MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. Therefore, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. Indeed, the strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes. Here, we discuss the insights that the crystal structures of MHC class II molecules provide into the molecular mechanisms by which sequence polymorphisms might contribute to disease susceptibility.
The strength of the genetic association between specific MHC class II alleles and an individual's susceptibility to particular chronic inflammatory diseases renders these alleles the main known risk factor for many such diseases.
The peptide-binding grooves of MHC class II molecules can be described in terms of pockets that must accommodate the side chains of residues at positions P1, P4, P6 and P9 of the peptide. Analyses of the characteristics of these pockets, as revealed by the crystal structures of MHC class II molecules, provide insights into how sequence polymorphisms determine the population of peptides a particular MHC class II molecule can bind, and indicate molecular mechanisms that could determine disease susceptibility.
Structure-based analysis indicates that differential peptide binding between two closely related HLA-DQ6 molecules is central to their positive and negative association with the chronic neurological disorder narcolepsy, an observation that is consistent with narcolepsy being an autoimmune disease.
Coeliac disease is an autoimmune-like disorder that is caused by an immune response to antigens present in wheat gluten. HLA-DQ2, and to a lesser extent HLA-DQ8, have peptide-binding-groove characteristics that strongly favour the binding of gluten-derived peptides, consistent with the association of these MHC class II molecules with coeliac disease.
Crystal structures for the type-1-diabetes-associated MHC class II molecules HLA-DQ8, HLA-DQ2 and mouse H2-IAg7 reveal a distinctive P9 pocket, which might indicate similar pathophysiological pathways for developing type 1 diabetes in humans and non-obese diabetic mice. A comparison of the structures of disease-associated versus protective MHC class II molecules reveals a second characteristic; the P6 pocket shows a consistent trend in volume size that correlates from positive to negative association with type 1 diabetes.
T cells are thought to play an important role in the development of rheumatoid arthritis and an immunodominant T-cell epitope from type II collagen is a candidate autoantigen. The structures of the disease-associated HLA-DR4.1 and HLA-DR1 molecules reveal P4 pockets that have in common an ability to bind acidic residues, plus shallow P6 and P9 pockets that are particularly well suited to binding the glycine-rich sequences typical of type-II-collagen-derived peptides.
Distinctive structural characteristics of the multiple-sclerosis-associated MHC class II molecules HLA-DR2a and HLA-DR2b separately result in peptide residues P6–P9 assuming a raised position above the respective peptide-binding grooves. This differs considerably from the canonical mode of peptide presentation by other MHC class II molecules and might favour T-cell receptors that sample a reduced portion of the peptide, hence increasing the likelihood of a disease inducing crossreactivity.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Brown, J. H. et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364, 33–39 (1993). The classic analysis of an MHC class II molecule in complex with a single peptide. This structure detailed the fundamental characteristics of the peptide-binding groove.
Stern, L. J. et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368, 215–221 (1994).
Schueler-Furman, O., Altuvia, Y. & Margalit, H. Examination of possible structural constraints of MHC-binding peptides by assessment of their native structure within their source proteins. Proteins 45, 47–54 (2001).
Li, Y., Li, H., Martin, R. & Mariuzza, R. A. Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 proteins. J. Mol. Biol. 304, 177–188 (2000). This paper reports the crystal structure of HLA-DR2a in complex with an immunodominant epitope from MBP. Together with reference 5, the structure illustrates how the same peptide can be bound in different conformations by different MHC class II molecules.
Smith, K. J., Pyrdol, J., Gauthier, L., Wiley, D. C. & Wucherpfennig, K. W. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J. Exp. Med. 188, 1511–1520 (1998). This paper reports the crystal structure of HLA-DR2b in complex with the multiple-sclerosis-associated immunodominant epitope from MBP described in reference 4. When presented in the context of HLA-DR2b, this epitope is known to elicit disease-causing T-cell responses.
Okun, M. L., Lin, L., Pelin, Z., Hong, S. & Mignot, E. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 25, 27–35 (2002).
Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22 (1998).
Matsuki, K. et al. DQ (rather than DR) gene marks susceptibility to narcolepsy. Lancet 339, 1052 (1992).
Mignot, E. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699 (2001).
Taheri, S., Zeitzer, J. M. & Mignot, E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu. Rev. Neurosci. 25, 283–313 (2002).
Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).
Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med. 6, 991–997 (2000).
Siebold, C. et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc. Natl Acad. Sci. USA 101, 1999–2004 (2004). This structural analysis of HLA-DQ6.2 reveals features of the peptide-binding groove that correlate with susceptibility to narcolepsy and protection against type 1 diabetes.
Farrell, R. J. & Kelly, C. P. Celiac sprue. N. Engl. J. Med. 346, 180–188 (2002).
Sollid, L. M. et al. Evidence for a primary association of celiac disease to a particular HLA-DQ α/β heterodimer. J. Exp. Med. 169, 345–350 (1989).
