T-HELPER CELL SUBSETS IN THE PATHOGENESIS OF SYSTEMIC LUPUS-ERYTHEMATOSUS

It has been established that CD4(+) T cells play an essential role in the development of systemic lupus erythematosus (SLE). Since CD4(+) T cells differentiate upon activation into two defined subsets, TH1 and TH2, differing in their capacities of cytokine production with distinc t immunopathological consequences, it becomes important to understand the respective roles of TH subsets in the pathogenesis of SLE. Our ana lysis on 4 different substrains of autoimmune-prone MRL mice revealed that the progression of SLE in these mice is correlated with an enhanc ed expression of interferon-gamma (a TH1 type cytokine regulating the production of IgG2a and IgG3) vs interleukin-4 (IL-4; a TH2 type cytok ine regulating the production of IgG1), in parallel with an increased production of IgG2a and IgG3 autoantibodies over IgG1. In addition, st udies on lupus-prone mice expressing an IL-4 transgene have shown that the constitutive expression of IL-4, biasing autoimmune responses tow ards a TH2 phenotype, inhibits the development of lupus nephritis. The se results suggest that the development and progression of murine lupu s is determined by the type of TH responses (either acceleration by TH 1 responses or protection by TH2 responses) inducing the generation of more or less pathogenic autoantibodies. In fact, murine IgG3 has been shown to be extremely nephritogenic, generating <<mire-loop>> lupus-l ike glomerular lesions, because of their cryoglobulin activity associa ted with a unique physicochemical property of IgG3 constant region. Ou r results underline the importance in the pathogenesis of SLE of the q ualitative aspects of autoantibody responses controlled by subpopulati ons of TH cells.