HLA Class II Differentiates Between Thyroid and Polyglandular Autoimmunity

Abstract

The HLA class II genes are susceptibility genes for autoimmune endocrine diseases; however, scarce data are available pertaining to the determinants of genetic susceptibility to polyglandular autoimmunity (PGA). A total of 300 consecutive and unselected patients with either PGA or monoglandular autoimmune thyroid disease (AITD) and 100 healthy control subjects were genotyped for the HLA class II DRB1, -DQA1, and -DQB1 alleles. Compared to patients with AITD and controls, the HLA-DRB1*03 (p_c =0.001), *04 (p_c<0.001), -DQA1*03 (p_c<0.001), and -DQB1*02 (p_c =0.001) alleles were increased in patients with PGA. When dividing patients with Hashimoto’s thyroiditis (HT) into those with PGA (PGA-HT) vs. those with HT as monoglandular disease, significant differences for the DRB1*03 (p_c=0.001) and DQA1*03 (p_c=0.001) alleles were observed. In contrast, the DQB1*02 allele was more prevalent in PGA patients with Graves’ disease (PGA-GD) vs. those with monoglandular GD (p_c=0.002). The HLA-DRB1*15 (p_c =0.001), -DQA1*01 (p_c =0.001), -DQB1*05 (p_c =0.002) and -DQB1*06 (p_c =0.002) alleles were significantly less present in PGA compared to monoglandular AITD and controls, thus indicating protective alleles. The HLA class II alleles differentiate between mono- and polyglandular autoimmunity in patients with autoimmune thyroid disease.

Key words

polyglandular autoimmunity - immunogenetics - HLA class II alleles - autoimmune thyroid disease

