Gram-negative pathogens and molecular mimicry: is there a case for mistaken identity? Response (2000)

We would like to express our thanks for the thoughtful comments of Drs Inman and Albert. They have highlighted issues that we were unable to discuss in the brief format of our letter to Nature Medicine1.Lo W-F. et al.Molecular mimicry mediated by MHC class Ib molecules after infection with Gram-negative pathogens.Nat. Med. 2000; 6: 215-218Crossref PubMed Scopus (141) Google Scholar. However, it should be pointed out that we do not claim that our paper is a definitive study that ‘proves’ the concept of molecular mimicry, as Inman and Albert imply. Instead, our study is a natural and logical progression of our long-term research goals that focus on the function of cytotoxic T lymphocytes (CTLs) in the host response to Gram-negative bacteria2.Lo W-F. et al.T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules.J. Immunol. 1999; 162: 5398-5406Crossref PubMed Google Scholar. Inman and Albert correctly state that the primary sequence of a molecular mimic might appear unrelated to the natural T-cell-peptide epitope. We would add that the repertoire of molecular mimics can include a wide range of peptides, including those with clear sequence homology (e.g. mHsp60 residues 216–224), as well as those with no homology but which form a mimic when bound to a major histocompatibility (MHC) molecule. We do not agree that ‘… a basic assumption of the mimicry hypothesis is that if sequence homology exists... so too must functional homology’. For example, we have identified a homologous peptide in the mycobacterial GroEL molecule; however, this peptide is not recognized by our Salmonella-specific CTLs. Thus, sequence homology does not necessarily equal functionality. We have not been able to demonstrate Hsp-mediated CTL reactivity in uninfected mice2.Lo W-F. et al.T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules.J. Immunol. 1999; 162: 5398-5406Crossref PubMed Google Scholar. One possibility is that these CTLs do exist, but their function is regulated (anergy?), and these CTLs are driven to expand only after infection. Inman and Albert speculate that the reactivity of the clone SalTc1.69 towards lipopolysaccharide (LPS)- or interferon (IFN)-stimulated targets might be mediated by the Toll-like receptor (TLR). This would be a novel and unprecedented mechanism that cannot be unequivocally excluded; however, we have observed CTL reactivity towards uninfected, stressed Qa-1+, TLR2/42.Lo W-F. et al.T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules.J. Immunol. 1999; 162: 5398-5406Crossref PubMed Google Scholar L-cell fibroblasts and thus we think that this hypothesis is unlikely to explain our results. We agree with Inman and Albert that the human leukocyte antigen (HLA)-B locus polymorphism is associated with reactive arthritis (ReA). However, association of ReA/Reiters with HLA-B27 is not exclusive: 20–30% of patients express other HLA-B alleles. These data suggest that additional immunological complexities exist; for example, a panel of T-cell clones derived from synovial fluid of individuals with ReA identified bacterial-specific CD8+ T cells3.Hermann E. et al.HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis.Lancet. 1993; 342: 646-650Abstract PubMed Scopus (309) Google Scholar, 4.Hermann E. T cells in reactive arthritis.APMIS. 1993; 101: 177-186Crossref PubMed Scopus (29) Google Scholar, but only ∼1% of the clones were HLA-B27 restricted. This observation suggests that HLA-B27-restricted T cells are not the only disease-relevant population in the synovia. This group also identified a CD8+-T-cell clone from a Yersinia-induced ReA patient that recognized an epitope shared among several bacteria and was class I dependent, HLA-A/B/C independent5.Hermann E. et al.MHC-unrestricted recognition of bacteria-infected target cells by human CD8+ cytotoxic T lymphocytes.Cell. Immunol. 1992; 143: 253-260Crossref PubMed Scopus (18) Google Scholar. This reactivity is similar to the pattern we have observed in our murine system2.Lo W-F. et al.T cell responses to Gram-negative intracellular bacterial pathogens: a role for CD8+ T cells in immunity to Salmonella infection and the involvement of MHC class Ib molecules.J. Immunol. 1999; 162: 5398-5406Crossref PubMed Google Scholar. Also, we would argue that a role for the involvement of Hsp in ReA and autoimmunity should not be dismissed because: (1) in studies that examined bacterial-induced ReA, T cells that preferentially recognize bacterial Hsp60 have been identified6.Hermann E. et al.Proliferative response of synovial fluid and peripheral blood mononuclear cells to arthritogenic and non-arthritogenic microbial antigens and to the 65-kDa mycobacterial heat-shock protein.Med. Microbiol. Immunol. 1990; 179: 215-224Crossref PubMed Scopus (19) Google Scholar, 7.Probst P. et al.Multiclonal synovial T cell response to Yersinia enterocolitica in reactive arthritis: the Yersinia 61-kDa heat-shock protein is not the major target antigen.J. Infect. Dis. 1993; 167: 385-391Crossref PubMed Scopus (31) Google Scholar, 8.Mertz A.K. et al.Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heat-shock protein 60 drives a major immune response.Arthr. Rheum. 1998; 41: 315-326Crossref PubMed Scopus (46) Google Scholar; and (2) Yersinia-reactive CD4+ cells can recognize both human Hsp60 and stressed cells9.Hermann E. et al.Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells.Eur. J. Immunol. 1991; 21: 2139-2143Crossref PubMed Scopus (93) Google Scholar. We agree that current knowledge falls short of ‘proving mimicry as the primary inciting mechanism in autoimmune disease’. The possibility also exists that mimicry might not be an inciting event but contributes to sustaining the tissue injury. Recently, data supportive of a role for Hsp-reactive T cells in autoimmune pathology have been reported10.Steinhoff U. et al.Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells.Immunity. 1999; 11: 349-358Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar. These studies showed that adoptive transfer of a CD8+-T-cell clone that recognized an H-2b-restricted peptide from Mycobacterium GroEL and cross-recognized a peptide derived from its self-counterpart, mHsp60, homed to the gut and induced autoimmune pathology10.Steinhoff U. et al.Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells.Immunity. 1999; 11: 349-358Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar. Clearly, one must now determine if these T cells exist in the human setting and, if so, devise therapeutic strategies to modulate their function.