Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

HLA and kidney disease: from associations to mechanisms

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Cooper, G. S., Bynum, M. L. & Somers, E. C. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun. 33, 197–207 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  2. Goodnow, C. C. Multistep pathogenesis of autoimmune disease. Cell 130, 25–35 (2007).

    CAS  Article  PubMed  Google Scholar 

  3. Dendrou, C. A., Petersen, J., Rossjohn, J. & Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 18, 325–339 (2018).

    CAS  Article  PubMed  Google Scholar 

  4. Yang, J. Y. & Sarwal, M. M. Transplant genetics and genomics. Nat. Rev. Genet. 18, 309–326 (2017).

    CAS  Article  PubMed  Google Scholar 

  5. DeWolf, S. & Sykes, M. Alloimmune T cells in transplantation. J. Clin. Invest. 127, 2473–2481 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  6. Kransdorf, E. P., Pando, M. J., Gragert, L. & Kaplan, B. HLA population genetics in solid organ transplantation. Transplantation 101, 1971–1976 (2017).

    Article  PubMed  Google Scholar 

  7. Chaplin, D. D. & Kemp, M. E. The major histocompatibility complex and autoimmunity. Year Immunol. 3, 179–198 (1988).

    CAS  PubMed  Google Scholar 

  8. Price, P. et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol. Rev. 167, 257–274 (1999).

    CAS  Article  PubMed  Google Scholar 

  9. Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).

    CAS  Article  PubMed  Google Scholar 

  10. Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).

    CAS  Article  Google Scholar 

  11. Ooi, J. D. et al. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545, 243–247 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Davis, M. M. & Bjorkman, P. J. T cell antigen receptor genes and T cell recognition. Nature 334, 395–402 (1988).

    CAS  Article  PubMed  Google Scholar 

  13. Patel, R., Mickey, M. R. & Terasaki, P. I. Leucocyte antigens and disease. I. Association of HLA2 and chronic glomerulonephritis. BMJ 2, 424–426 (1969).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Marsh, S. G. et al. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75, 291–455 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Holdsworth, S. R., Gan, P. Y. & Kitching, A. R. Biologics for the treatment of autoimmune renal diseases. Nat. Rev. Nephrol. 12, 217–231 (2016).

    CAS  Article  PubMed  Google Scholar 

  16. Phelps, R. G. & Rees, A. J. The HLA complex in Goodpasture’s disease: a model for analyzing susceptibility to autoimmunity. Kidney Int. 56, 1638–1653 (1999).

    CAS  Article  PubMed  Google Scholar 

  17. Kitagawa, W. et al. The HLA-DRB1 1501 allele is prevalent among Japanese patients with anti-glomerular basement membrane antibody-mediated disease. Nephrol. Dial. Transplant. 23, 3126–3129 (2008).

    CAS  Article  PubMed  Google Scholar 

  18. Yang, R., Cui, Z., Zhao, J. & Zhao, M. H. The role of HLA-DRB1 alleles on susceptibility of Chinese patients with anti-GBM disease. Clin. Immunol. 133, 245–250 (2009).

    CAS  Article  PubMed  Google Scholar 

  19. Cui, Z. et al. MHC class II risk alleles and amino acid residues in idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 28, 1651–1664 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Le, W. B. et al. HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-related membranous nephropathy. J. Am. Soc. Nephrol. 28, 1642–1650 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Sekula, P. et al. Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies. Nephrol. Dial. Transplant. 32, 325–332 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Stanescu, H. C. et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N. Eng. J. Med. 364, 616–626 (2011).

    CAS  Article  Google Scholar 

  23. Summers, S. A. et al. TH1 and TH17 cells induce proliferative glomerulonephritis. J. Am. Soc. Nephrol. 20, 2518–2524 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Westhorpe, C. L. V. et al. Effector CD4(+) T cells recognize intravascular antigen presented by patrolling monocytes. Nat. Commun. 9, 747 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Chang, J. et al. CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN. J. Am. Soc. Nephrol. 28, 47–55 (2017).

    CAS  Article  PubMed  Google Scholar 

  26. Kruger, T. et al. Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J. Am. Soc. Nephrol. 15, 613–621 (2004).

    Article  PubMed  Google Scholar 

  27. Soos, T. J. et al. CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int. 70, 591–596 (2006).

    CAS  Article  PubMed  Google Scholar 

  28. Tucci, M. et al. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 58, 251–262 (2008).

    CAS  Article  PubMed  Google Scholar 

  29. Muller, C. A., Markovic-Lipkovski, J., Risler, T., Bohle, A. & Muller, G. A. Expression of HLA-DQ, -DR, and -DP antigens in normal kidney and glomerulonephritis. Kidney Int. 35, 116–124 (1989).