• References

• 1 Eisenbarth GS, Wilson PW, Ward F, Buckley C, Lebovita H. The polyglandular failure syndrome: disease inheritance, HLA type, and immune function. Ann Intern Med 1979; 91: 528-533
• 2 Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann 1980; 9: 154-162
• 3 Hansen MP, Kahaly GJ. Autoimmune polyglandular syndromes. Dtsch Med Wochenschr 2013; 138: 319-326 quiz 27–28
• 4 Myhre AG, Undlien DE, Lovas K, Uhlving S, Nedrebo BG, Fougner KJ, Trovik T, Sorheim JI, Husebye ES. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features. J Clin Endocrinol Metab 2002; 87: 618-623
• 5 Hansen MP, Erlich M, Kahaly GJ. Addison’s disease and Pluriglandular syndromes. J Klin Endokrinol Stoffw 2013; 6: 5-11
• 6 Bernecker C, Halim F, Haase M, Willenberg HS, Ehlers M, Schott M. MicroRNA Expressions in PMBCs, CD4+, and CD8+ T-Cells from Patients Suffering from Autoimmune Addison’s Disease. Horm Metab Res 2013; 45: 599-604
• 7 Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7: 481-493
• 8 Dittmar M, Libich C, Brenzel T, Kahaly GJ. Increased familial clustering of autoimmune thyroid diseases. Horm Metab Res 2011; 43: 200-204
• 9 Dittmar M, Woletz K, Kahaly GJ. Reduced DNASE1 gene expression in thyroid autoimmunity. Horm Metab Res 2013; 45: 257-260
• 10 Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P, Antonelli A. IP-10 in Autoimmune Thyroiditis. Horm Metab Res 2014; 46: 597-602
• 11 Bernecker C, Ostapczuk M, Vordenbäumen S, Ehlers M, Thiel A, Schinner S, Willenberg H, Scherbaum WA, Schott M. HLA-A2 Phenotype may be Protective Against Graves’ Disease but not Against Hashimoto’s Thyroiditis in Caucasians. Horm Metab Res 2013; 45: 74-77
• 12 Dultz G, Matheis N, Dittmar M, Bender K, Kahaly GJ. CTLA-4 CT60 polymorphism in thyroid and polyglandular autoimmunity. Horm Metab Res 2009; 41: 426-429
• 13 Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Acta Biomed 2003; 74: 9-33
• 14 Maurer A, Schwarting A, Kahaly GJ. Polyglandular autoimmune syndromes. Z Rheumatol 2011; 70: 752-754 756–759
• 15 Majeroni BA, Patel P. Autoimmune polyglandular syndrome, type II. Am Fam Physician 2007; 75: 667-670
• 16 Hansen MP, Wunderlich SA, Storz SM, Matheis N, Knuf M, Kahaly GJ. The polyglandular autoimmune syndrome – quality of life and family clustering. Dtsch Med Wochenschr 2014; 139: 1876-1882
• 17 Hunger-Battefeld W, Fath K, Mandecka A, Kiehntopf M, Kloos C, Muller UA, Wolf G. Prevalence of polyglandular autoimmune syndrome in patients with diabetes mellitus type 1. Med Klin (Munich) 2009; 104: 183-191
• 18 Hansen MP, Matheis N, Kahaly GJ. Type 1 diabetes and polyglandular autoimmune syndrome: A review. World J Diabetes 2015; 6: 67-79
• 19 EMBL-EBI. IPD – IMGT/HLA. 2015 [updated 19.01.2015]. Available from: http://www.ebi.ac.uk/ipd/imgt/hla/stats.html
• 20 Krensky AM. The HLA system, antigen processing and presentation. Kidney Int Suppl 1997; 58: S2-S7
• 21 Bondinas GP, Moustakas AK, Papadopoulos GK. The spectrum of HLA-DQ and HLA-DR alleles, 2006: a listing correlating sequence and structure with function. Immunogenetics 2007; 59: 539-553
• 22 Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep 2011; 11: 533-542
• 23 Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem 2011; 57: 176-185
• 24 Weinstock C, Matheis N, Barkia S, Haager MC, Janson A, Markovic A, Bux J, Kahaly GJ. Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes. Tissue Antigens 2011; 77: 317-324
• 25 Flesch BK, Matheis N, Alt T, Weinstock C, Bux J, Kahaly GJ. HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III. J Clin Endocrinol Metab 2014; 99: E177-E182
• 26 Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med 2009; 67: 376-387
• 27 Huber A, Menconi F, Corathers S, Jacobson EM, Tomer Y. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev 2008; 29: 697-725
• 28 Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009; 161: 11-20
• 29 Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004; 350: 2068-2079
• 30 Levin L, Ban Y, Concepcion E, Davies TF, Greenberg DA, Tomer Y. Analysis of HLA genes in families with autoimmune diabetes and thyroiditis. Hum Immunol 2004; 65: 640-647
• 31 Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010; 6: 270-277
• 32 Wallaschofski H, Meyer A, Tuschy U, Lohmann T. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Horm Metab Res 2003; 35: 120-124
• 33 Djilali-Saiah I, Bertin E, Larger E, Timsit J, Assan R, Boitard C, Bach JF, Caillat-Zucman S. Major histocompatibility class II genes polymorphism in insulin dependent diabetes mellitus with or without associated thyroid autoimmunity. Hum Immunol 1998; 59: 176-182
• 34 Santamaria P, Barbosa JJ, Lindstrom AL, Lemke TA, Goetz FC, Rich SS. HLA-DQB1-associated susceptibility that distinguishes Hashimoto’s thyroiditis from Graves’ disease in type I diabetic patients. J Clin Endocrinol Metab 1994; 78: 878-883
• 35 Hashimoto K, Maruyama H, Nishiyama M, Asaba K, Ikeda Y, Takao T, Iwasaki Y, Kumon Y, Suehiro T, Tanimoto M, Mizobuchi M, Nakamura 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: 253-260
• 36 Badenhoop K, Walfish PG, Rau H, Fischer S, Nicolay A, Bogner U, Schleusener H, Usadel KH. Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. J Clin Endocrinol Metab 1995; 80: 2112-2117
• 37 Roman SH, Greenberg D, Rubinstein P, Wallenstein S, Davies TF. Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families. J Clin Endocrinol Metab 1992; 74: 496-503
• 38 Tomer Y, Barbesino G, Greenberg DA, Concepcion E, Davies TF. Mapping the major susceptibility loci for familial Graves’ and Hashimoto’s diseases: evidence for genetic heterogeneity and gene interactions. J Clin Endocrinol Metab 1999; 84: 4656-4564
• 39 Villano MJ, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocrinol Metab 2009; 94: 1458-1466