Associations of Human Leukocyte Antigens with Autoimmune Diseases: Challenges in Identifying the Mechanism

Overview

Journal J Hum Genet

Specialty Genetics

Date 2015 Aug 21

PMID 26290149

Citations 32

Authors

Hiroko Miyadera

Katsushi Tokunaga

Affiliations

Soon will be listed here.

Abstract

The mechanism of genetic associations between human leukocyte antigen (HLA) and susceptibility to autoimmune disorders has remained elusive for most of the diseases, including rheumatoid arthritis (RA) and type 1 diabetes (T1D), for which both the genetic associations and pathogenic mechanisms have been extensively analyzed. In this review, we summarize what are currently known about the mechanisms of HLA associations with RA and T1D, and elucidate the potential mechanistic basis of the HLA-autoimmunity associations. In RA, the established association between the shared epitope (SE) and RA risk has been explained, at least in part, by the involvement of SE in the presentation of citrullinated peptides, as confirmed by the structural analysis of DR4-citrullinated peptide complex. Self-peptide(s) that might explain the predispositions of variants at 11β and 13β in DRB1 to RA risk have not currently been identified. Regarding the mechanism of T1D, pancreatic self-peptides that are presented weakly on the susceptible HLA allele products are recognized by self-reactive T cells. Other studies have revealed that DQ proteins encoded by the T1D susceptible DQ haplotypes are intrinsically unstable. These findings indicate that the T1D susceptible DQ haplotypes might confer risk for T1D by facilitating the formation of unstable HLA-self-peptide complex. The studies of RA and T1D reveal the two distinct mechanistic basis that might operate in the HLA-autoimmunity associations. Combination of these mechanisms, together with other functional variations among the DR and DQ alleles, may generate the complex patterns of DR-DQ haplotype associations with autoimmunity.

Citing Articles

The Limitation of HLA Diversity as a Risk Factor for Pediatric-Onset Autoimmune Rheumatic Disease.

Kalampokis I, Wong C, Ma J, Smith L, Masten B, Chabot-Richards D J Clin Med. 2025; 14(3).

PMID: 39941587 PMC: 11818087. DOI: 10.3390/jcm14030916.

Identification of Endometriosis Pathophysiologic-Related Genes Based on Meta-Analysis and Bayesian Approach.

Kang J, Ahn K, Oh J, Lee T, Hwang S, Uh Y Int J Mol Sci. 2025; 26(1.

PMID: 39796277 PMC: 11720405. DOI: 10.3390/ijms26010424.

Asymmetrical Damage of the Wrist Joint Induces Lateralized Cortical Bone Loss in the Metacarpal Diaphysis in Patients with Rheumatoid Arthritis.

Nakashima A, Fujii H, Kuroda M, Zoshima T, Mizushima I, Nomura H J Clin Med. 2025; 13(24.

PMID: 39768575 PMC: 11676186. DOI: 10.3390/jcm13247652.

Fifty years of HLA-associated type 1 diabetes risk: history, current knowledge, and future directions.

Noble J Front Immunol. 2024; 15:1457213.

PMID: 39328411 PMC: 11424550. DOI: 10.3389/fimmu.2024.1457213.

Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region.

Smith C, Strausz S, Spence J, Ollila H, Pritchard J medRxiv. 2024; .

PMID: 39132491 PMC: 11312630. DOI: 10.1101/2024.07.29.24311183.

References

Mackie S, Taylor J, Martin S, Wordsworth P, Steer S, Wilson A . A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population. Genes Immun. 2011; 13(2):120-8. DOI: 10.1038/gene.2011.60. View

Dessen A, Lawrence C, Cupo S, Zaller D, Wiley D . X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity. 1997; 7(4):473-81. DOI: 10.1016/s1074-7613(00)80369-6. View

Deng H, Apple R, Clare-Salzler M, Trembleau S, Mathis D, Adorini L . Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease. J Exp Med. 1993; 178(5):1675-80. PMC: 2191262. DOI: 10.1084/jem.178.5.1675. View

Auger I, Toussirot E, Roudier J . Molecular mechanisms involved in the association of HLA-DR4 and rheumatoid arthritis. Immunol Res. 1997; 16(1):121-6. DOI: 10.1007/BF02786328. View

Lee K, Wucherpfennig K, Wiley D . Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol. 2001; 2(6):501-7. DOI: 10.1038/88694. View

Morgan A, Thomson W, Martin S, Carter A, Erlich H, Barton A . Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population. Arthritis Rheum. 2009; 60(9):2565-76. DOI: 10.1002/art.24752. View

Nepom G . A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes. 1990; 39(10):1153-7. DOI: 10.2337/diab.39.10.1153. View

Stadinski B, Delong T, Reisdorph N, Reisdorph R, Powell R, Armstrong M . Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010; 11(3):225-31. PMC: 3166626. DOI: 10.1038/ni.1844. View

Yang J, Chow I, Sosinowski T, Torres-Chinn N, Greenbaum C, James E . Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc Natl Acad Sci U S A. 2014; 111(41):14840-5. PMC: 4205657. DOI: 10.1073/pnas.1416864111. View

10.

Walk T, Otto H, Jung G, Bach J, van Endert P, Caillat-Zucman S . Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes. Diabetes. 1999; 48(10):1937-47. DOI: 10.2337/diabetes.48.10.1937. View

11.

Latek R, Suri A, Petzold S, Nelson C, Kanagawa O, UNANUE E . Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. Immunity. 2000; 12(6):699-710. DOI: 10.1016/s1074-7613(00)80220-4. View

12.

Okada Y, Kim K, Han B, Pillai N, Ong R, Saw W . Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum Mol Genet. 2014; 23(25):6916-26. PMC: 4245039. DOI: 10.1093/hmg/ddu387. View

13.

Morel P, Dorman J, Todd J, McDevitt H, Trucco M . Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988; 85(21):8111-5. PMC: 282365. DOI: 10.1073/pnas.85.21.8111. View

14.

Ohnishi Y, Tsutsumi A, Sakamaki T, Sumida T . T cell epitopes of type II collagen in HLA-DRB1*0101 or DRB1*0405-positive Japanese patients with rheumatoid arthritis. Int J Mol Med. 2003; 11(3):331-5. View

15.

Diab B, Lambert N, LFaqihi F, de Preval C, Coppin H . Human collagen II peptide 256-271 preferentially binds to HLA-DR molecules associated with susceptibility to rheumatoid arthritis. Immunogenetics. 1998; 49(1):36-44. DOI: 10.1007/s002510050461. View

16.

Raychaudhuri S, Sandor C, Stahl E, Freudenberg J, Lee H, Jia X . Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012; 44(3):291-6. PMC: 3288335. DOI: 10.1038/ng.1076. View

17.

Trembleau S, Hoffmann M, Meyer B, Nell V, Radner H, Zauner W . Immunodominant T-cell epitopes of hnRNP-A2 associated with disease activity in patients with rheumatoid arthritis. Eur J Immunol. 2010; 40(6):1795-808. DOI: 10.1002/eji.200939482. View

18.

Crawford F, Stadinski B, Jin N, Michels A, Nakayama M, Pratt P . Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci U S A. 2011; 108(40):16729-34. PMC: 3189014. DOI: 10.1073/pnas.1113954108. View

19.

Hill J, Southwood S, Sette A, Jevnikar A, Bell D, Cairns E . 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. 2003; 171(2):538-41. DOI: 10.4049/jimmunol.171.2.538. View

20.

Hashimoto K, Maruyama H, Nishiyama M, Asaba K, Ikeda Y, Takao T . Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population. Horm Res. 2005; 64(5):253-60. DOI: 10.1159/000089293. View