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HLA and kidney disease: from associations to mechanisms

Nature Reviews Nephrology volume 14, pages 636–655 (2018)Cite this article

Subjects

Abstract

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.

Key points

  • The HLA, which is the most polymorphic region of the human genome, is associated with various kidney diseases; some of these diseases are immune-mediated whereas in others the pathogenesis is uncertain or the relevance of HLA is less clear.

  • Advances in molecular techniques and the use of model systems have helped define the mechanistic basis of HLA associations and in some instances have epistatically linked HLA to other genes.

  • The characteristics of some renal diseases potentially enable them to serve as archetypes for the study of HLA associations in other conditions.

  • Exactly how HLA facilitates the development of immune kidney diseases at the level of HLA–peptide–T cell receptor interactions is a fundamental research question; mechanistic insights will have clear translational implications for the development of more targeted therapies.

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Fig. 1: Basic biology of HLA.
Fig. 2: Sites of actions of HLA class I and II within the immune system in autoimmune and renal disease.
Fig. 3: Sites of actions of HLA class II within the kidney.
Fig. 4: Mechanisms of HLA-mediated risk and protection.

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Acknowledgements

The authors acknowledge funding support from the National Health and Medical Research Council of Australia (NHMRC; 1104422, 1084869 and 1128267) to A.R.K. and S.R.H., from NHMRC (1115805) for A.R.K. as a member of the European Union RELENT (RELapses prevENTion in chronic autoimmune disease) consortium, and for the NHMRC Centre for Research Excellence, the Centre for Personalised Immunology (1079648). J.R. is supported by an Australian Research Council Laureate Fellowship. K.J.R. is supported by an NHMRC Medical/Dental Postgraduate Research Scholarship (1150684) and the Royal Australasian College of Physicians.

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Nature Reviews Nephrology thanks A. Rees, M.H. Zhao and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

    Kate J. Robson, Joshua D. Ooi, Stephen R. Holdsworth & A. Richard Kitching

  2. Department of Nephrology, Monash Health, Clayton, Victoria, Australia

    Kate J. Robson, Stephen R. Holdsworth & A. Richard Kitching

  3. Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Jamie Rossjohn

  4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia

    Jamie Rossjohn

  5. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK

    Jamie Rossjohn

  6. NHMRC Centre for Personalised Immunology, Monash University, Clayton, Victoria, Australia

    A. Richard Kitching

  7. Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia

    A. Richard Kitching

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K.J.R. and A.R.K. conducted literature searches, researched data and selected relevant articles; K.J.R., J.D.O. and A.R.K. planned the format of the article; K.J.R., J.D.O., S.R.H., J.R. and A.R.K. wrote the article; and K.J.R. and A.R.K. reviewed, edited and finalized the article for submission.

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Related links

GWAS catalogue: https://www.ebi.ac.uk/gwas/

HLA alleles, proteins and nomenclature: http://hla.alleles.org

Immune Epitope Database: http://www.iedb.org/

IPD-IMGT/HLA database: https://www.ebi.ac.uk/ipd/imgt/hla/

PheWAS resources: https://phewascatalog.org/

The Systemic Atlas: https://systemhcatlas.org

Supplementary information

Glossary

Self-peptides

Peptides derived from endogenous (host) proteins that are often displayed on HLA class I and II.

CD8+ T cells

T cells that recognize peptide–HLA class I complexes. When activated, they can induce target cell death and produce pro-inflammatory cytokines.

CD4+ T cells

T cells that recognize peptide–HLA class II complexes. They direct immune responses as T helper cells or maintain tolerance and regulate responses as Treg cells.

Non-self-peptides

Peptides derived from foreign proteins, such as microbial pathogens, that are often displayed on HLA class I and II.

Polymorphisms

A polymorphism is a DNA sequence variation within an allele that can result in a different gene product.

Haplotype

A group of alleles on the same chromosome that are commonly inherited as a unit.

Linkage disequilibrium

The non-random association of alleles at two different loci, such that the observed population frequency of the allele combination exceeds that expected by chance.

8.1 ancestral haplotype

Also known as the HLA-A1-B8-DR3-DQ2 haplotype, the 8.1 ancestral haplotype is common in European populations, most likely owing to common ancestral descent inherited in linkage disequilibrium.

Clonotypic

In the context of the TCR, a clonotype describes the unique combination of nucleotide sequences that exists after gene rearrangement.

Allomorph

The unique HLA molecule arising from one (class I) or two (class II) particular alleles.

Variable domain

The αβ TCR is made up of α and β-chains each with constant and variable domains. With genetic recombination, the variable domain is highly diverse, ensuring a very broad repertoire of different TCRs.

T cell cross reactivity

The capacity of a T cell, via its TCR, to recognize more than one peptide–MHC complex.

Alloreactivity

Cellular or humoral reactivity to antigens (for example, HLA) not present in the particular individual but expressed by other individuals of the species.

Biased TCR usage

A phenomenon whereby, despite the diversity of the TCR repertoire, there is preferential use of a limited number of TCRs in an immune response.

Dominantly protective allele

An HLA allele that confers protection from the specified disease even in the presence of a co-inherited risk allele.

Epitope spreading

The broadening of an immune response involving reactivity not only to the initial focused epitope but also to other epitopes on the same or a different protein.

Peptide-binding register

The particular amino acid sequence of a peptide that binds to the peptide-binding groove of the MHC.

Immunodominant peptide epitopes

T cell responses are usually specific for one or only a few epitopes within a particular antigen, referred to as immunodominant.

Epitope capture

A process whereby a high-affinity peptide that binds to one HLA molecule preferentially, effectively limits the binding to another HLA allomorph with a lower affinity for the same or a similar peptide.

Shared epitope

Refers to a sequence motif at amino acids 70–74 of the HLA-DR chain that is shared by HLA alleles implicated in rheumatoid arthritis and found in the majority of individuals with this disease.

Citrullination

The post-translational modification of proteins via the conversion of arginine to citrulline. Reactivity to these altered self-proteins is common in rheumatoid arthritis.

Epistasis

Interactions between different genetic loci that potentially affect phenotype in health or disease.

Molecular mimicry

A phenomenon whereby a pathogen-derived peptide sufficiently similar to a self-peptide can induce loss of tolerance.

Type B adverse drug reactions

(ADRs). Type B ADRs are less common than type A ADRs, tend to be idiosyncratic and unpredictable and are often immune-mediated.

DNASTAR Jameson–Wolf method

A computer algorithm that uses a primary amino acid sequence to predict the structural features of a protein and its potential antigenic determinants.

Phenome-wide association study

(PheWAS). A study that examines the effects of one or a limited number of genetic variants in multiple phenotypes.

Type A ADRs

Type A ADRs can be predicted on the basis of the drug’s pharmacological properties and mechanism of action.

Delayed type hypersensitivity

A cell-mediated effector immune response, occurring 24 hours to several days after antigen re-exposure.

Haptenation

The process whereby a small molecule (hapten) such as a drug or drug metabolite binds covalently to an endogenous peptide or protein that is itself not usually antigenic. The resultant complex can elicit an immune response.

P-i concept

The p-i (or ‘pharmacological interaction with immune receptors’) concept describes a non-covalent, reversible interaction between a drug and the MHC at the surface of an immune cell.

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Robson, K.J., Ooi, J.D., Holdsworth, S.R. et al. HLA and kidney disease: from associations to mechanisms. Nat Rev Nephrol 14, 636–655 (2018). https://doi.org/10.1038/s41581-018-0057-8

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