CYTOKINE DYSREGULATION AND THE INITIATION OF SYSTEMIC AUTOIMMUNITY

Autoimmunity (Al) exemplifies the potent and destructive activity expr essed by the immune system when normal constraints against self-reacti vity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) fro m young AI-prone mice [1-3]. There are two points in particular that w e believe speak to the importance of this observation: (i) Cytokine dy sregulation is distinguished from many of the aberrancies reported in Al-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarka bly consistent characteristic of M phi from strains that develop manif estations of systemic Al, including MRL/+, NZB, NZB/W F1, BXSB, and NO D, and distinguishes these strains from mice whose disease is predicat ed on defects in apoptosis (e.g., the lpr and gld mutations). The mult igenic basis for disease and renal pathology in the former strains mor e closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key media tors of lymphocyte growth and function, a defect in the cytokine netwo rk has the potential to disrupt the normal regulation of self-reactivi ty, leading to the initiation of systemic AI.