| Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease. Imbalance between T and B lymphocyte plays an important role in the development and pathogenesis of RA. The critical role of B cell in RA pathogenesis has been reassessed recently. It is now established that B cell has many more functions in RA than just producing autoantibodies, such as rheumatoid factor (RF), anti-cyclic citrullinated proteins (CCP) and so on, B cell is also the potent antigen-presenting cell (APC) and plays a critical role in the activation of T cell in the synovium of RA. Furthermore, B cell does not only respond to but also produce proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interlukin (IL). B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) play the vital role in the maturation, proliferation and survival of B cell. Mounting evidences in human and animal models support a tight relation between BLyS/APRIL and the development of autoimmune disease.TACI-Ig contains the BLyS/APRIL-binding extracellular portion of the TACI (transmembrane activator or calcium-modulating cyclophylin ligand-interactor) molecule fused to the Fc portion of human immunoglobulin (Ig) G1 and can be used to neutralize BLyS and APRIL and prevent them from binding to their receptors. TACI-Ig not only suppresses B cells development and differentiation, decreases the amount of maturation B cells, but also inbihits the activation of some T cells. Administration of TACI-Ig significantly ameliorates the disease symptoms in collagen-induced arthritis (CIA) mice and systemic lupus erythematosus (SLE) - prone NZB/NZW F1 mice. Some clinical trials of TACI-Ig (atacicept) in RA and SLE therapy are undergoing. But there is no study about effects of TACI-Ig on rat adjuvant arthritis (AA) reported thus far, which a model involves primarily T cells autoimmune reaction to joints. This study based on rat AA, to examine how TACI-Ig plays a therapeutic role by affecting the T helper lymphocyte (Th) related proinflammatory cytokines and Igs levels.ObjectiveIn this study, we examined the effects of TACI-Ig on arthritis assessment, histopathological manifestion and spleen index; we also explored the effects of TACI-Ig on BLyS, Th17 related cytokine IL-17, Th1 related cytokine IFN-γ, and IgG1, IgG2a, IgM levels; we examined the correlations between the arthritis assessment and the spleen BLyS, IL-17, IFN-γ, IgG1, IgG2a, IgM levels.MethodsThe model of rat AA was induced by a single intradermal injection of 0.1ml of CFA (complete Freund's adjuvant) into the right hind metatarsal footpad of rat. Animals were divided into seven groups randomly, including TACI-Ig groups (0.7, 2.1 and 6.3 mg/kg), rhTNFR:Fc group (2.8 mg/kg), IgG-Fc group (6.3 mg/kg), normal group and model group. Drugs were administered subcutaneously every other day to AA rats. Rats were inspected daily for signs of arthritis by arthritis global assessment and swollen joint count. We used hematoxylin and eosin (HE) stain method for histopathological evaluation. BLyS, IL-17, IFN-γ, IgG1, IgG2a and IgM levels in rat's spleen were detected by ELISA. We used the Spearman correlation coefficients to examine the correlations between the arthritis assessment and the spleen BLyS, IL-17, IFN-γ, IgG1, IgG2a and IgM levels.Results1 TACI-Ig ameliorated the AA rat's arthritis symptom, decreased spleen index and alleviated histopathological manifestationsThe secondary inflammatory reaction occurred about on day15. Arthritis global assessment and swollen joint count of AA rat increased significantly. Immune response resulted in increased cellularity and size in the follicles, periarterial lymphatic sheath (PALS) and marginal zone (MZ), and appearance of prominent germinal center (GC) in white pulp. Synoviocytes proliferated over three to eight layers with pannus formation, and infiltrated with inflammatory cells. TACI-Ig decreased arthritis global assessment and swollen joint count, decreased spleen index, alleviated histopathological manifestations.2 TACI-Ig decreased the levels of BLyS, IL-17, IFN-γand Igs in spleen of AA ratBLyS, IL-17, IFN-γ, IgG1, IgG2a and IgM levels in AA rat's spleen were significantly higher when compared to the normal rat. TACI-Ig decreased the above cytokines and Igs levels. Conclusion1 TACI-Ig decreased arthritis global assessment and swollen joint count, decreased spleen index, alleviated histopathological manifestations.2 TACI-Ig decreased BLyS, IL-17, IFN-γ, IgG1, IgG2a and IgM levels in AA rat's spleen.3 The results showed that the arthritis global assessment significantly correlated with the BLyS, IL-17, IFN-γ, IgG2a levels. TACI-Ig attenuated the progression of rat AA by reducing Th related proinflammatory cytokines and Igs levels in spleen of AA rat, which played the important role in the pathogenesis of RA. |
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