    CAS  Article  PubMed  Google Scholar 

  30. Goldwich, A. et al. Podocytes are nonhematopoietic professional antigen-presenting cells. J. Am. Soc. Nephrol. 24, 906–916 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Steinmetz, O. M. et al. Analysis and classification of B cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 74, 448–457 (2008).

    CAS  Article  PubMed  Google Scholar 

  32. Giles, J. R., Kashgarian, M., Koni, P. A. & Shlomchik, M. J. B. Cell-specific MHC class II deletion reveals multiple nonredundant roles for B cell antigen presentation in murine lupus. J. Immunol. 195, 2571–2579 (2015).

    CAS  PubMed  Article  Google Scholar 

  33. Hall, B. M. et al. Increased expression of HLA-DR antigens on renal tubular cells in renal transplants: relevance to the rejection response. Lancet 2, 247–251 (1984).

    CAS  Article  PubMed  Google Scholar 

  34. Alexopoulos, E., Seron, D., Hartley, R. B. & Cameron, J. S. Lupus nephritis: correlation of interstitial cells with glomerular function. Kidney Int. 37, 100–109 (1990).

    CAS  Article  PubMed  Google Scholar 

  35. Wilkinson, R., Wang, X., Roper, K. E. & Healy, H. Activated human renal tubular cells inhibit autologous immune responses. Nephrol. Dial. Transplant. 26, 1483–1492 (2011).

    CAS  Article  PubMed  Google Scholar 

  36. Todd, J. A. et al. A molecular basis for MHC class II — associated autoimmunity. Science 240, 1003–1009 (1988).

    CAS  Article  PubMed  Google Scholar 

  37. Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Pociot, F. & Lernmark, A. Genetic risk factors for type 1 diabetes. Lancet 387, 2331–2339 (2016).

    CAS  Article  PubMed  Google Scholar 

  39. Raj, P. et al. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. eLife 5, e12089 (2016).

  40. Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Harkiolaki, M. et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 30, 348–357 (2009).

    CAS  Article  PubMed  Google Scholar 

  42. Hudson, B. G., Tryggvason, K., Sundaramoorthy, M. & Neilson, E. G. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N. Engl. J. Med. 348, 2543–2556 (2003).

    CAS  Article  PubMed  Google Scholar 

  43. Rich, C. et al. Myelin oligodendrocyte glycoprotein-35-55 peptide induces severe chronic experimental autoimmune encephalomyelitis in HLA-DR2-transgenic mice. Eur. J. Immunol. 34, 1251–1261 (2004).

    CAS  Article  PubMed  Google Scholar 

  44. Ooi, J. D. et al. The HLA-DRB1*15:01-restricted Goodpasture’s T cell epitope induces GN. J. Am. Soc. Nephrol. 24, 419–431 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Cairns, L. S. et al. The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture’s disease. J. Am. Soc. Nephrol. 14, 2801–2812 (2003).

    CAS  Article  PubMed  Google Scholar 

  46. Tsai, S. et al. Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells. Proc. Natl Acad. Sci. USA 110, 3471–3476 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Koning, F., Thomas, R., Rossjohn, J. & Toes, R. E. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat. Rev. Rheumatol. 11, 450–461 (2015).

    CAS  Article  PubMed  Google Scholar 

  48. Gregersen, J. W. et al. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443, 574–577 (2006).

    CAS  Article  PubMed  Google Scholar 

  49. Illing, P. T. et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486, 554–558 (2012).

    CAS  Article  PubMed  Google Scholar 

  50. Netzer, K. O. et al. The goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17–31 and 127–141 of the NC1 domain. J. Biol. Chem. 274, 11267–11274 (1999).

    CAS  Article  PubMed  Google Scholar 

  51. Rees, A. J., Peters, D. K., Compston, D. A. & Batchelor, J. R. Strong association between HLA-DRW2 and antibody-mediated Goodpasture’s syndrome. Lancet 1, 966–968 (1978).

    CAS  Article  PubMed  Google Scholar 

  52. Fisher, M., Pusey, C. D., Vaughan, R. W. & Rees, A. J. Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes. Kidney Int. 51, 222–229 (1997).

    CAS  Article  PubMed  Google Scholar 

  53. Dunckley, H. et al. HLA-DR and -DQ genotyping in anti-GBM disease. Dis. Markers 9, 249–256 (1991).

    CAS  PubMed  Google Scholar 

  54. Huey, B. et al. Associations of HLA-DR and HLA-DQ types with anti-GBM nephritis by sequence-specific oligonucleotide probe hybridization. Kidney Int. 44, 307–312 (1993).

    CAS  Article  PubMed  Google Scholar 

  55. Mercier, B. et al. HLA class II typing of Goodpasture’s syndrome affected patients. J. Am. Soc. Nephrol. 3, 658 (1992).

