The percentage of cell surface expression of activation markers under marker M2 is indicated in the histograms. spite of generating UL6 reactivity. Other lines of evidence also failed to support the molecular mimicry hypothesis, such as the failure to affect HSK severity upon tolerization of susceptible BALB/c and B-cell-deficient mice with IgG2ab or UL6 peptides. An additional study system revealed that HSK could be induced in mouse strains, such as the OT2 RAG1?/? mice (T cell receptor transgenic recognizing OVA323C339) that were unable to produce CD4+ T-cell responses to any detectable HSV antigens. AXIN1 Our results cast doubt on Furilazole the molecular mimicry hypothesis as an explanation for the pathogenesis of HSK and indicate that if autoimmunity is involved its likely proceeds via a bystander activation mechanism. That autoimmune diseases result from virus infection is an attractive hypothesis, but it has yet to be proven, at least for any human autoimmune syndrome (39). However, several animal models clearly link viruses and autoimmunity (11, 19, 25, 38, 40), although the mechanisms by which viruses trigger autoreactivity remain uncertain. The explanations for this include molecular mimicry and bystander activation (12, 39). The latter represents a complex which could include the release of normally sequestered antigens from damaged cells that now become immunogenic, alteration of host protein structure (27), and the subversion of host cells, causing proinflammatory mediator production or the Furilazole synthesis of abnormal products such as autoantibodies (39). The more simple and perhaps most appealing idea to explain the genesis of virus-induced autoimmunity is molecular mimicry (19). This suggests that causative viruses express epitopes that cross-react with a host protein and that the initial immune response to viruses carries over to include anti-host reactivity (40). Proving unequivocally the molecular mimicry hypothesis in any model has been difficult (39). One model advocated to support the molecular mimicry hypothesis is a blinding inflammatory reaction in the cornea set off by infection with herpes simplex Furilazole virus (HSV). This lesion, termed herpetic stromal keratitis (HSK), is orchestrated by CD4+ T cells that are suggested to recognize autoantigens in the cornea (31, 36). One such autoantigen Furilazole may be a 16 amino acid peptide shared by the immunoglobulin G2ab (IgG2ab) isotype (2). A peptide of almost identical amino acid sequence is found in the UL6 protein of HSV, and this has been advocated as the molecular mimic which elicits the HSK syndrome (41). Supporting the corneal autoantigen hypothesis is the observation that mice such as C57BL/6 (B6) and CB.17, which express the Ig2ab isotype and so are immunologically tolerant to the autoantigen, are highly resistant to HSK development (2, 21, 35). In addition, viral mutants that lack the mimicking peptide fail to induce HSK in susceptible mouse strains and lesions can be adoptively transferred to virus-infected nude mice with UL6 and IgG2a immune T cells (2, 41). Accordingly, the case for HSK representing an autoimmune reaction set off by a virus that acts as a molecular mimic appears persuasive. In the present report, we readdress the role of autoimmunity and molecular mimicry between IgG2a and UL6 peptides in HSK pathogenesis by using a mouse model involving different mice strains on the same genetic background as used in the previous reports and a strain of HSV type 1 (HSV-1) (strain RE) usually used for the induction of HSK lesions. Mice strains used in the study included susceptible BALB/c (B/c) mice, resistant B6 mice, and B6 -chain knockout (Bk/o) mice. The latter do not produce immunoglobulin (Ig) and therefore would lack tolerance to the corneal autoantigen shared with the IgG2ab isotype. Several observations failed to support the molecular mimicry hypothesis. First, analysis of in vivo delayed-type hypersensitivity (DTH) reactions and in vitro T-cell responses of draining lymph node and splenocytes revealed none of the expected cross-reactivities. Accordingly, mice ocularly infected with HSV failed to generate demonstrable in vivo and in vitro responses to either the UL6 or IgG2ab peptides. Second, although infection with recombinant vaccinia virus expressing the UL6 protein induced T cells that reacted with the UL6 peptide, neither cross-reactivity with the IgG2ab peptide nor cross-reactivity with HSV could be demonstrated. Moreover, mice immunized with either UL6 or IgG2ab peptides elicited T cells that reacted only with homologous peptides. Third, attempts to change the susceptibility of B/c or Bk/o mice by tolerizing them to the.