Abstract
Lupus autoimmunity is the product of interactions of a vast array of self tissues, lymphopoetic cells, self antigens, and soluble macromolecules. Clearly, the immune system evolved to enhance the survival of the species, not for the generation of autoimmune syndromes. This has led the scientific community to seek specific immunologic defects or irregularities that may be responsible for this aberrant response. Unfortunately, no single overwhelming defect has been identified as a specific trigger in spite of the fact that lupus autoimmunity is not subtle in its expression. In the absence of obvious malfunctions of the immune system, is it possible that the immune system is functioning in a manner in which it was designed with the exception that the target of the response is self antigen, not a foreign pathogen? With few exceptions, the central features of immunity to foreign antigens are identical to those important in experimental models of lupus autoimmunity. For example, autoimmune-prone mice depleted of either B or T lymphocytes fail to exhibit the typical immunologic or pathologic outcomes of this disease (1–3). However, these mice also fail to respond to pathogens or conventional immunization with foreign protein as compared with unmanipulated mice (4). If all the components of immunity, or indeed autoimmunity, are in place, why are autoimmune diseases still an uncommon occurrence? This chapter examines the selection and activation of lymphocytes as they arise in the immune system with particular relevance to those forms of self antigen and costimulatory components that may impinge on the response to self antigens.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Santoro, T. J., Portanova, J. P., and Kotzin, B. L. (1988) The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL 1pr/lpr mice. J. Exp. Med. 167, 713–721.
Peng, S. L., Madaio, M. P., Hughes, D. P. M., Crispe, N., Owen, M. J., Wen, L. Hayday, A. C., and Craft, J. C. (1996) Murine lupus in the absence of oc13 T cells. J. Immunol. 156, 4041–4049.
Shlomchik, M. J., Madaio, M. P., Ni, D., Trounstein, M., and Huszar D. (1994) The role of B cells in /pr//pr-induced autoimmunity. J. Exp. Med. 180, 1295–1306.
Constant, S., Sant’Angelo, D., Pasqualini, T., Taylor, T., Levin, D., Flavell, R., and Bottomly, K. (1995) Peptide and protein antigens require distinct antigen-presenting cell subsets for the priming of CD4+ T cells. J. Immunol. 154, 4915–4923.
Bevan, M. J. (1997) In thymic selection, peptide diversity gives and takes away. Immunity 7, 175–178.
Ignatowicz, L., Rees, W., Pacholczyk, R., Ignatowicz, H., Kushnir, E., Kappler, J., and Mar-rack, P. (1997) T cells can be activated by peptides that are unrelated in sequence to their selecting peptide. Immunity 7, 179–186.
Tourne, S., Miyazaki, T., Oxenius, A., Klein, L., Fehr, T., Kyewski, B., Benoist, C., and Mathis, D. (1997) Selection of a broad repertoire of CD4+ T cells in H-2MaO mice. Immunity 7, 187–196.
Grubin, C.E., Kovats, S., deRoos, P., and Rudensky, A.Y. (1997) Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II bound self peptides. Immunity 7, 197–208.
Surh, C. D., Lee, D. S., Fung-Leung, W.-P., Karlsson, L., and Sprent, J. (1997) Thymic selection by a single MHC/peptide ligand produces a semidiverse repertoire of CD4+ T cells. Immunity 7, 209–220.
Hu, Q., Bazemore Walker, C. R., Girao, C., Opferman, J. T., Sun, J., Shabanowitz, J., Hunt, D. F., and Ashton-Rickardt, P. G. (1997) Specific recognition of thymic self-peptides induces the positive selection of cytotoxic T lymphocytes. Immunity 7, 221–232.
Jameson, S. C., Hogquist, K. S., and Bevan, M. J. (1995) Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126.
Hogquist, K. A., Tomlinson, A. J., Kieper, W. C., McGargill, M. A., Hart, M. C., Naylor, S., and Jameson, S. C. (1997) Identification of a naturally occurring ligand for thymic positive selection. Immunity 6, 389–399.