    Google Scholar 

  56. Luo, H. et al. The association of HLA-DQB1, -DQA1 and -DPB1 alleles with anti- glomerular basement membrane (GBM) disease in Chinese patients. BMC Nephrol. 12, 21 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  57. Xie, L. J. et al. The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture’s disease. Immunology 151, 395–404 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. McAdoo, S. P. et al. Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients. Kidney Int. 92, 693–702 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Jayne, D. R., Marshall, P. D., Jones, S. J. & Lockwood, C. M. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int. 37, 965–970 (1990).

    CAS  Article  PubMed  Google Scholar 

  60. Beck, L. H. Jr et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Hofstra, J. M., Beck, L. H. Jr, Beck, D. M., Wetzels, J. F. & Salant, D. J. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin. J. Am. Soc. Nephrol. 6, 1286–1291 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Tomas, N. M. et al. Thrombospondin type1 domain-containing 7A in idiopathic membranous nephropathy. N. Engl. J. Med. 371, 2277–2287 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Klouda, P. T. et al. Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet 2, 770–771 (1979).

    CAS  Article  PubMed  Google Scholar 

  64. Le Petit, J. C., Laurent, B. & Berthoux, F. C. HLA-DR3 and idiopathic membranous nephritis (IMN) association. Tissue Antigens 20, 227–228 (1982).

    Article  PubMed  Google Scholar 

  65. Muller, G. A. et al. Strong association of idiopathic membranous nephropathy (IMN) with HLA-DR 3 and MT-2 without involvement of HLA-B 18 and no association to BfF1. Tissue Antigens 17, 332–337 (1981).

    CAS  Article  PubMed  Google Scholar 

  66. Vaughan, R. W., Demaine, A. G. & Welsh, K. I. A. DQA1 allele is strongly associated with idiopathic membranous nephropathy. Tissue Antigens 34, 261–269 (1989).

    CAS  Article  PubMed  Google Scholar 

  67. Lv, J. et al. Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy. J. Am. Soc. Nephrol. 24, 1323–1329 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Bullich, G. et al. HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy. Clin. J. Am. Soc. Nephrol. 9, 335–343 (2014).

    CAS  Article  PubMed  Google Scholar 

  69. Saeed, M., Beggs, M. L., Walker, P. D. & Larsen, C. P. PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes. Genes Immun. 15, 556–561 (2014).

    CAS  Article  PubMed  Google Scholar 

  70. Ramachandran, R. et al. PLA2R antibodies, glomerular PLA2R deposits and variations in PLA2R1 and HLA-DQA1 genes in primary membranous nephropathy in South Asians. Nephrol. Dial. Transplant. 31, 1486–1493 (2016).

    CAS  Article  PubMed  Google Scholar 

  71. Tomura, S. et al. Strong association of idiopathic membranous nephropathy with HLA-DR2 and MT1 in Japanese. Nephron 36, 242–245 (1984).

    CAS  Article  PubMed  Google Scholar 

  72. Hiki, Y., Kobayashi, Y., Itoh, I. & Kashiwagi, N. Strong association of HLA-DR2 and MT1 with idiopathic membranous nephropathy in Japan. Kidney Int. 25, 953–957 (1984).

    CAS  PubMed  Article  Google Scholar 

  73. Ogahara, S., Naito, S., Abe, K., Michinaga, I. & Arakawa, K. Analysis of HLA class II genes in Japanese patients with idiopathic membranous glomerulonephritis. Kidney Int. 41, 175–182 (1992).

    CAS  Article  PubMed  Google Scholar 

  74. Jennette, J. C. et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 65, 1–11 (2013).

    CAS  Article  PubMed  Google Scholar 

  75. Hilhorst, M., van Paassen, P. & Tervaert, J. W. Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J. Am. Soc. Nephrol. 26, 2314–2327 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Eng. J. Med. 367, 214–223 (2012).

    CAS  Article  Google Scholar 

  77. Murty, G. E., Mains, B. T., Middleton, D., Maxwell, A. P. & Savage, D. A. HLA antigen frequencies and Wegener’s granulomatosis. Clin. Otolaryngol. Allied Sci. 16, 448–451 (1991).

    CAS  Article  PubMed  Google Scholar 

  78. Papiha, S. S., Murty, G. E., Ad’Hia, A., Mains, B. T. & Venning, M. Association of Wegener’s granulomatosis with HLA antigens and other genetic markers. Ann. Rheum. Dis. 51, 246–248 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Heckmann, M. et al. The Wegener’s granulomatosis quantitative trait locus on chromosome 6p21.3 as characterised by tagSNP genotyping. Ann. Rheum. Dis. 67, 972–979 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. Hilhorst, M. et al. HLA-DPB1 as a risk factor for relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a cohort study. Arthritis Rheumatol. 68, 1721–1730 (2016).