Lundin, K. E., Scott, H., Fausa, O., Thorsby, E. & Sollid, L. M. T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease patient preferentially recognize gliadin when presented by DQ8. Hum. Immunol. 41, 285–291 (1994).
Lundin, K. E. et al. Gliadin-specific, HLA-DQ(α1*0501, β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187–196 (1993).
van de Wal, Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J. Immunol. 161, 1585–1588 (1998).
Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Med. 4, 713–717 (1998).
Kim, C. Y., Quarsten, H., Bergseng, E., Khosla, C. & Sollid, L. M. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc. Natl Acad. Sci. USA 101, 4175–4179 (2004). The structure of HLA-DQ2 in complex with a gluten-derived peptide shows how MHC class II peptide-binding-groove characteristics allow the binding of peptides from atypical protein sequences, in this case gliadin, leading to susceptibility to coeliac disease.
Suri, A., Walters, J. J., Gross, M. L. & Unanue, E. R. Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity. J. Clin. Invest. 115, 2268–2276 (2005).
Atkinson, M. A. & Eisenbarth, G. S. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358, 221–229 (2001).
Kent, S. C. et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435, 224–228 (2005).
Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQ β gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987). The classic analysis demonstrating that MHC class II polymorphisms can be linked to an autoimmune disease.
Todd, J. A. & Wicker, L. S. Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models. Immunity 15, 387–395 (2001).
Baisch, J. M. et al. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N. Engl. J. Med. 322, 1836–1841 (1990).
Cucca, F. et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum. Mol. Genet. 10, 2025–2037 (2001).
Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).
Robinson, C. P. et al. A novel NOD-derived murine model of primary Sjogren's syndrome. Arthritis Rheum. 41, 150–156 (1998).
Lee, K. H., Wucherpfennig, K. W. & Wiley, D. C. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nature Immunol. 2, 501–507 (2001). This paper provided the first structural analysis of an HLA-DQ molecule, HLA-DQ8. The structure was of HLA-DQ8 in complex with a peptide derived from human insulin (a candidate autoantigen in type 1 diabetes).
Latek, R. R. et al. Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. Immunity 12, 699–710 (2000).
Corper, A. L. et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288, 505–511 (2000).
Fremont, D. H., Hendrickson, W. A., Marrack, P. & Kappler, J. Structures of an MHC class II molecule with covalently bound single peptides. Science 272, 1001–1004 (1996).
Yamagata, K. et al. Aspartic acid at position 57 of DQ β chain does not protect against type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 32, 762–764 (1989).
Awata, T., Kuzuya, T., Matsuda, A., Iwamoto, Y. & Kanazawa, Y. Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 35, 419–424 (1992).
Zhu, Y., Rudensky, A. Y., Corper, A. L., Teyton, L. & Wilson, I. A. Crystal structure of MHC class II I-Ab in complex with a human CLIP peptide: prediction of an I-Ab peptide-binding motif. J. Mol. Biol. 326, 1157–1174 (2003).
Ettinger, R. A. & Kwok, W. W. A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. J. Immunol. 160, 2365–2373 (1998).
Qiao, S. W. et al. Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation. J. Immunol. 175, 254–261 (2005).
Arentz-Hansen, H. et al. The intestinal T cell response to α-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J. Exp. Med. 191, 603–612 (2000).
Lee, D. M. & Weinblatt, M. E. Rheumatoid arthritis. Lancet 358, 903–911 (2001).
Stastny, P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N. Engl. J. Med. 298, 869–871 (1978).
Wordsworth, B. P. et al. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc. Natl Acad. Sci. USA 86, 10049–10053 (1989).
Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).
Hammer, J. et al. Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association. J. Exp. Med. 181, 1847–1855 (1995).
Van Boxel, J. A. & Paget, S. A. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N. Engl. J. Med. 293, 517–520 (1975).
Andersson, E. C. et al. Definition of MHC and T cell receptor contacts in the HLA-DR4-restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice. Proc. Natl Acad. Sci. USA 95, 7574–7579 (1998).
Rosloniec, E. F. et al. An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen. J. Exp. Med. 185, 1113–1122 (1997).
Kremer, J. M. et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N. Engl. J. Med. 349, 1907–1915 (2003).
Fugger, L., Rothbard, J. B. & Sonderstrup-McDevitt, G. Specificity of an HLA-DRB1*0401-restricted T cell response to type II collagen. Eur. J. Immunol. 26, 928–933 (1996).
Svendsen, P. et al. Tracking of proinflammatory collagen-specific T cells in early and late collagen-induced arthritis in humanized mice. J. Immunol. 173, 7037–7045 (2004).
Latham, K. A., Whittington, K. B., Zhou, R., Qian, Z. & Rosloniec, E. F. Ex vivo characterization of the autoimmune T cell response in the HLA-DR1 mouse model of collagen-induced arthritis reveals long-term activation of type II collagen-specific cells and their presence in arthritic joints. J. Immunol. 174, 3978–3985 (2005).
