The Journal of Immunology, Vol 146, Issue 11 3757-3762, Copyright © 1991 by American Association of Immunologists

ARTICLES

Recognition of peptides that are immunopathogenic but cryptic. Mechanisms that allow lymphocytes sensitized against cryptic peptides to initiate pathogenic autoimmune processes

WJ Lipham, TM Redmond, H Takahashi, JA Berzofsky, B Wiggert, GJ Chader and I Gery
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.

Interphotoreceptor retinoid binding protein (IRBP) is a glycoprotein that localizes in the retina and induces inflammatory changes in this tissue in immunized animals. Certain IRBP-derived peptide determinants are also immunopathogenic, and we have previously shown that these determinants could be either immunodominant or cryptic. Lymphocytes sensitized against the cryptic peptides do not recognize whole IRBP in vitro, and yet these lymphocytes must recognize the protein in vivo to initiate the autoimmune pathogenic process. We have examined here two hypothetical explanations for this dissociation: 1) It is possible that when IRBP is processed in vitro, immunodominant peptide determinants compete with the cryptic ones and inhibit their interaction with the MHC molecules on the APC. This explanation was ruled out here by the finding that the immunodominant peptide 1179-1191 ("W10") did not inhibit the response to a cryptic one, 1158-1180 ("R4"), when added at equivalent and even moderately higher concentrations. 2) The second hypothesis proposes that the cryptic antigenic sites are not generated from IRBP by the APC in vitro, whereas enzymes in the retina digest the protein to yield fragments that generate these antigenic sites upon processing by the APC. In line with this hypothesis, we have found that cleavage of IRBP by certain endoproteinases (Asp-N, Glu-C, or V-8) produced molecules that were recognized in culture by lymphocytes sensitized to the immunopathogenic but cryptic peptide R4. This study, therefore, describes a putative Ag processing mechanism that results in IRBP recognition and, consequently, the initiation of an autoimmune process by lymphocytes sensitized against a cryptic peptide. Furthermore, experiments with R4 and other cryptic peptides have shown that cleavage fragments of up to 38 residues in length can be presented by APC, to stimulate lymphocytes sensitized against these peptides. No responses were stimulated, however, by fragments of 75 or more residues. The data thus provide new insights into the processing and presentation of cryptic peptide determinants by APC.

This article has been cited by other articles:

				A. Bharat, R. C. Fields, E. P. Trulock, G. A. Patterson, and T. Mohanakumar Induction of IL-10 Suppressors in Lung Transplant Patients by CD4+25+ Regulatory T Cells through CTLA-4 Signaling J. Immunol., October 15, 2006; 177(8): 5631 - 5638. [Abstract] [Full Text] [PDF]

				H. Zhu, K. Liu, J. Cerny, T. Imoto, and K. D. Moudgil Insertion of the Dibasic Motif in the Flanking Region of a Cryptic Self-Determinant Leads to Activation of the Epitope-Specific T Cells J. Immunol., August 15, 2005; 175(4): 2252 - 2260. [Abstract] [Full Text] [PDF]

				P. Sinha, H. H. Chi, H. R. Kim, B. E. Clausen, B. Pederson, E. E. Sercarz, I. Forster, and K. D. Moudgil Mouse Lysozyme-M Knockout Mice Reveal How the Self-Determinant Hierarchy Shapes the T Cell Repertoire against This Circulating Self Antigen in Wild-Type Mice J. Immunol., August 1, 2004; 173(3): 1763 - 1771. [Abstract] [Full Text] [PDF]

				M. Durai, H. R. Kim, and K. D. Moudgil The Regulatory C-Terminal Determinants within Mycobacterial Heat Shock Protein 65 Are Cryptic and Cross-Reactive with the Dominant Self Homologs: Implications for the Pathogenesis of Autoimmune Arthritis J. Immunol., July 1, 2004; 173(1): 181 - 188. [Abstract] [Full Text] [PDF]

				A. Miyakoshi, W. K. Yoon, Y. Jee, and Y. Matsumoto Characterization of the Antigen Specificity and TCR Repertoire, and TCR-Based DNA Vaccine Therapy in Myelin Basic Protein-Induced Autoimmune Encephalomyelitis in DA Rats J. Immunol., June 15, 2003; 170(12): 6371 - 6378. [Abstract] [Full Text] [PDF]

				E. C. Tsark, W. Wang, Y.-C. Teng, D. Arkfeld, G. R. Dodge, and S. Kovats Differential MHC Class II-Mediated Presentation of Rheumatoid Arthritis Autoantigens by Human Dendritic Cells and Macrophages J. Immunol., December 1, 2002; 169(11): 6625 - 6633. [Abstract] [Full Text] [PDF]

				M. A. Haque, J. W. Hawes, and J. S. Blum Cysteinylation of MHC Class II Ligands: Peptide Endocytosis and Reduction Within APC Influences T Cell Recognition J. Immunol., April 1, 2001; 166(7): 4543 - 4551. [Abstract] [Full Text] [PDF]

				C. Duthoit, V. Estienne, F. Delom, J.-M. Durand-Gorde, B. Mallet, P. Carayon, and J. Ruf Production of Immunoreactive Thyroglobulin C-Terminal Fragments during Thyroid Hormone Synthesis Endocrinology, July 1, 2000; 141(7): 2518 - 2525. [Abstract] [Full Text] [PDF]

				M. Kuwana, T. A. Medsger Jr., and T. M. Wright Analysis of Soluble and Cell Surface Factors Regulating Anti-DNA Topoisomerase I Autoantibody Production Demonstrates Synergy Between Th1 and Th2 Autoreactive T Cells J. Immunol., June 15, 2000; 164(12): 6138 - 6146. [Abstract] [Full Text] [PDF]

				C. Ma, P. E. Whiteley, P. M. Cameron, D. C. Freed, A. Pressey, S.-L. Chen, B. Garni-Wagner, C. Fang, D. M. Zaller, L. S. Wicker, et al. Role of APC in the Selection of Immunodominant T Cell Epitopes J. Immunol., December 15, 1999; 163(12): 6413 - 6423. [Abstract] [Full Text] [PDF]

				K. D. Moudgil, S. Southwood, A. Ametani, K. Kim, A. Sette, and E. E. Sercarz The Self-Directed T Cell Repertoire Against Mouse Lysozyme Reflects the Influence of the Hierarchy of Its Own Determinants and Can Be Engaged by a Foreign Lysozyme J. Immunol., October 15, 1999; 163(8): 4232 - 4237. [Abstract] [Full Text] [PDF]

				L. R. B. Soares, P. L. Orr, M. R. Garovoy, and G. Benichou Differential Activation of T Cells by Natural Antigen Peptide Analogues: Influence on Autoimmune and Alloimmune In Vivo T Cell Responses J. Immunol., May 15, 1998; 160(10): 4768 - 4775. [Abstract] [Full Text] [PDF]