Alam, S. M., Travers, P. J., Wung, J. L., Nasholds, W., Redpath, S., Jameson, S. C., and Gascoigne, N. J. R. (1996) T cell receptor affinity and positive selection. Nature 381, 616–620.
Ashton-Rickardt, P. G., Bandiera, A., Delaney, J. R., van Kaer, L., Pircher, H. P., Zinkernagel, R. M., and Tonegawa, S. (1994) Evidence for a differential avidity model of T cell selection in the thymus. Cell 76, 651–663.
Hogquist, K. A., Gavin, M. A., and Bevan, M. J. (1993) Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymus organ culture. J. Exp. Med. 177, 1469–1473.
Ignatowicz, L., Kappler, J., and Marrack, P. (1996) The repertoire of T cells selected by a single MHC/peptide ligand. Cell 84, 521–529.
Martin, W. D., Hicks, G. G., Mendiratta, S. K., Leva, H. I., Ruley, H. E., and van Kaer, L. (1996) H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation and T cell repertoire selection. Cell 84, 543–550.
Egwuagu, C. E., Charukamnoetkanok, P., and Gery, I. (1997) Thymic expression of autoantigens correlates with resistance to autoimmune disease. J. Immunol. 159, 3109–3112.
Antonia, S. J., Geiger, T., Miller, J., and Flavell, R A. (1995) Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein. Int. Immunol. 7, 715–725.
Wucherpfennig, K. W. and Strominger, J. L. (1995) Molecular mimicry in T cell mediated autoimmunity• viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705.
Gaither, K. K., Fox, O. F., Yamatata, H., Mamula, M. J., Reichlin, M., and Harley, J. B. (1987) Implications of anti-Ro/Sjogren’s syndrome A antigen autoantibody in normal sera for autoimmunity J. Clin. Invest. 79, 841–846.
Burns, J., Rosenzweig, A., Zweiman, B., and Lisak, R P., (1983) Isolation of myelin basic protein-reactive T cell lines from normal human blood. Cell. Immunol. 81, 435–440.
Schild, H., Rotzschke, O., Kalbacher, H., and Rammensee, H. G. (1990) Limit of T cell tolerance to self proteins by peptide presentation. Science 247, 1587–1589.
Sercarz, E., Lehmann, P. V., Ametani, A., Benichou, G., Miller, A., and Moudgil, K. (1993) Dominance and crypticity of T cell antigenic determinants. Ann. Rev. Immunol. 11, 729–766.
Moudgil, K. D. and Sercarz, E. E. (1993) Dominant determinants in hen eggwhite lysozyme correspond to the cryptic determinants within its self-homolog, mouse lysozyme: Implications in the shaping of the T cell repertoire and autoimmunity J. Exp. Med. 178, 2131–2138.
Mamula, M. (1993) The inability to process a self peptide allows T cells to escape tolerance. J. Exp. Med. 177, 567–571.
Lehmann, P. V., Forsthuber, T., Miller, A., and Sercarz, E. E. (1992) Spreading of T cell autoimmunity to cryptic determinants of an autoantigen. Nature 358, 155–157.
Garza, K. M., Griggs, N. D., and Tung, K. S. K. (1997) Neonatal injection of an ovarian peptide induces autoimmune ovarian disease in female mice: requirement of endogenous neonatal ovaries. Immunity 6, 89–96.
Bockenstedt, L. K., Gee, R., and Mamula, M. J. (1995) Self peptides in the initiation of lupus autoimmunity. J. Immunol. 154, 3516–3524.
Kaufman, D. L., Clare-Salzier, M., Tian, J., Forsthuber, T., Ting, G. S. P., Robinson, P., Atkinson, M. A., Sercarz, E. E., Tobin, A. J., and Lehmann, P. V. (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366, 69–72.
McRae, B.L., Vanderlugt, C. L., Dal Canto, M. C., and Miller, S. D. (1995) Functional evidence for epitope spreading in the relapsing pathology of EAE in the SJL/J mouse. J. Exp. Med. 182, 75–85.
Fatenejad, S., Brooks, W., Schwartz, A., and Craft, J. (1994) Pattern of anti-small nuclear ribonucleoprotein antibodies in MRL/MP-1pr/lpr mice suggests that the intact U1 snRNP particle is their autoimmunogenic target. J. Immunol. 152, 5523–5531.