    CAS  Article  PubMed  Google Scholar 

  81. Jagiello, P. et al. New genomic region for Wegener’s granulomatosis as revealed by an extended association screen with 202 apoptosis-related genes. Hum. Genet. 114, 468–477 (2004).

    CAS  Article  PubMed  Google Scholar 

  82. Xie, G. et al. Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 65, 2457–2468 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Merkel, P. A. et al. Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol. 69, 1054–1066 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Wu, Z. et al. HLA-DPB1 variant rs3117242 is associated with anti-neutrophil cytoplasmic antibody-associated vasculitides in a Han Chinese population. Int. J. Rheum. Dis. 20, 1009–1015 (2017).

    CAS  Article  PubMed  Google Scholar 

  85. Cao, Y. et al. DRB1 15 allele is a risk factor for PR3ANCA disease in African Americans. J. Am. Soc. Nephrol. 22, 1161–1167 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Kawasaki, A. et al. Protective role of HLA-DRB1 13:02 against microscopic polyangiitis and MPO-ANCA-positive vasculitides in a Japanese population: a case-control study. PLOS ONE 11, e0154393 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. Tsuchiya, N. Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1 09:01 haplotype. Clin. Exp. Nephrol. 17, 628–630 (2013).

    CAS  Article  PubMed  Google Scholar 

  88. Tsuchiya, N., Kobayashi, S., Hashimoto, H., Ozaki, S. & Tokunaga, K. Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese. Genes Immun. 7, 81–84 (2006).

    CAS  Article  PubMed  Google Scholar 

  89. Tsuchiya, N. et al. Genetic background of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: association of HLA-DRB1*0901 with microscopic polyangiitis. J. Rheumatol. 30, 1534–1540 (2003).

    CAS  PubMed  Google Scholar 

  90. Luo, H., Chen, M., Yang, R., Xu, P. C. & Zhao, M. H. The association of HLA-DRB1 alleles with antineutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese patients. Hum. Immunol. 72, 422–425 (2011).

    CAS  Article  PubMed  Google Scholar 

  91. Vaglio, A. et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum. 56, 3159–3166 (2007).

    CAS  Article  PubMed  Google Scholar 

  92. Wieczorek, S., Hellmich, B., Gross, W. L. & Epplen, J. T. Associations of Churg-Strauss syndrome with the HLA-DRB1 locus, and relationship to the genetics of antineutrophil cytoplasmic antibody-associated vasculitides: comment on the article by Vaglio et al. Arthritis Rheum. 58, 329–330 (2008).

    CAS  Article  PubMed  Google Scholar 

  93. Allen, A. C., Harper, S. J. & Feehally, J. Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy. Clin. Exp. Immunol. 100, 470–474 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Yu, H. H. et al. Genetics and immunopathogenesis of IgA nephropathy. Clin. Rev. Allergy Immunol. 41, 198–213 (2011).

    CAS  Article  PubMed  Google Scholar 

  95. Xie, J., Shapiro, S. & Gharavi, A. Genetic studies of IgA nephropathy: what have we learned from genome-wide association studies. Contribut. Nephrol. 181, 52–64 (2013).

    Article  Google Scholar 

  96. Feehally, J. & Barratt, J. The genetics of IgA nephropathy: an overview from western countries. Kidney Dis. 1, 33–41 (2015).

    Article  Google Scholar 

  97. Freedman, B. I., Spray, B. J. & Heise, E. R. HLA associations in IgA nephropathy and focal and segmental glomerulosclerosis. Am. J. Kidney Dis. 23, 352–357 (1994).

    CAS  Article  PubMed  Google Scholar 

  98. Berthoux, F. C. et al. HLA-Bw35 and mesangial IgA glomerulonephritis. N. Eng. J. Med. 298, 1034–1035 (1978).

    CAS  Google Scholar 

  99. Hiki, Y., Kobayashi, Y., Ookubo, M. & Kashiwagi, N. The role of HLA-DR4 in the long-term prognosis of IgA nephropathy. Nephron 54, 264–265 (1990).

    CAS  Article  PubMed  Google Scholar 

  100. Hiki, Y., Kobayashi, Y., Tateno, S., Sada, M. & Kashiwagi, N. Strong association of HLA-DR4 with benign IgA nephropathy. Nephron 32, 222–226 (1982).

    CAS  Article  PubMed  Google Scholar 

  101. Kasahara, M. et al. Role of HLA in IgA nephropathy. Clin. Immunol. Immunopathol. 25, 189–195 (1982).

    CAS  Article  PubMed  Google Scholar 

  102. Kashiwabara, H., Shishido, H., Tomura, S., Tuchida, H. & Miyajima, T. Strong association between IgA nephropathy and HLA-DR4 antigen. Kidney Int. 22, 377–382 (1982).

