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 distinct immunopathological consequences, it becomes important to understand the respective roles of TH subsets in the pathogenesis of SLE. Our analysis on 4 different substrains of autoimmune-prone MRL mice revealed that the progression of SLE in these mice is correlated with an enhanced expression of interferon-gamma (a TH1 type cytokine regulating the production of IgG2a and IgG3) vs interleukin-4 (IL-4; a TH2 type cytokine regulating the production of IgG1), in parallel with an increased production of IgG2a and IgG3 autoantibodies over IgG1. In addition, studies on lupus-prone mice expressing an IL-4 transgene have shown that the constitutive expression of IL-4, biasing autoimmune responses towards a TH2 phenotype, inhibits the development of lupus nephritis. These results suggest that the development and progression of murine lupus is determined by the type of TH responses (either acceleration by TH1 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 "wire-loop" lupus-like glomerular lesions, because of their cryoglobulin activity associated with a unique physicochemical property of IgG3 constant region. Our results underline the importance in the pathogenesis of SLE of the qualitative aspects of autoantibody responses controlled by subpopulations of TH cells.