EXACERBATION OF COLLAGEN-INDUCED ARTHRITIS IN RATS BY RAT CYTOMEGALOVIRUS IS ANTIGEN-SPECIFIC

Collagen-Induced Arthritis (CIA) is an experimentally induced and gene tically controlled animal model of chronic joint inflammation. In rats , there are informative strain differences in susceptibility to CIA. D A rats (RT1(avl)) develop severe CIA after immunization with bovine (B II), chick (CII), or homologous rat (RII) type II collagens. In contra st, the MHC-congenic DA.1N(BN) and WF.1N(BN) rats (RT1(n)) are relativ ely resistant to CIA and develop moderate CIA in response to immunizat ion with CII but not BII or RII. We previously found that simultaneous infection with rat cytomegalovirus (RCMV) greatly exacerbates the sev erity of arthritis that develops in BII-immunized DA rats. To examine the mechanism of RCMV amplification of CIA, the effect of simultaneous infection with RCMV on arthritis and autoimmunity to type II collagen was determined in WF.1N and DA.1N rats after immunization with BII, C II and RII. RCMV increased the incidence of CIA and the level of autoi mmunity to type II collagen (skin-testing and IgG antibody titer) sele ctively in DA.1N and WF.1N rats immunized with CII, but not in litterm ates immunized with BII, although the transient reversal of CD4(+)/CD8 (+) mononuclear cell ratios in peripheral blood that is associated wit h RCMV infection occurred equally in both BII- and CII-immunized DA.1N rats. Likewise, RCMV infection moderately increased the levels of ant i-RII autoimmunity and arthritis in DA rats sub-optimally immunized wi th RII but had no consistent effect on either anti-RII immunity or art hritis in RII-immunized DA.1N and WF.1n rats. The data show that RCMV augments arthritis only in rats that are genetically susceptible to CI A and that are appropriately immunized with a species of type II colla gen that is arthritogenic for the MHC-haplotype being tested. Two poss ible mechanisms ace suggested by these data: RCMV-associated increases in anti-RII autoimmunity in rats with CIA may result from amino acid sequence homologies between RCMV and type II collagen; alternatively, virus-induced pro-inflammatory cytokines may activate RII-reactive lym phocytes thereby potentiating autoimmunity and arthritis.