    CAS  Article  PubMed  Google Scholar 

  103. Naito, S., Kohara, M. & Arakawa, K. Association of class II antigens of HLA with primary glomerulopathies. Nephron 45, 111–114 (1987).

    CAS  Article  PubMed  Google Scholar 

  104. Abe, J., Kohsaka, T., Tanaka, M. & Kobayashi, N. Genetic study on HLA class II and class III region in the disease associated with IgA nephropathy. Nephron 65, 17–22 (1993).

    CAS  Article  PubMed  Google Scholar 

  105. Hiki, Y., Kobayashi, Y., Ookubo, M., Obata, F. & Kashiwagi, N. Association of HLA-DQw4 with IgA nephropathy in the Japanese population. Nephron 58, 109–111 (1991).

    CAS  Article  PubMed  Google Scholar 

  106. Feehally, J. et al. HLA has strongest association with IgA nephropathy in genome-wide analysis. J. Am. Soc. Nephrol. 21, 1791–1797 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Gharavi, A. G. et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat. Genet. 43, 321–327 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Kiryluk, K. et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat. Genet. 46, 1187–1196 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Yu, X. Q. et al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat. Genet. 44, 178–182 (2012).

    CAS  Article  Google Scholar 

  110. Raguenes, O., Mercier, B., Cledes, J., Whebe, B. & Ferec, C. HLA class II typing and idiopathic IgA nephropathy (IgAN): DQB1*0301, a possible marker of unfavorable outcome. Tissue Antigens 45, 246–249 (1995).

    CAS  Article  PubMed  Google Scholar 

  111. Peru, H. et al. HLA class 1 associations in Henoch Schonlein purpura: increased and decreased frequencies. Clin. Rheumatol. 27, 5–10 (2008).

    Article  PubMed  Google Scholar 

  112. Ren, S. M. et al. Association between HLAA and B polymorphisms and susceptibility to Henoch-Schonlein purpura in Han and Mongolian children from inner Mongolia. Gen. Mol. Res. 11, 221–228 (2012).

    CAS  Article  Google Scholar 

  113. Amoli, M. M. et al. HLA-DRB1 01 association with Henoch-Schonlein purpura in patients from northwest Spain. J. Rheumatol. 28, 1266–1270 (2001).

    CAS  PubMed  Google Scholar 

  114. Amoli, M. M. et al. Henoch-Schonlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations. J. Rheumatol. 29, 945–947 (2002).

    PubMed  Google Scholar 

  115. López-Mejías, R. et al. Brief Report: association of HLA–DRB1*01 With IgA Vasculitis (Henoch-Schönlein). Arthritis Rheumatol. 67, 823–827 (2015).

    Article  PubMed  Google Scholar 

  116. Amoroso, A. et al. Immunogenetics of Henoch-Schoenlein disease. Eur. J. Immunogenet. 24, 323–333 (1997).

    CAS  Article  PubMed  Google Scholar 

  117. Sun, C. et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat. Genet. 48, 323–330 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Graham, R. R. et al. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am. J. Hum. Genet. 71, 543–553 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Xu, R. et al. Association analysis of the MHC in lupus nephritis. J. Am. Soc. Nephrol. 28, 3383–3394 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. Fronek, Z. et al. Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus. Arthritis Rheum. 33, 1542–1553 (1990).

    CAS  Article  PubMed  Google Scholar 

  121. Bastian, H. M. et al. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus 11, 152–160 (2002).

    CAS  Article  PubMed  Google Scholar 

  122. Bastian, H. M. et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA) XL II: factors predictive of new or worsening proteinuria. Rheumatology 46, 683–689 (2007).

    CAS  Article  PubMed  Google Scholar 

  123. Marchini, M. et al. HLA class II antigens associated with lupus nephritis in Italian SLE patients. Hum. Immunol. 64, 462–468 (2003).

    CAS  Article  PubMed  Google Scholar 

  124. Wunnenburger, S. et al. Associations between genetic risk variants for kidney diseases and kidney disease etiology. Sci. Rep. 7, 13944 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Chung, S. A. et al. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J. Am. Soc. Nephrol. 25, 2859–2870 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Niu, Z., Zhang, P. & Tong, Y. Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: a meta-analysis. Int. J. Rheum. Dis. 18, 17–28 (2015).

    CAS  Article  PubMed  Google Scholar 

  127. Chowdhary, V. R. et al. A central role for HLA-DR3 in anti-Smith antibody responses and glomerulonephritis in a transgenic mouse model of spontaneous lupus. J. Immunol. 195, 4660–4667 (2015).

