MHC class II proteins and disease: a structural perspective

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Abstract

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.

Key Points

  • 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.

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Figure 1: Mining the structural database.
Figure 2: Structural characteristics of HLA-DQ6.2 that are associated with narcolepsy.
Figure 3: Structural characteristics of HLA-DQ2 that are associated with coeliac disease.
Figure 4: Binding pockets that are implicated in type 1 diabetes.
Figure 5: HLA-DR1 and HLA-DR4.1: structural characteristics associated with rheumatoid arthritis.
Figure 6: Structural characteristics of HLA-DR2 molecules that are associated with multiple sclerosis.

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Acknowledgements

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.

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Correspondence to E. Yvonne Jones or Lars Fugger.

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DATABASES

OMIM

Coeliac disease

multiple sclerosis

narcolepsy

rheumatoid arthritis

type 1 diabetes

FURTHER INFORMATION

E. Yvonne Jones's laboratory

RCSB Protein Data Bank

Glossary

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.

Anchor

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.

Deamidation

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.

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