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HLA class II and autoimmunity: Epitope selection vs differential expression
ARTICLE IN PRESS Acta histochemica 111 (2009) 379—381
www.elsevier.de/acthis
HLA class II and autoimmunity: Epitope selection vs differential expression Brigitte Mu ¨ller-Hilke Institute of Immunology, University of Rostock, 18057 Rostock, Germany
KEYWORDS HLA; Autoimmunity; Promoter polymorphism
Summary Autoimmune diseases like rheumatoid arthritis (RA), multiple sclerosis, psoriasis and insulin-dependent diabetes mellitus are subject to a complex pathogenesis controlled by multiple genes and numerous environmental factors. The strongest genetic association is with certain HLA class II haplotypes and we here summarize the evidence supporting differential expression as a mechanism supporting the autoimmune process. & 2008 Elsevier GmbH. All rights reserved.
Genetic heterogeneity of the HLA locus Ever since the association of autoimmune diseases and HLA class II haplotypes has been recognized, HLA.DRB1 alleles have been classified as either associated or protective (Svejgaard et al., 1983; Lang et al., 1990; Weyand et al., 1995). Indeed, more than 450 different HLA.DRB1 alleles sequenced up to date argue in favour of a strong genetic pressure on diversification and the capacity to present every possible peptide (Marsh et al., 2005). Major research efforts focused on the elucidation of structural similarities of diseaseassociated molecules and polymorphisms in the third hypervariable region of the HLA class II molecule encoding the peptide-binding cleft have been scrutinized. In the case of rheumatoid arthritis (RA)-associated HLA.DRB1 alleles, the Tel.: +49 381 4945883; Fax: +49 381 4945882.
E-mail address: [email protected]
identification of a ‘‘shared epitope’’ led to the hypothesis that epitope selection (the presentation of a disease-inducing epitope) in combination with molecular mimicry (a high homology between the disease inducing and a self-epitope) induces and promotes autoimmunity (Gregersen et al., 1987). As the majority of autoimmune diseases are associated with the HLA.DRB1*03 and/or the *04 super-haplotypes, this hypothesis has the unlikely implication that very similar epitopes can induce very different diseases. At a closer inspection, the polymorphism within the HLA locus is not restricted to the exons but extends into the promoter regions. Interestingly, the degree of exon polymorphism among both HLA classes is comparable, while the polymorphism among the HLA class II promoters is conspicuously higher than among HLA class I (Mitchison et al., 2005; Mu ¨ller-Hilke and Mitchison, 2006). This is true for human and mouse and argues that polymorphisms in the promoter regions are unlikely to result
0065-1281/$ - see front matter & 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.acthis.2008.11.011
ARTICLE IN PRESS 380 from simple linkage with the exons. Instead, some additional evolutionary force drives class II promoter diversity and this may be related to the complex regulatory function of these genes orchestrating the immune response.
Promoter polymorphism and differential expression In the mouse, the availability of inbred strains and monoclonal antibodies recognizing the various MHC class II haplotypes facilitated a detailed functional analysis of promoter polymorphisms. Thus, the protein expression of H-2 molecules from the four haplotypes H-2b, H-2d, H-2kand H-2q was determined, whereby I-Ek and I-Ab are well recognized as protective alleles and I-Aq is associated with collagen-induced arthritis. Indeed, differential expression has been demonstrated for activated macrophages with the protective alleles being about 100-fold more abundantly expressed than the disease associated one (Baumgart et al., 1998). These protein data were well backed-up by in vitro experiments quantifying the transcriptional activity (Guardiola et al., 1996). Unlike the mouse, the human situation is much more complex due to the extremely high polymorphism and the polygenicity of the HLA locus, the heterozygosity and the lack of monoclonal antibodies discriminating all the alleles. In order to evaluate the various promoters we are therefore confined to in vitro work comparing the transcriptional activities and measuring binding affinities of transcription factors to the respective sequences. It is worth remembering though that this vast HLA polymorphism provided the initial basis on which promoter structures were defined and many HLA.DRB1 promoters have since been screened for polymorphic changes in and around the known S-, X-, Y-, CAAT- and TATA-boxes (Glimcher and Kara, 1992). Because they are encoded on the same allelic lineage, the HLA.DRB1*04, *07 and *09 superhaplotypes were recently compared, the former one associated with RA, the latter two considered neutral. Oligonucleotides representing the various boxes and their permutations were generated and nuclear extracts from antigen-presenting cells (APCs) tested for binding to these sequences. Differential expression of the non-polymorphic HLA.DRB4 encoded by all super-haplotypes was inferred from an increased binding of nuclear factors to the respective TATA-box (Heldt et al., 2003).