    CAS  PubMed  Article  Google Scholar 

  128. Janwityanuchit, S., Verasertniyom, O., Vanichapuntu, M. & Vatanasuk, M. Anti-Sm: its predictive value in systemic lupus erythematosus. Clin. Rheumatol. 12, 350–353 (1993).

    CAS  Article  PubMed  Google Scholar 

  129. Levinson, R. D. et al. Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest. Ophthal. Vis. Sci. 44, 653–657 (2003).

    Article  PubMed  Google Scholar 

  130. Mackensen, F. et al. HLA-DRB1 0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone. Br. J. Ophthalmol. 95, 971–975 (2011).

    CAS  Article  PubMed  Google Scholar 

  131. Perasaari, J. et al. HLA associations with tubulointerstitial nephritis with or without uveitis in Finnish pediatric population: a nation-wide study. Tissue Antigens 81, 435–441 (2013).

    CAS  Article  PubMed  Google Scholar 

  132. Matzaraki, V., Kumar, V., Wijmenga, C. & Zhernakova, A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 18, 76 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. Wilson, C. B. & Dixon, F. J. Quantitation of acute and chronic serum sickness in the rabbit. J. Exp. Med. 134, 7–18 (1971).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Vaughan, R. W., Zurowska, A., Moszkowska, G., Kondeatis, E. & Clark, A. G. HLA-DRB and -DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy. Tissue Antigens 52, 130–134 (1998).

    CAS  Article  PubMed  Google Scholar 

  135. Bhimma, R., Hammond, M. G., Coovadia, H. M., Adhikari, M. & Connolly, C. A. HLA class I and II in black children with hepatitis B virus-associated membranous nephropathy. Kidney Int. 61, 1510–1515 (2002).

    Article  PubMed  Google Scholar 

  136. Bhimma, R. et al. HLA associations with HBV carriage and proteinuria. Pediatr. Nephrol. 17, 724–729 (2002).

    Article  PubMed  Google Scholar 

  137. Park, M. H. et al. Two subtypes of hepatitis B virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans. Tissue Antigens 62, 505–511 (2003).

    CAS  Article  PubMed  Google Scholar 

  138. Adhikari, M., Coovadia, H. M. & Hammond, M. G. Associations between HLA antigens and nephrotic syndrome in African and Indian children in South Africa. Nephron 41, 289–292 (1985).

    CAS  Article  PubMed  Google Scholar 

  139. Hwang, S. J. et al. Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis C. Tissue Antigens 59, 31–37 (2002).

    CAS  Article  PubMed  Google Scholar 

  140. Zignego, A. L. et al. Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun. 15, 500–505 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Sasazuki, T., Hayase, R., Iwamoto, I. & Tsuchida, H. HLA and acute poststreptococcal glomerulonephritis. N. Eng. J. Med. 301, 1184–1185 (1979).

    CAS  Google Scholar 

  142. Bakr, A., Mahmoud, L. A., Al-Chenawi, F. & Salah, A. HLA-DRB1* alleles in Egyptian children with post-streptococcal acute glomerulonephritis. Pediatr. Nephrol. 22, 376–379 (2007).

    Article  PubMed  Google Scholar 

  143. Mori, K., Sasazuki, T., Kimura, A. & Ito, Y. HLA-DP antigens and post-streptococcal acute glomerulonephritis. Acta Paediatr. 85, 916–918 (1996).

    CAS  Article  PubMed  Google Scholar 

  144. Payen, D. et al. A multicentre study of acute kidney injury in severe sepsis and septic shock: association with inflammatory phenotype and HLA genotype. PLOS One 7, e35838 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Alfiler, C. A., Roy, L. P., Doran, T., Sheldon, A. & Bashir, H. HLA-DRw7 and steroid-responsive nephrotic syndrome of childhood. Clin. Nephrol. 14, 71–74 (1980).

    CAS  PubMed  Google Scholar 

  146. de Mouzon-Cambon, A., Ohayon, E., Bouissou, F. & Barthe, P. HLA-DR typing in children with glomerular diseases. Lancet 2, 868 (1980).

    Article  PubMed  Google Scholar 

  147. Nunez-Roldan, A., Villechenous, E., Fernandez-Andrade, C. & Martin-Govantes, J. Increased HLA-DR7 and decreased DR2 in steroid-responsive nephrotic syndrome. N. Eng. J. Med. 306, 366–367 (1982).

    CAS  Google Scholar 

  148. Konrad, M. et al. HLA class II associations with idiopathic nephrotic syndrome in children. Tissue Antigens 43, 275–280 (1994).

    CAS  Article  PubMed  Google Scholar 

  149. Clark, A. G. et al. Genes encoding the beta-chains of HLA-DR7 and HLA-DQw2 define major susceptibility determinants for idiopathic nephrotic syndrome. Clin. Sci. 78, 391–397 (1990).

    CAS  Article  Google Scholar 

  150. Gbadegesin, R. A. et al. HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1701–1710 (2015).

    CAS  Article  PubMed  Google Scholar 

  151. Karp, A. M. & Gbadegesin, R. A. Genetics of childhood steroid-sensitive nephrotic syndrome. Pediatr. Nephrol. 32, 1481–1488 (2017).

    Article  PubMed  Google Scholar 

  152. Fu, G., Chen, Y., Schuman, J., Wang, D. & Wen, R. Phospholipase Cγ2 plays a role in TCR signal transduction and T cell selection. J. Immunol. 89, 2326–2332 (2012).

    Article  CAS  Google Scholar 

  153. Coggeshall, K. M., McHugh, J. C. & Altman, A. Predominant expression and activation-induced tyrosine phosphorylation of phospholipase Cγ2 in B lymphocytes. Proc. Natl Acad. Sci. USA 89, 5660–5664 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. Wang, D. et al. Phospholipase Cγ2 is essential in the functions of B cell and several Fc receptors. Immunity 13, 25–35 (2000).

    Article  PubMed  Google Scholar 

  155. Zhou, Q. et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713–720 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Donadi, E. A., Voltarelli, J. C., Paula-Santos, C. M., Kimachi, T. & Ferraz, A. S. Association of Alport’s syndrome with HLA-DR2 antigen in a group of unrelated patients. Braz. J. Med. Biol. Res. 31, 533–537 (1998).

    CAS  Article  PubMed  Google Scholar 

  158. Barocci, S. et al. Alport syndrome: HLA association and kidney graft outcome. Eur. J. Immunogenet. 31, 115–119 (2004).

    CAS  Article  PubMed  Google Scholar 

  159. Jervell, J. & Solheim, B. HLA-antigens in long standing insulin dependent diabetics with terminal nephropathy and retinopathy with and without loss of vision. Diabetologia 17, 391 (1979).

    CAS  Article  PubMed  Google Scholar 

  160. Walton, C. et al. HLA antigens and risk factors for nephropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 27, 3–7 (1984).

    CAS  Article  PubMed  Google Scholar 

  161. Cordovado, S. K. et al. Nephropathy in type 1 diabetes is diminished in carriers of HLA-DRB1*04: the genetics of kidneys in diabetes (GoKinD) study. Diabetes 57, 518–522 (2008).

    CAS  Article  PubMed  Google Scholar 

  162. Lipner, E. M. et al. HLA class I and II alleles are associated with microvascular complications of type 1 diabetes. Hum. Immunol. 74, 538–544 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Karnes, J. H. et al. Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci. Transl Med. 9, eaai8708 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  164. Razanskaite-Virbickiene, D., Danyte, E. & Zalinkevicius, R. HLA-DRB1*03 as a risk factor for microalbuminuria in same duration of type 1 diabetes: a case control study. BMC Nephrol. 17, 38 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. Watts, G. F., Taub, N., Gant, V., Wilson, I. & Shaw, K. M. The immunogenetics of early nephropathy in insulin-dependent diabetes mellitus: association between the HLAA2 antigen and albuminuria. Q. J. Med. 83, 461–471 (1992).

    CAS  PubMed  Google Scholar 

  166. Dyck, R., Bohm, C. & Klomp, H. Increased frequency of HLA A2/DR4 and A2/DR8 haplotypes in young Saskatchewan Aboriginal people with diabetic end-stage renal disease. Am. J. Nephrol. 23, 178–185 (2003).

    Article  PubMed  Google Scholar 

  167. Perez-Luque, E. et al. Contribution of HLA class II genes to end stage renal disease in mexican patients with type 2 diabetes mellitus. Hum. Immunol. 61, 1031–1038 (2000).

    CAS  Article  PubMed  Google Scholar 

  168. Ma, Z. J., Sun, P., Guo, G., Zhang, R. & Chen, L. M. Association of the HLA-DQA1 and HLA-DQB1 alleles in type 2 diabetes mellitus and diabetic nephropathy in the Han ethnicity of China. J. Diabetes Res. 2013, 452537 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. Lindholm, E. et al. The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients. Diabetologia 49, 2745–2755 (2006).

    CAS  Article  PubMed  Google Scholar 

  170. Bharadwaj, M. et al. Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex. Annu. Rev. Pharmacol. Toxicol. 52, 401–431 (2012).

    CAS  Article  PubMed  Google Scholar 

  171. Keller, A. N. et al. Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. Nat. Immunol. 18, 402–411 (2017).

    CAS  Article  PubMed  Google Scholar 

  172. Kim, J. H. et al. CD1a on Langerhans cells controls inflammatory skin disease. Nat. Immunol. 17, 1159–1166 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Jarrett, R. et al. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci. Transl Med. 8, 325 (2016).

