Chapter 15 : Molecular Mimicry and Determinant Spreading

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Molecular Mimicry and Determinant Spreading, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818074/9781555811945_Chap15-1.gif /docserver/preview/fulltext/10.1128/9781555818074/9781555811945_Chap15-2.gif


One of the most intensively studied animal models of autoimmunity is insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic (NOD) mouse. This chapter considers how molecular mimicry, when viewed in the broader context of degeneracy of T-cell recognition specificity, provides a rationale for the existence of frequent autoimmunity. Whether the initiating event is a viral infection or inflammation at a site where APCs become ready to present and process self-antigens or foreign antigens efficiently, the commonality is the presentation of unusual, generally nondisplayed antigenic determinants to T cells which have evaded the mechanisms of self-tolerance induction. For autoimmunity to occur, it is absolutely necessary for the initiating response to expand. Accordingly, since so many T cells potentially can be addressed by a large diversity of ligands, it is clear that many, apparently redundant regulatory mechanisms must have evolved to ensure the sanctity of the self from errant breakaway clones. In the first decades of the 21st century investigators will need to define and learn to mobilize and maintain these regulators.

Citation: Quinn A, Sercarz E. 2000. Molecular Mimicry and Determinant Spreading, p 215-222. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch15
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Atkinson, M. A.,, M. A. Bowman,, L. Campbell,, B. L. Darrow,, D. L. Kaufman,, and N. K. Maclaren. 1994. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J. Clin. Investig. 94: 2125 2129.
2. Bhardwaj, V.,, V. Kumar,, H. M. Geysen,, and E. E. Sercarz. 1993. Degenerate recognition of a dissimilar antigenic peptide by myelin basic protein-reactive T cells. Implications for thymic education and autoimmunity. J. Immunol. 151: 5000 5010.
3. Chambers, C. A.,, and J. P. Allison. 1999. Costimulatory regulation of T cell function. Curr. Opin. Cell Biol. 11: 203 210.
3a. Cohen, I.R. 2000. Tending Adam's Garden: Evolving the Immune Cognitive Self. Academic Press, San Diego, Calif.
4. Dal Canto, M. C.,, R. W. Melvold,, B. S. Kim,, and S. D. Miller. 1995. Two models of multiple sclerosis: experimental allergic encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus (TMEV) infection. A pathological and immunological comparison. Microsc. Res. Tech. 32: 215 229.
5. Drakesmith, H.,, D. O'Neil,, S. C. Schneider,, M. Binks,, P. Medd,, E. Sercarz,, P. Beverley,, and B. Chain. 1998. In vivo priming of T cells against cryptic determinants by dendritic cells exposed to interleukin 6 and native antigen. Proc. Natl. Acad. Sci. USA 95: 14903 14908.
6. Easton, A. J.,, and R. P. Eglin. 1988. The detection of coxsackievirus RNA in cardiac tissue by in situ hybridization. J. Gen. Virol. 69: 285 291.
7. Feuer, J.,, and H. Spiera. 1997. Acute rheumatic fever in adults: a resurgence in the Hasidic Jewish community. J. Rheumatol. 24: 337 340.
8. Fujinami, R. S. 1988. Virus-induced autoimmunity through molecular mimicry. Ann. N. Y. Acad. Sci. 540: 210 217.
9. Gammon, G.,, H. M. Geysen,, R. J. Apple,, E. Pickett,, M. Palmer,, A. Ametani,, and E. E. Sercarz. 1991. T cell determinant structure: cores and determinant envelopes in three mouse major histocompatibility complex haplotypes. J. Exp. Med. 173: 609 617.
10. Horwitz, M. S.,, L. M. Bradley,, J. Harbertson,, T. Krahl,, J. Lee,, and N. Sarvetnick. 1998. Diabetes induced by coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat. Med. 4: 781 785.
11. Huber, S. A.,, and L. P. Job. 1983. Cellular immune mechanisms in coxsackievirus group B, type 3 induced myocarditis in BALB/c mice. Adv. Exp. Med. Biol. 161: 491 508.
12. Itoh, M.,, T. Takahashi,, N. Sakaguchi,, Y. Kuniyasu,, J. Shimizu,, F. Otsuka,, and S. Sakaguchi. 1999. Thymus and autoimmunity: production of CD25 +CD4 + naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162: 5317 5326.
13. Kaufman, D. L.,, M. Clare-Salzler,, J. Tian,, T. Forsthuber,, G. S. Ting,, P. Robinson,, M. A. Atkinson,, E. E. Sercarz,, A. J. Tobin,, and P. V. Lehmann. 1993. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366: 69 72.