Dessen, A., Lawrence, C. M., Cupo, S., Zaller, D. M. & Wiley, D. C. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity 7, 473–481 (1997). The structural analysis of the rheumatoid-arthritis-associated molecule HLA-DR4 revealed a peptide-binding groove that is well suited to binding the glycine-rich peptides derived from type II collagen. The structure showed that a sequence common to all the main rheumatoid-arthritis-associated MHC class II molecules allows negatively charged P4 residues to be accommodated.
Hill, J. A. et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541 (2003).
Marshall, K. et al. Prediction of peptide affinity to HLA-DRB1*0401. J. Immunol. 154, 5927–5933 (1995).
Hennecke, J. & Wiley, D. C. Structure of a complex of the human α/β T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity. J. Exp. Med. 195, 571–581 (2002).
Hammer, J., Takacs, B. & Sinigaglia, F. Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J. Exp. Med. 176, 1007–1013 (1992).
Wucherpfennig, K. W. et al. Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris. Proc. Natl Acad. Sci. USA 92, 11935–11939 (1995).
Keegan, B. M. & Noseworthy, J. H. Multiple sclerosis. Annu. Rev. Med. 53, 285–302 (2002).
Fogdell, A., Hillert, J., Sachs, C. & Olerup, O. The multiple sclerosis- and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 46, 333–336 (1995).
Oksenberg, J. R. et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am. J. Hum. Genet. 74, 160–167 (2004).
Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).
Oksenberg, J. R. et al. Selection for T-cell receptor Vβ-Dβ-Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 362, 68–70 (1993).
Krogsgaard, M. et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85–99 complex. J. Exp. Med. 191, 1395–1412 (2000).
Madsen, L. S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Genet. 23, 343–347 (1999).
Lang, H. L. et al. A functional and structural basis for TCR crossreactivity in multiple sclerosis. Nature Immunol. 3, 940–943 (2002). The structure of HLA-DR2a, in complex with a peptide derived from EBV, was compared with the structure of HLA-DR2b in complex with the immunodominant epitope from MBP, revealing a clear example of molecular mimicry. These complexes stimulate crossreactive T cells.
Wucherpfennig, K. W. et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J. Exp. Med. 179, 279–290 (1994).
Vogt, A. B. et al. Ligand motifs of HLA-DRB5*0101 and DRB1*1501 molecules delineated from self-peptides. J. Immunol. 153, 1665–1673 (1994).
Hahn, M., Nicholson, M. J., Pyrdol, J. & Wucherpfennig, K. W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nature Immunol. 6, 490–496 (2005).
Li, Y. et al. Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule. EMBO J. 24, 2968–2979 (2005).
Maynard, J. et al. Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 22, 81–92 (2005).
Bornstein, M. B. et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N. Engl. J. Med. 317, 408–414 (1987).
Stern, J. N. et al. Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 102, 1620–1625 (2005).
Stuart, D. I., Levine, M., Muirhead, H. & Stammers, D. K. Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 Å. J. Mol. Biol. 134, 109–142 (1979).
We thank R. Esnouf for discussion. Work in the authors' laboratories is supported by the Danish and British Medical Research Councils, Cancer Research UK, the Karen Elise Jensen Foundation, the Lundbeck Foundation, the Danish Multiple Sclerosis Society, the European Commission Integrated Programme SPINE (Structural Proteomics in Europe) and the European Commission Descartes Prize. E.Y.J. is a Cancer Research UK Principal Research Fellow.
The authors declare no competing financial interests.
- Linkage disequilibrium
Two genetic factors are in linkage disequilibrium when the frequency with which they occur together in a population departs from random expectation, as calculated by the product of their individual frequencies.
Peptide ligands of most MHC molecules are anchored into the binding groove by specific binding to particular pockets in the groove. Each MHC molecule has specificity for two or three anchors.
The modification of glutamine to glutamic acid, or asparagine to aspartic acid. The amine group (NH2) of the side chain is replaced by a hydroxyl group (OH) resulting in a negatively charged amino acid.
- Alanine-scanning analyses
Each residue of the peptide is separately substituted by alanine and the effect on T-cell receptor stimulation and binding by MHC class II molecules is assayed.
About this article
Molecular polymorphism and expression of MHC I α, II α, II β and II invariant chain in the critically endangered Dabry's sturgeon (Acipenser dabryanus)
Developmental & Comparative Immunology (2020)
MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells
Transcriptome analysis revealed potential mechanisms of differences in physiological stress responses between caged male and female magpies
BMC Genomics (2019)
Identification of HLA-DRB1*04:10 allele as risk allele for Japanese moyamoya disease and its association with autoimmune thyroid disease: A case-control study
PLOS ONE (2019)
Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese
Journal of Neuroinflammation (2019)