Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

Abstract

The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN76–100 (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG76–100 in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN76–100-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN1–39 that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.

Commentary: Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)‐specific autoantibody repertoire

“…This may explain the high frequency of antibody responses recognizing linear MOG peptides, but not the intact molecule, in patients with MS [23]. However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].…”

“…This may explain the high frequency of antibody responses recognizing linear MOG peptides, but not the intact molecule, in patients with MS [23]. However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].Genes within the MHC selectively censor the ability of H2-b mice to mount an antibody response to discontinuous (demyelinating) rat MOG Igd epitopes, whilst leaving the response to linear epitopes intact. This effect could involve protease activities encoded within the MHC, the selective deletion of MOG-reactive B cell clones mediated by structural homologues of MOG, or even strainspecific differences in the expression of MOG outside the CNS [46].…”

“…The solution of the crystal structures of MOG Igd [49,50] and its complex with the chimeric antigen-binding fragment (Fab) of the demyelinating MOG-specific monoclonal antibody 8-18C5 [47] has recently provided an insight into the structural constraints imposed on the demyelinating antibody response. The three-dimensional structure of MOG Igd allows us to identify those solventexposed amino acids that may provide targets for autoantibody-mediated demyelination [49,50].…”

“…However, the MOG-specific antibody response in patients with MS recognizes a far more complex repertoire of linear epitopes [33,47] than marmosets [36] or rodents [26-28, 46, 48] do. This peptide-specific response in man does not recognize the native protein [33] and is therefore unlikely to mediate demyelination in vivo, but further studies are required to determine whether or not these responses have any other pathological significance.…”

“…The sample size is too small to make any definitive conclusions but this observation does raise the possibility that antibodies bind to MOG epitopes that are generated during the MBP-induced inflammatory response. If this is the case, this antibody response (together with antibodies recognizing other exposed determinants) may influence lesional pathology by accelerating the clearance of myelin debris from the lesions by activated macrophages.However, the MOG-specific antibody response in patients with MS recognizes a far more complex repertoire of linear epitopes [33,47] than marmosets [36] or rodents [26-28, 46, 48] do. This peptide-specific response in man does not recognize the native protein [33] and is therefore unlikely to mediate demyelination in vivo, but further studies are required to determine whether or not these responses have any other pathological significance.…”