Abstract
NZB/W mice develop a disease similar to human systemic lupus erythematosus (SLE), including autoantibody production, hyper-gammaglobulinaemia and inflammation of the kidneys. It is known that large numbers of lymphocytes infiltrate the kidneys of these mice but the role of this organ for the production of antibodies is not clear. Here, we compare the role of bone marrow, spleen and inflamed kidneys of NZB/W mice for the activation of B cells and for the persistence of antibody secreting cells (ASC). ASC are present in the kidneys of mice with full blown disease, as many as in the spleen and bone marrow, and 50 times more than in the kidneys of normal mice. In the kidneys, ASC are located mainly in the outer medulla, close to B- and T cell infiltrates. The specificity of the ASC in the inflamed kidneys is not restricted to self-antigens. After immunization of NZB/W mice with Ovalbumin (OVA), the antigen-specific ASC are found initially exclusively in the spleen. Weeks later, during a period of at least 3 months, OVA-specific ASC are found in stable and high numbers within the bone marrow and the kidneys of these mice, but no longer in the spleen. As determined by FACS, B cells with a germinal center phenotype (B220+/PNA+) are found only in very low numbers in the kidneys, but in high numbers in the spleen of NZB/W mice. By histology, germinal centers could not be detected in the kidneys, but in the spleen. The lack of B cell activation and the kinetics of the appearance of OVA-specific ASC suggest that in autoimmune NZB/W mice kidneys, plasma cells generated during an immune reaction in secondary lymphoid organs, later accumulate and persist, like in bone marrow. These experiments identify the inflamed kidneys of NZB/W mice as site of prime relevance for the homeostasis of plasma cells, irrespective of their specificity, suggesting that chronically inflamed tissue attracts plasma cells as such and extends the overall capacity of the body for plasma cells, allowing autoreactive plasma cells to survive for long times within the inflamed tissue and to provide exorbitant titers of antibodies locally.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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