The genotype determines the B cell response in mercury-treated mice

Abstract

Background: Mercury causes in mouse strains of the H-2s haplotype an autoimmune syndrome with antibodies to the nucleolar protein fibrillarin and systemic immune complex (IC) deposits. Other strains, like BALB/C (H-2d), develop only IC deposits, and most strains are resistant. However, mercury activates the murine immune system and causes lymphoproliferation in most strains: H-2s strains are high-responders also in this respect, while the relation between lymphoproliferation and autoimmune manifestations is unclear for other strains. We examined the B cell response to mercury in order to better understand the relation between lymphoproliferation and systemic autoimmunity, using the high-responder H-2s strains (A.SW and SJL), the intermediate responder strain BALB/C (H-2d), and the A. TL (H-2tl) and DBA/2 (H-2d) strains which are resistant to systemic autoimmunity.

Methods: During 4-7 weeks of subcutaneous mercuric chloride injections, the number of B cells and the expression of cell surface activation and proliferation markers was monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig isotype levels as well anti-ssDNA and anti-DNP antibodies were determined by ELISA. Serum ANA were monitored weekly by indirect immunofluorescence technique.

Results: Mercury-treated A.SW and SJL mice (H-2s) developed an increased expression of the proliferation marker CD71 on B cells, an increased number of B cells in the spleen, and an early, strong, but transient increase in serum Ig concentrations of Th1- as well as Th2-regulated Ig isotypes. Mercury-treated H-2s mice rapidly developed a polyclonal B cell response including the IgM isotype, but also antinucleolar antibodies (ANoA) of the IgG isotype with a clumpy pattern, characteristic for antifibrillarin antibodies. The IgG ANoA response was of a long duration and high titer. The A.TL strain (H-2tl) showed only a slight, restricted B cell activation. The BALB/C strain developed a slight, transient B cell activation dominated by IgG1 and IgE, and antinuclear antibodies (ANA). The DBA/2 strain showed only a minimal B cell response without ANA.

Conclusion: Mercury induces an early, transient, polyclonal B cell activation linked to the H-2A or H-2K locus in H-2s strains on the A background. This polyclonal response differs from the long-lasting, high-titered IgG autoantibody response to a nucleolar antigen with characteristics of fibrillarin in H-2s strains, which indicates that these responses arise from separate mechanisms. Another group of strains, exemplified by BALB/C (H-2d), responds to mercury with a slight, transient, Th2-dominated B cell response, a restricted antibody specificity targeting the cell nucleus, and systemic IC deposits. Another H-2d strain, DBA, is essentially resistant to mercury, illustrating the importance of non-H-2 genes for regulating the response to mercury.