The time course and characterization of mercuric chloride-induced immunopathology in the brown Norway rat.

Abstract

Mercuric chloride (HgCl2) induces an autoimmune syndrome in the Brown Norway (BN) rat which includes widespread tissue injury. There is necrotizing leucocytoclastic vasculitis in the gut with maximal injury occurring 2 weeks after the start of HgCl2 injections. There is evidence that disease is driven by Th2-like cell (CD4+CD45RClow) activity and that Th1-like cells (CD4+CD45RChigh) may be protective. Using the established protocol of five injections of HgCl2 over 10 days, we have studied in greater detail the presence and extent of vasculitis and changes in T cell subsets from 12 h to 20 days after the first injection. Animals were killed at various time points and necropsies performed. Tissue injury was scored both macroscopically and histologically, with immunohistochemistry for T cell subsets. Flow cytometry was used to determine T cell subsets in peripheral blood, mesenteric lymph node (LN) and spleen. Tissue injury was seen as early as 24 h after the first injection of HgCl2. The size of lesions and extent of vasculitis increased over the next two weeks with partial resolution at day 20. We confirmed that of peripheral blood T cells in the BN rat, less than 20% were CD8+ and a similar proportion were CD4+CD45RChigh, but found that less than 75% of CD8+ T cells were CD45RChigh (in other strains of rat more than 90% CD8+ T cells are CD45RChigh). Within 48 h, HgCl2 caused a rise in the proportion of CD4+ T cells in spleen, LN and peripheral blood which then fell towards normal at peak tissue injury. The proportion of CD4+CD45RClow T cells rose in the first week, but subsequently fell, with reciprocal changes in CD4+CD45RChigh T cells. There was an increase in CD8+ T cells towards peak disease. The speed of onset of tissue injury suggests that cells other than T cells may be involved in the primary induction of vasculitis, although Th2-like cells may be important in further tissue injury and in B cell activation. The rise in CD8+ and Th1-like cells towards peak disease supports the hypothesis that they are involved in disease regulation.