Antigen Mimicry in Autoimmune Disease Sharing of Amino Acid Residues Critical for Pathogenic T Cell Activation
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Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation. A M Luo, … , D Hunt, K S Tung J Clin Invest. 1993;92(5):2117-2123. https://doi.org/10.1172/JCI116812. Research Article A nonamer peptide from murine nicotinic acetylcholine receptor delta chain (ACR delta), which shared four amino acid residues with a nonamer peptide of murine ovarian zona pellucida glycoprotein ZP3, induced murine autoimmune oophoritis and IgG autoantibody to the zona pellucida. Crossreaction between the ACR delta and ZP3 peptides was established by the response of a ZP3 peptide-specific, oophoritogenic T cell clone to both peptides in association with IA (alpha k beta b). By substituting the ZP3 peptides with a single alanine, four amino acids within the ZP3 peptide were found to be important for ovarian autoimmune disease, autoantibody response, and stimulation of the ZP3-specific T cell clone. Substitution with conservative amino acids of three residues also ablated activity, whereas the fourth, a phenylalanine, was replaceable by tyrosine without loss of activity. Of the four critical amino acids, three were shared between the ZP3 peptide and the ACR delta peptide. Moreover, polyalanine peptides with the four critical ZP3 amino acids or the four amino acids common to the ZP3 and ACR delta peptides induced immune response to ZP3 and elicited severe ovarian autoimmune disease. Thus, organ-specific autoimmune disease can occur through immune response against unrelated self (or foreign) peptides that share with a self-peptide sufficient common amino acid residues critical for activation of pathogenic, autoreactive T cells. Find the latest version: https://jci.me/116812/pdf Antigen Mimicry in Autoimmune Disease Sharing of Amino Acid Residues Critical for Pathogenic T Cell Activation An-Ming Luo,* Kristine M. Garza,* Donald Hunt, and Kenneth S. K. Tung* Departments of *Pathology and tChemistry, University of Virginia, Charlottesville, Virginia 22908 Abstract with, and provoked antibody against, the myelin basic protein (3). Another was the induction of myasthenia gravis in rabbits A nonamer peptide from murine nicotinic acetylcholine recep- immunized with a chemical analogue ofacetylcholine, through tor a chain (ACR8), which shared four amino acid residues with induction of antiidiotype antibody that crossreacted with the a nonamer peptide of murine ovarian zona pellucida glycopro- nicotinic acetylcholine receptor (ACR)' (4). tein ZP3, induced murine autoimmune oophoritis and IgG au- Since activation of T cell response to self-peptides is a piv- toantibody to the zona pellucida. Crossreaction between the otal event in the pathogenesis of organ-specific autoimmune ACR5 and ZP3 peptides was established by the response of a diseases, crossreaction between foreign and self-peptides recog- ZP3 peptide-specific, oophoritogenic T cell clone to both pep- nized by T cells should, in principle, be more pertinent than tides in association with 1A(d'#). By substituting the ZP3 autoantibodies in antigen mimicry (5). We have therefore ex- peptides with a single alanine, four amino acids within the ZP3 plored this possibility based on a model of murine ovarian peptide were found to be important for ovarian autoimmune autoimmune disease (oophoritis) elicited by a well-character- disease, autoantibody response, and stimulation ofthe ZP3-spe- ized ovarian peptide (6). cific T cell clone. Substitution with conservative amino acids of ZP3 is a glycoprotein in the zona pellucida, its 0-linked three residues also ablated activity, whereas the fourth, a phe- oligosaccharide being the major sperm receptor in fertilization nylalanine, was replaceable by tyrosine without loss of activity. (7). Within the murine ZP3 sequence (8) is a 13-mer ZP3 Of the four critical amino acids, three were shared between the peptide (ZP3 330-342) that has two overlapping antigenic do- ZP3 peptide and the ACR5 peptide. Moreover, polyalanine mains: ZP3 336-342, a 7-mer linear sequence recognized by peptides with the four critical ZP3 amino acids or the four ZP3 antibody (9), and ZP3 330-337, the minimal octomer amino acids common to the ZP3 and ACR5 peptides induced sequence that induces oophoritis, pathology transferrable by immune response to ZP3 and elicited severe ovarian autoim- pathogenic CD4' T cells (6). Murine autoimmune oophoritis mune disease. Thus, organ-specific autoimmune disease can is a model of human premature ovarian failure in which oo- occur through immune response against unrelated self (or for- phoritis and autoantibodies to ovarian antigens have been doc- eign) peptides that share with a self-peptide sufficient common umented ( 10). In addition, premature ovarian failure often amino acid residues critical for activation of pathogenic, autore- coexists with autoimmune adrenalitis, autoimmune thyroid- active T cells. (J. Clin. Invest. 1993. 92:2117-2123.) Key itis, and myasthenia gravis ( 11). It is currently unclear as to words: autoimmune disease * premature ovarian failure * myas- why multiple autoimmune diseases should occur in the same thenia gravis * molecular mimicry. peptide vaccines individual. In this paper, we present evidence for antigen mim- icry between the murine ZP3 peptide and a peptide from the Introduction murine ACR5 chain (ACR6). Mice immunized with the non- amer ACR6 peptide developed oophoritis and autoantibodies Antigen mimicry has long been proposed as a potential mecha- to the zona pellucida. The evidence for, and the mechanism nism underlying organ-specific human autoimmune diseases underlying, the crossreaction between the ZP3 and the ACR5 ( 1). Idiopathic encephalitis, neuritis, and myelitis often occur peptides will be presented. after viral infection, and autoantibodies have been detected in these patients that react with neural antigens. Investigations in Methods the past have focused on foreign antigenic determinants recog- nized by autoantibodies (2). Although foreign antigens in- Induction ofmurine autoimmune oophoritis. Adult female (C57BL/6 duced antibody responses that crossreacted with self molecules, X A/J)F, (B6AF1 ) mice were purchased from The Jackson Laboratory autoimmune disease rarely developed in the immunized ani- (Bar Harbor, ME) or the National Cancer Institute (Frederick, MD). mals. There are some exceptions. For example, focal encephalo- Each peptide (at 50-,ug dose, dissolved in deionized/distilled water) myelitis was induced in rabbits immunized with a peptide from was emulsified in an equal volume of CFA containing 1 mg/ml of hepatitis B virus; the viral peptide shared common sequence Mycobacterium tuberculosis (H37Ra; Difco Laboratories, Detroit, MI) or in incomplete Freund's adjuvant (ICFA). Each mouse received 0.1 ml of the peptide and adjuvant emulsion, distributed in the two hind footpads. Histologic evidence of autoimmune oophoritis was de- Address correspondence to Dr. Kenneth S. K. Tung, Department of termined 14 d later. Pathology, University of Virginia, Box 214, Charlottesville, VA 22908. Histology and immunohistochemistry. The ovaries fixed in the Received for publication 29 March 1993 and in revised form 15 Bouin's fixative were embedded in paraffin. Approximately 50 serial June 1993. step sections per ovary, 5 ,lm thick, were stained with hematoxylin and J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 1. Abbreviations used in this paper: ACR, ACR6, and ACRy, acetyl- 0021-9738/93/11/2117/07 $2.00 choline receptor, 6 and y chains; EAE, experimental autoimmune en- Volume 92, November 1993, 2117-2123 cephalomyelitis. Molecular Mimicry and Autoimmune Diseases 2117 eosin. Histopathology of oophoritis was evaluated as coded specimens, adult B6AF, female mice. Ovarian pathology in cell recipients was with severity graded from 1 to 4: 1, focal inflammation in interstitial examined 10 d after cell transfer. space; 2 and 3, increasing multifocal inflammatory foci and/or granu- Cytokine assays. IL-2, IL-4, tumor necrosis factor, and interferon y loma between and within ovarian follicles; 4, loss of ovarian follicles were quantitated as described elsewhere ( 13). and ovarian atrophy (6). Statistical analysis. Significance in disease incidence differences For direct immunofluorescence study, frozen mouse ovaries were was determined by the chi-square analysis. embedded in OCT compound, and 5-,Mm-thick sections were cut in a cryostat. After the tissue sections were fixed in 90% ethanol for 15 min, they were rinsed in PBS and then incubated with fluorescein isothio- Results cyanate-conjugated goat antiserum IgG containing antibody to mouse Igs, IgG heavy chain or IgM heavy chain (Southern Biotechnology, Birmingham, AL) for 30 min. After the sections were rinsed in PBS, a A peptidefrom murineACR delta chain elicits murine autoim- coverslip was applied over glycerol containing 10% PBS; the images mune oophoritis. Among truncated ZP3 328-342 peptides, were examined and photographed with a fluorescence microscope ZP3 330-338 was the shortest oophoritogenic peptide found to (Olympus Corp. of America, New Hyde Park, NY). stimulate mitogenic response of an oophoritogenic T cell line Indirect immunoperoxidase technique was used to detect infiltrat- (6). A search in the protein sequence library revealed two mu- ing T cells in frozen ovarian sections with the hamster monoclonal rine ACR that share partial sequence homology with anti-mouse CD3 antibody ( 145-2C1 1), followed by biotinylated goat peptides antiserum IgG to hamster IgG (Vector Laboratories,