title: Cytokine dysregulation and the initiation of systemic autoimmunity.
abstract: Autoimmunity (AI) exemplifies the potent and destructive activity expressed by the immune system when normal constraints against self-reactivity are lost or compromised. We have previously described a dramatic and intrinsic defect in cytokine expression in macrophages (M phi) from young AI-prone mice [1-3]. There are two points in particular that we believe speak to the importance of this observation: (i) Cytokine dysregulation is distinguished from many of the aberrancies reported in AI-prone mouse strains in that, as an inherent trait, it cannot arise as a consequence of the disease process. (ii) This defect is a remarkably consistent characteristic of M phi from strains that develop manifestations of systemic AI, including MRL/+, NZB, NZB/W F1, BXSB, and NOD, and distinguishes these strains from mice whose disease is predicated on defects in apoptosis (e.g., the lpr and gld mutations). The multigenic basis for disease and renal pathology in the former strains more closely mirror human lupus than do the disease manifestations of lpr and gld mice. In light of clear evidence that cytokines are key mediators of lymphocyte growth and function, a defect in the cytokine network has the potential to disrupt the normal regulation of self-reactivity, leading to the initiation of systemic AI.
authors.affiliation: Immunology Research Unit, Boston University Medical Center, MA 02118.
authors.forename: D
authors.initials: D
authors.lastname: Hartwell
authors.forename: J
authors.initials: J
authors.lastname: Levine
authors.forename: M
authors.initials: M
authors.lastname: Fenton
authors.forename: C
authors.initials: C
authors.lastname: Francis
authors.forename: C
authors.initials: C
authors.lastname: Leslie
authors.forename: D
authors.initials: D
authors.lastname: Beller
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger