Wenda Gao
Published: 2002-02-17
Total Pages: 206
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Polyclonal lymphocyte activation and hypergammaglobulinemia characterize the acute phase of Chagas' disease, a debilitating condition caused by Trypanosoma cruzi. Such pathogenic hyper-reactivities not only compromise specific host defense against the pathogen, but may also contribute to infection-induced chronic autoimmune responses. Characterizing parasite-derived factors driving non-specific immune responses will provide insights for parasite evasion of host specific immunity. This study shows that T. cruzi trans-sialidase (TS) is one such polyclonal activator for normal murine lymphoid and non-lymphoid cells in at least three aspects. First, TS induces aggregation of immune cells and secretion of cytokines, such as IL-6. Second, TS is a T-independent B cell mitogen, directly stimulating polyclonal B cell proliferation independent of IL-6, CD40, CD43, Toll-like receptor-4 (TLR-4), and mIg crosslinking. While TS is mitogenic to wild-type B cells, mostly CD5- B2 cells, it fails to induce any proliferation of B cells from Bruton's tyrosine kinase (Btk)-defective X-linked immune deficient (xid) mice, suggesting that Btk is involved in TS signaling. Furthermore, in vivo administration of TS is followed by polyclonal Ig secretion that peaks 4-6 days after injection, before detectable TS-specific antibodies. Third, although TS does not directly stimulate T cells, it potentiates antigen specific and nonspecific T cell responses through the activation of APC, such as macrophages and B cells. TS potentiation is observed in splenocytes deficient of CD28, ICAM-1, CD40L or CD43. However, optimal TS-potentiation requires IL-6 and Btk, as it is significantly reduced in splenocytes from IL-6 -/- and xid mice. The C-terminal tandem repeat domain (LTR), but not the N-terminal catalytic domain (CD) of TS, is the active moiety that mediates TS-induced cell aggregation, IL-6 secretion, B cell and macrophage activation. At non-mitogenic concentrations, however, LTR inhibits mouse T cell activation and blocks TS-potentiated T cell response. A working model for the actions of TS, its domains and TS receptor is proposed. The results indicate that TS is a parasite-derived factor that directly and indirectly activates both APC and T cells, disturbing host lymphocyte homeostasis and cytokine regulation. Thus, TS may drive polyclonal lymphocyte activation in acute infection, potentially contributing to the immune evasion of the parasite, as well as the autoimmune abnormality in chronic Chagas' disease.