B. Mu ¨ller-Hilke
Differential expression and autoimmunity How then does a differential MHC class II expression translate into autoimmunity? Our concept implies that an elevated number of MHC class II molecules at the immunological synapse strengthens the interaction between the APC and the T helper cell and due to an extended signalling from the APC facilitates the development of Th1 (Mu ¨llerHilke and Mitchison, 2006). Likewise, a similar shift in the Th1/Th2 balance can be achieved by increasing antigen dosage (Hosken et al., 1995). Polarization towards Th1 has been implicated in chronic inflammation (Liblau et al., 1995; vanRoon et al., 2006) and indeed, the elevated expression of protective MHC class II haplotypes in the mouse led to an increase in Th1 development (Heldt et al., 2003). For humans, this proof of concept is still missing. However, the HLA.DRB4 promoter-binding nuclear factors with a higher affinity and thus likely to lead to an elevated expression has been shown to segregate with radiographic progression in early RA (Heldt et al., 2003). Future experiments will have to reveal in more detail the intricate network between epitope selection and promoter polymorphisms and how these translate into differential expression, T cell polarization and chronic inflammation.
References Baumgart M, Moos V, Schuhbauer D, Muller B. Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects. Proc Natl Acad Sci USA 1998;95(12):6936–40. Glimcher LH, Kara CJ. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol 1992; 10:13–49. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30(11):1205–13. Guardiola J, Maffei A, Lauster R, Mitchison NA, Accolla RS, Sartoris S. Functional significance of polymorphism among MHC class II gene promoters. Tissue Antigens 1996;48(6):615–25. Heldt C, Listing J, Sozeri O, Blasing F, Frischbutter S, Muller B. Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis. Arthritis Rheum 2003;48(10): 2779–87. Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A. The effect of antigen dose on CD4+ T helper cell
ARTICLE IN PRESS HLA class II and autoimmunity phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med 1995;182(5): 1579–84. Lang B, Melchers I, Urlacher A, Tanzi-Fetta RF, Kohlbrenner S, Tongio MM, et al. HLA-DR1 and DRw6 association in DR4-negative rheumatoid arthritis patients. Rheumatol Int 1990;10(4):171–5. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995;16(1):34–8. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, et al. Nomenclature for factors of the HLA system, 2004. Hum Immunol 2005;66(5):571–636.
381 Mitchison NA, Ono SJ, Stephens HA. Does the polymorphism of MHC class II promoters matter? Cell Immunol 2005;233(2):162–5. Mu ¨ller-Hilke B, Mitchison NA. The role of HLA promoters in autoimmunity. Curr Pharm Des 2006;12(29):3743–52. Svejgaard A, Platz P, Ryder LP. HLA and disease 1982—a survey. Immunol Rev 1983;70:193–218. van Roon JA, Bijlsma JW, Lafeber FP. Diversity of regulatory T cells to control arthritis. Best Pract Res Clin Rheumatol 2006;20(5):897–913. Weyand CM, McCarthy TG, Goronzy JJ. Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J Clin Invest 1995;95(5):2120–6.
www.elsevier.de/acthis
HLA class II and autoimmunity: Epitope selection vs differential expression Brigitte Mu ¨ller-Hilke Institute of Immunology, University of Rostock, 18057 Rostock, Germany
KEYWORDS HLA; Autoimmunity; Promoter polymorphism
Summary Autoimmune diseases like rheumatoid arthritis (RA), multiple sclerosis, psoriasis and insulin-dependent diabetes mellitus are subject to a complex pathogenesis controlled by multiple genes and numerous environmental factors. The strongest genetic association is with certain HLA class II haplotypes and we here summarize the evidence supporting differential expression as a mechanism supporting the autoimmune process. & 2008 Elsevier GmbH. All rights reserved.
Genetic heterogeneity of the HLA locus Ever since the association of autoimmune diseases and HLA class II haplotypes has been recognized, HLA.DRB1 alleles have been classified as either associated or protective (Svejgaard et al., 1983; Lang et al., 1990; Weyand et al., 1995). Indeed, more than 450 different HLA.DRB1 alleles sequenced up to date argue in favour of a strong genetic pressure on diversification and the capacity to present every possible peptide (Marsh et al., 2005). Major research efforts focused on the elucidation of structural similarities of diseaseassociated molecules and polymorphisms in the third hypervariable region of the HLA class II molecule encoding the peptide-binding cleft have been scrutinized. In the case of rheumatoid arthritis (RA)-associated HLA.DRB1 alleles, the Tel.: +49 381 4945883; Fax: +49 381 4945882.
E-mail address: [email protected]
identification of a ‘‘shared epitope’’ led to the hypothesis that epitope selection (the presentation of a disease-inducing epitope) in combination with molecular mimicry (a high homology between the disease inducing and a self-epitope) induces and promotes autoimmunity (Gregersen et al., 1987). As the majority of autoimmune diseases are associated with the HLA.DRB1*03 and/or the *04 super-haplotypes, this hypothesis has the unlikely implication that very similar epitopes can induce very different diseases. At a closer inspection, the polymorphism within the HLA locus is not restricted to the exons but extends into the promoter regions. Interestingly, the degree of exon polymorphism among both HLA classes is comparable, while the polymorphism among the HLA class II promoters is conspicuously higher than among HLA class I (Mitchison et al., 2005; Mu ¨ller-Hilke and Mitchison, 2006). This is true for human and mouse and argues that polymorphisms in the promoter regions are unlikely to result
0065-1281/$ - see front matter & 2008 Elsevier GmbH. All rights reserved. doi:10.1016/j.acthis.2008.11.011
ARTICLE IN PRESS 380 from simple linkage with the exons. Instead, some additional evolutionary force drives class II promoter diversity and this may be related to the complex regulatory function of these genes orchestrating the immune response.
