title: Heterologous protein incites abnormal plasma cell accumulation and autoimmunity in MRL-MpJ mice.
abstract: Although it is evident that there is complex interplay among genetic and environmental factors contributing to systemic autoimmunity, the events inciting autoreactivity are incompletely understood. Previously we demonstrated that MRL-MpJ mice posses a genetic background susceptible to autoimmunity development under conditions of altered inhibitory signaling. To gain better understanding of the influence of exogenous factors on autoreactivity in susceptible individuals, young MRL-MpJ mice were challenged with a single injection of heterologous protein and evaluated for evidence of autoimmunity. We found that MRL-MpJ mice developed high titer serum reactivity to DNA within 1 week of protein administration reaching maximal levels within 1 month. Importantly, the level of autoimmunity was sustained for an extended period of time (6 months). This was accompanied by a substantial increase in germinal center B cell and plasma cell numbers. In contrast, control mice showed no change in autoreactivity or lymphocyte homeostasis. Autoimmunity was dependent on marginal zone B cells as their depletion reduced serum auto-reactivity after challenge, thus suggesting immune stimulation with heterologous proteins can precipitate loss of B cell tolerance and autoimmunity in genetically prone individuals. This model may provide an important tool to further investigate the mechanisms whereby environmental stimuli trigger autoimmune reactivity in susceptible hosts.
authors.affiliation: Department of Medicine, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912, USA. tmcgaha@georgiahealth.edu
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Ma
authors.forename: Buvana
authors.initials: B
authors.lastname: Ravishankar
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gabunia
authors.forename: Malgorzata
authors.initials: M
authors.lastname: McMenamin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood* / Q000276:immunology; D015551:Autoimmunity; D004247:DNA / Q000276:immunology; D005260:Female; D018858:Germinal Center / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010950:Plasma Cells / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D004247:DNA