Tian, J., Lehmann, P. V., and Kaufman, D. L. (1997) Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens. J. Exp. Med. 186, 2039–2043.
Fatenejad, S., Mamula, M. J., and Craft, J. (1993) Role of intermolecular/intrastructural B and T cell determinants in the diversification of autoantibodies to ribonucleoprotein particles. Proc. Natl. Acad. Sci. USA 90, 12,010–12, 014.
Bloom, D. D., Davignon, J., Cohen, P., Eisenberg, R. A., and Clarke, S. H. (1993) Overlap of the anti-Sm and anti-DNA responses of MRLIMp-1pr/lpr mice. J. Immunol. 150, 1579–1590.
Mamula, M. J., Gee, R. J., Elliott, J., Jones, P., and Blier, P. R. (1997) A post-translational protein modification that elicits autoimmunity, submitted.
Roher, A. E., Lowenson, J. D., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Surcher-Neely, H. A., Heinrikson, R. L., Ball, M. J., and Greenberg, B. D. (1993) Structural alterations in the peptide backbone of 13-amyloid core protein may account for its deposition and stability in Alzheimer’ s disease. J. Biol. Chem. 268, 3072–3083.
Najbauer, J., Orpiszewski, J., and Aswad, D. W. (1996) Molecular aging of tubulin: accumulation of isoaspartyl sites in vitro and in vivo. Biochemistry 35, 5183–5190.
Aswad, D. W. (1995) Deamidation and Isoaspartate Formation in Peptides and Proteins (Aswad, D. W., ed.), CRC Press, Boca Raton, FL, pp. 31–46.
Galletti, P., Ingrosso, D., Manna, C., Clemente, G., and Zappia, V. (1995) Protein damage and methylation-mediated repair in the erythrocyte. Biochem. J. 306, 313–325.
Tsai, W. and Clarke, S. (1994) Amino acid polymorphisms of the human L-isoaspartyl/Daspartyl methyltransferase involved in protein repair. Biochem. Biophys. Res. Commun. 203, 491–497.
Cunningham, M.W. (1993) Molecular mimicry: bacterial antigen mimicry, in: The Molecular Pathology of Autoimmunity ( Bona, C.A., ed.), Harvard Academic, New York, pp. 245–256.
Shikhman, A. R., Greenspan, N. A., and Cunningham M. W. (1993) A subset of murine monoclonal antibodies crossreactive with cytoskeletal proteins and group A streptococcal M protein recognize N-acetyl-glucosamine. J. Immunol. 151, 3902–3913.
Wucherpfennig, K. W. and Strominger, J. L. (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705.
Roth, R., Nakamura, T., and Mamula, M. J. (1996) Costimulation and autoantigen specificity enable B cells to activate autoreactive T cells. J. Immunol. 157, 2924–2931.
Roth, R. and Mamula, M. J. (1997) Induction of lupus autoimmunity• snRNP specific B cells prime a diversified repertoire of autoreactive T cells, submitted.
James, J. A., Gross, T., Scofield, R. H., and Harley, J. B. (1995) Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: SmB/B’-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity J. Exp. Med. 181, 453–461.
Topfer, F., Gordon, T., and McCluskey, J. (1995) Intra-and intermolecular spreading of autoimmunity involving the nuclear self-antigens La(SS-B) and Ro(SS-A). Proc. Natl. Acad. Sci. USA 92, 875–879.
Mamula, M. J., Fatenejad, S., and Craft, J. (1994) B Cells process and present lupus autoantigens that initiate autoimmune T cell responses. J. Immunol. 152, 1453–1461.
Racke, M. K., Scott, D. E., Quigley, L., Gray, G. S., Abe, R., June, C. H., and Perrin, P. J. (1995) Distinct roles for B7–1 (CD80) and B7–2 (CD86) in the initiation of experimental allergic encephalomyelitis. J. Clin. Invest. 96, 2195–2203.