Promoter polymorphism and differential expression In the mouse, the availability of inbred strains and monoclonal antibodies recognizing the various MHC class II haplotypes facilitated a detailed functional analysis of promoter polymorphisms. Thus, the protein expression of H-2 molecules from the four haplotypes H-2b, H-2d, H-2kand H-2q was determined, whereby I-Ek and I-Ab are well recognized as protective alleles and I-Aq is associated with collagen-induced arthritis. Indeed, differential expression has been demonstrated for activated macrophages with the protective alleles being about 100-fold more abundantly expressed than the disease associated one (Baumgart et al., 1998). These protein data were well backed-up by in vitro experiments quantifying the transcriptional activity (Guardiola et al., 1996). Unlike the mouse, the human situation is much more complex due to the extremely high polymorphism and the polygenicity of the HLA locus, the heterozygosity and the lack of monoclonal antibodies discriminating all the alleles. In order to evaluate the various promoters we are therefore confined to in vitro work comparing the transcriptional activities and measuring binding affinities of transcription factors to the respective sequences. It is worth remembering though that this vast HLA polymorphism provided the initial basis on which promoter structures were defined and many HLA.DRB1 promoters have since been screened for polymorphic changes in and around the known S-, X-, Y-, CAAT- and TATA-boxes (Glimcher and Kara, 1992). Because they are encoded on the same allelic lineage, the HLA.DRB1*04, *07 and *09 superhaplotypes were recently compared, the former one associated with RA, the latter two considered neutral. Oligonucleotides representing the various boxes and their permutations were generated and nuclear extracts from antigen-presenting cells (APCs) tested for binding to these sequences. Differential expression of the non-polymorphic HLA.DRB4 encoded by all super-haplotypes was inferred from an increased binding of nuclear factors to the respective TATA-box (Heldt et al., 2003).
B. Mu ¨ller-Hilke
Differential expression and autoimmunity How then does a differential MHC class II expression translate into autoimmunity? Our concept implies that an elevated number of MHC class II molecules at the immunological synapse strengthens the interaction between the APC and the T helper cell and due to an extended signalling from the APC facilitates the development of Th1 (Mu ¨llerHilke and Mitchison, 2006). Likewise, a similar shift in the Th1/Th2 balance can be achieved by increasing antigen dosage (Hosken et al., 1995). Polarization towards Th1 has been implicated in chronic inflammation (Liblau et al., 1995; vanRoon et al., 2006) and indeed, the elevated expression of protective MHC class II haplotypes in the mouse led to an increase in Th1 development (Heldt et al., 2003). For humans, this proof of concept is still missing. However, the HLA.DRB4 promoter-binding nuclear factors with a higher affinity and thus likely to lead to an elevated expression has been shown to segregate with radiographic progression in early RA (Heldt et al., 2003). Future experiments will have to reveal in more detail the intricate network between epitope selection and promoter polymorphisms and how these translate into differential expression, T cell polarization and chronic inflammation.
References Baumgart M, Moos V, Schuhbauer D, Muller B. Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects. Proc Natl Acad Sci USA 1998;95(12):6936–40. Glimcher LH, Kara CJ. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol 1992; 10:13–49. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30(11):1205–13. Guardiola J, Maffei A, Lauster R, Mitchison NA, Accolla RS, Sartoris S. Functional significance of polymorphism among MHC class II gene promoters. Tissue Antigens 1996;48(6):615–25. Heldt C, Listing J, Sozeri O, Blasing F, Frischbutter S, Muller B. Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis. Arthritis Rheum 2003;48(10): 2779–87. Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A. The effect of antigen dose on CD4+ T helper cell
ARTICLE IN PRESS HLA class II and autoimmunity phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med 1995;182(5): 1579–84. Lang B, Melchers I, Urlacher A, Tanzi-Fetta RF, Kohlbrenner S, Tongio MM, et al. HLA-DR1 and DRw6 association in DR4-negative rheumatoid arthritis patients. Rheumatol Int 1990;10(4):171–5. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995;16(1):34–8. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, et al. Nomenclature for factors of the HLA system, 2004. Hum Immunol 2005;66(5):571–636.
381 Mitchison NA, Ono SJ, Stephens HA. Does the polymorphism of MHC class II promoters matter? Cell Immunol 2005;233(2):162–5. Mu ¨ller-Hilke B, Mitchison NA. The role of HLA promoters in autoimmunity. Curr Pharm Des 2006;12(29):3743–52. Svejgaard A, Platz P, Ryder LP. HLA and disease 1982—a survey. Immunol Rev 1983;70:193–218. van Roon JA, Bijlsma JW, Lafeber FP. Diversity of regulatory T cells to control arthritis. Best Pract Res Clin Rheumatol 2006;20(5):897–913. Weyand CM, McCarthy TG, Goronzy JJ. Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J Clin Invest 1995;95(5):2120–6.