14. Kumar, V. 1998. Determinant spreading during experimental autoimmune encephalomyelitis: is it potentiating, protecting or participating in the disease? Immunol. Rev. 164: 73 80.
15. Kumar, V.,, V. Bhardwaj,, L. Soares,, J. Alexander,, A. Sette,, and E. Sercarz. 1995. Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4/5 or interferon gamma by T cells. Proc. Natl. Acad. Sci. USA 92: 9510 9514.
16. Kumar, V.,, and E. Sercarz. 1996. Dysregulation of potentially pathogenic self reactivity is crucial for the manifestation of clinical autoimmunity. J. Neurosci. Res. 45: 334 339.
17. Kumar, V.,, and E. E. Sercarz. 1993. The involvement of T cell receptor peptide-specific regulatory CD4 + T cells in recovery from antigen-induced autoimmune disease. J. Exp. Med. 178: 909 916.
18. Lehmann, P. V.,, T. Forsthuber,, A. Miller,, and E. E. Sercarz. 1992. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358: 155 157.
19. Lehmann, P. V.,, E. E. Sercarz,, T. Forsthuber,, C. M. Dayan,, and G. Gammon. 1993. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol. Today 14: 203 208.
20. McRae, B. L.,, C. L. Vanderlugt,, M. C. Dal Canto,, and S. D. Miller. 1995. Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J. Exp. Med. 182: 75 85.
21. Moudgil, K. D.,, T. T. Chang,, H. Eradat,, A. M. Chen,, R. S. Gupta,, E. Brahn,, and E. E. Sercarz. 1997. Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J. Exp. Med. 185: 1307 1316.
22. Nanda, N. K.,, K. K. Arzoo,, H. M. Geysen,, A. Sette,, and E. E. Sercarz. 1995. Recognition of multiple peptide cores by a single T cell receptor. J. Exp. Med. 182: 531 539.
23. Nanda, N. K.,, and E. E. Sercarz. 1995. The positively selected T cell repertoire: is it exclusively restricted to the selecting MHC? Int. Immunol. 7: 353 358.
24. Oldstone, M. B. 1989. Molecular mimicry as a mechanism for the cause and a probe uncovering etiologic agent(s) of autoimmune disease. Curr. Top. Microbiol. Immunol. 145: 127 135.
25. Pinilla, C.,, R. Martin,, B. Gran,, J. R. Appel,, C. Boggiano,, D. B. Wilson,, and R. A. Houghten. 1999. Exploring immunological specificity using synthetic peptide combinatorial libraries. Curr. Opin. Immunol. 11: 193 202.
26. Shimizu, J.,, S. Yamazaki,, and S. Sakaguchi. 1999. Induction of tumor immunity by removing CD25 +CD4 + T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163: 5211 5218.
27. Speir, J. A.,, K. C. Garcia,, A. Brunmark,, M. Degano,, P. A. Peterson,, L. Teyton,, and I. A. Wilson. 1998. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes. Immunity 8: 553 562.
28. Takacs, K.,, and D. M. Altmann. 1998. The case against epitope spread in experimental allergic encephalomyelitis. Immunol. Rev. 164: 101 110.
29. Takacs, K.,, P. Chandler,, and D. M. Altmann. 1997. Relapsing and remitting experimental allergic encephalomyelitis: a focused response to the encephalitogenic peptide rather than epitope spread. Eur. J. Immunol. 27: 2927 2934.
30. Tsunoda, I.,, and R. S. Fujinami. 1996. Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus. J. Neuropathol. Exp. Neurol. 55: 673 686.
31. Tuohy, V. K.,, M. Yu,, B. Weinstock-Guttman,, and R. P. Kinkel. 1997. Diversity and plasticity of self recognition during the development of multiple sclerosis. J. Clin. Investig. 99: 1682 1690.
32. Tuohy, V. K.,, M. Yu,, L. Yin,, J. A. Kawczak,, J. M. Johnson,, P. M. Mathisen,, B. Weinstock-Guttman,, and R. P. Kinkel. 1998. The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Rev. 164: 93 100.
33. Vanderlugt, C. L.,, K. L. Neville,, K. M. Nikcevich,, T. N. Eagar,, J. A. Bluestone,, and S. D. Miller. 2000. Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J. Immunol. 164: 670 678.
34. Weiss, L. M.,, L. A. Movahed,, M. E. Billingham,, and M. L. Cleary. 1991. Detection of coxsackievirus B3 RNA in myocardial tissues by the polymerase chain reaction. Am. J. Pathol. 138: 497 503.


Generic image for table
Table 1

Examples of degeneracy, redundancy, and pleiotropy

Citation: Quinn A, Sercarz E. 2000. Molecular Mimicry and Determinant Spreading, p 215-222. In Cunningham M, Fujinami R (ed), Molecular Mimicry, Microbes, and Autoimmunity. ASM Press, Washington, DC. doi: 10.1128/9781555818074.ch15

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error