    Article  CAS  Google Scholar 

  174. Hung, S. I. et al. HLAB*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc. Natl Acad. Sci. USA 102, 4134–4139 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. Ng, C. Y. et al. Impact of the HLA-B(*)58:01 allele and renal impairment on allopurinol-induced cutaneous adverse reactions. J. Invest. Dermatol. 136, 1373–1381 (2016).

    CAS  Article  PubMed  Google Scholar 

  176. Yun, J. et al. Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response. Clin. Exp. Allergy 43, 1246–1255 (2013).

    CAS  Article  PubMed  Google Scholar 

  177. Chung, W. H. et al. Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. Ann. Rheum. Dis. 74, 2157–2164 (2015).

    CAS  Article  PubMed  Google Scholar 

  178. Baldwin, D. S., Levine, B. B., McCluskey, R. T. & Gallo, G. R. Renal failure and interstitial nephritis due to penicillin and methicillin. N. Engl. J. Med. 279, 1245–1252 (1968).

    CAS  Article  PubMed  Google Scholar 

  179. Karpinski, J., Jothy, S., Radoux, V., Levy, M. & Baran, D. D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature. Am. J. Nephrol. 17, 528–532 (1997).

    CAS  Article  PubMed  Google Scholar 

  180. Sakkas, L. I., Chikanza, I. C., Vaughan, R. W., Welsh, K. I. & Panayi, G. S. Gold induced nephropathy in rheumatoid arthritis and HLA class II genes. Ann. Rheum. Dis. 52, 300–301 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. Wooley, P. H. et al. HLA-DR antigens and toxic reaction to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis. N. Engl. J. Med. 303, 300–302 (1980).

    CAS  Article  PubMed  Google Scholar 

  182. Hamdi, N. M., Al-Hababi, F. H. & Eid, A. E. HLA class I and class II associations with ESRD in Saudi Arabian population. PLOS One 9, e111403 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  183. Mosaad, Y. M. et al. Association between human leukocyte antigens (HLAA, B, and -DR) and end-stage renal disease in Kuwaiti patients awaiting transplantation. Ren. Fail. 36, 1317–1321 (2014).

    Article  PubMed  Google Scholar 

  184. Dai, C. S. et al. Association between human leucocyte antigen subtypes and risk of end stage renal disease in Taiwanese: a retrospective study. BMC Nephrol. 16, 177 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. Robinson, J. et al. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res. 43, D423–D431 (2015).

    CAS  Article  PubMed  Google Scholar 

  186. Purcell, A. W., Croft, N. P. & Tscharke, D. C. Immunology by numbers: quantitation of antigen presentation completes the quantitative milieu of systems immunology! Curr. Opin. Immunol. 40, 88–95 (2016).

    CAS  Article  PubMed  Google Scholar 

  187. Macdonald, W. A. et al. T cell allorecognition via molecular mimicry. Immunity 31, 897–908 (2009).

    CAS  Article  PubMed  Google Scholar 

  188. Broughton, S. E. et al. Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. Immunity 37, 611–621 (2012).

    CAS  Article  PubMed  Google Scholar 

  189. Hall, C. L. The natural course of gold and penicillamine nephropathy: a longterm study of 54 patients. Adv. Exp. Med. Biol. 252, 247–256 (1989).

    CAS  Article  PubMed  Google Scholar 

  190. Vaughan, R. W. et al. An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients. Eur. J. Immunogenet. 22, 179–186 (1995).

    CAS  Article  PubMed  Google Scholar 

  191. Chevrier, D. et al. Idiopathic and secondary membranous nephropathy and polymorphism at TAP1 and HLA-DMA loci. Tissue Antigens 50, 164–169 (1997).

    CAS  Article  PubMed  Google Scholar 

  192. Jiyun, Y. et al. The genetic variants at the HLA-DRB1 gene are associated with primary IgA nephropathy in Han Chinese. BMC Med. Genet. 13, 33 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  193. Persson, U. et al. Patients with Goodpasture’s disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain. Nephrol. Dial. Transplant. 19, 2030–2035 (2004).

    CAS  Article  PubMed  Google Scholar 

  194. Thiri, M. et al. High-density association mapping and interaction analysis of PLA2R1 and HLA regions with idiopathic membranous nephropathy in Japanese. Sci. Rep. 6, 38189 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. Li, P. K. et al. The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians. Kidney Int. 39, 961–965 (1991).

    CAS  Article  PubMed  Google Scholar 

  196. Moore, R. H. et al. HLA DQ region gene polymorphism associated with primary IgA nephropathy. Kidney Int. 37, 991–995 (1990).

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Reviewer information

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to A. Richard Kitching.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-018-0057-8

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing