B-cell activation following murine cytomegalovirus infection: implications for autoimmunity.

Infection of susceptible mice with murine cytomegalovirus (MCMV) induces persistent inflammation, and the production of autoantibodies reactive with large numbers of proteins from all major organs. However the roles of polyclonal B-cell activation, autoreactive T-helper cells and host-virus cross-reactions in these phenomena have not been evaluated. The present study reveals six- to 20-fold increases in serum immunoglobulin levels in MCMV-infected BALB/c and CBA mice, with IgG3 and IgG2b most affected. Titres of antibodies reactive with autologous tissues and ovalbumin (OVA) also increased following MCMV infection, whilst responses to a synthetic antigen [polyvinyl pyrrolidone (PVP)] were unaffected or depressed. IgG2a was the isotype most affected in responses to OVA, MCMV antigens and autologous tissues, suggesting interferon-gamma (IFN-gamma) may contribute to responses induced in the presence of the relevant antigen. Increases in total and antigen-specific immunoglobulin levels were CD4 dependent, as they were reduced in infected mice depleted of these cells with anti-CD4 antibodies. Serological changes were preceded by B-cell expansion and activation evident from increased cell yields, frequencies of cells releasing immunoglobulin and proliferation of T-depleted spleen and lymph node preparations. Numbers of mature B cells and macrophages increased in the lymph nodes, but B-1a (CD5+ Ig+) cell counts remained low. Alterations in the B-cell phenotypic profiles were more complex in the spleen, but correction for increased cell yields revealed increases in some subpopulations.