Davidson, H. W. and Watts, C. (1989) Epitope directed processing of specific antigen by B lymphocytes. J. Cell. Biol. 109, 85–90.
Ozaki, S. and Berzofsky, J. A. (1987) Antibody conjugates mimic specific B cell presentation of antigen: relationship between T and B cell specificity. J. Immunol. 138, 4133–4142.
Watts, C. and Lanzavecchia, A. (1993) Suppressive effect of antibody on processing of T cell epitopes. J. Exp. Med. 178, 1459–1463.
Wolf, S. D., Dittel, B. N., Hardardottir, F., and Janeway, C. A., Jr. (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J. Exp. Med. 184, 2271–2278.
Serreze, D. V., Chapman, H.D., Varnum, D. S., Hanson, M. S., Reifsnyder, P. C., Richard, S. D., Fleming, S. A., Leiter, E. H., and Shultz L. D. (1996) B lymphocytes are essential for the initiation of T cell mediated autoimmune diabetes: Analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J. Exp. Med. 184, 2049–2053.
Hannum, L. G., Ni, D., Haberman, A. M., Weigert, M. and Shlomchik, M. J. (1996) A disease-related RF autoantibody is not tolerized in a normal mouse: implications of the origins of autantibodies in autoimmune disease. J. Exp. Med. 184, 1269–1278.
Goverman, J., Woods, A., Larson, L., Weiner, L. P., Hood, L., and Zaller, D. M. (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–560.
Chambers, C. A. and Allison, J. P. (1997) Co-stimulation in T cell responses. Curr. Opin. Immunol. 9, 396–104.
Tivol, E. A., Schweitzer, A. N., and Sharpe, A. H. (1996) Costimulation and autoimmunity. Curr. Opin. Immunol. 8, 822–830.
Kuchroo, V., Prabhu Das, M., Brown, J. A., Ranger, A. M., Zamvil, S. S., Sobel, R. A., Weiner, H. L., Nabavi, N., and Glimcher, L. H. (1995) B7–1 and B7–2 costimulatory molecules differentially activate the Thl/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–716.
Nakajima, A., Azuma, M., Kodera, S., Nuriya, S., Terashi, A., Abe, M., Hirose, S., Shirai, T., Yagita, H., and Okumura, K. (1995) Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule. Eur. J. Immunol. 25, 3060–3069.
Lane, P., Haller, C., and McConnell, F. (1996) Evidence that induction of tolerance in vivo involves active signaling via a B7 ligand-dependent mechanism: CTLA4Ig protects Vß8+ T cells from tolerance induction by the superantigen staphylococcal enterotoxin B. Eur. J. Immunol. 26, 858–862.
Tivol, E. A., Borriello, F., Schweitzer, A. N., Lynch, W. P., Bluestone, J. A., and Sharpe, A. H. (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547.
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., and Mak, T.W. (1995) Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270, 985–988.
Cross, A. H., Girard, T.J., Giacoletto, K. S., Evans, R. J., Keeling, R. M., Lin, R. F., Trotter, J. L., and Karr, R. W. (1995) Long term inhibition of murine experimental autoimmune encephalomyelitis using CTLA4-Fc supports a key role for CD 28 costimulation. J. Clin. Invest. 95, 2783–2789.
Perrin, P. J., Scott, D., Quigley, L., Albert, P. S., Feder, O., Gray, F. S., Abe, R., June, C. H., and Racke, M. K. (1995) Role of B7/CD28 CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. J. Immunol. 154, 1481–1490.
Khoury, S. J., Akalin, E., Chandraker, A., Turka, L. A., Linsley, P. S., Sayegh, M. H., and Hancock, W. W. (1995) CD28–B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Thl but spares Th2 cytokines in the central nervous system. J. Immunol. 155, 4521–4524.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Mamula, M.J. (1999). T Cell Autoimmunity in Lupus. In: Kammer, G.M., Tsokos, G.C. (eds) Lupus. Contemporary Immunology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-703-1_13
Download citation
DOI: https://doi.org/10.1007/978-1-59259-703-1_13
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-4757-5686-9
Online ISBN: 978-1-59259-703-1
eBook Packages: Springer Book Archive