10] and likewise, during the initiation period of its model PGIA [8] These processes most likely take place locally, in the joints, but, importantly, in the lymphatic tissues like the lymph nodes and the spleen [2,8]. These data indicate that Nkx mice are relatively resistant to GIA-induction which correlates with their impaired in vitro B cell responsiveness
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