Autoimmune Hypoparathyroidism

  • E. Helen Kemp
  • Anthony P. WeetmanEmail author


Autoimmunity is important with regard to the etiology and pathogenesis of hypoparathyroidism, and in this chapter, evidence for the involvement of autoimmune responses in the development of the disease will be discussed. Autoimmune hypoparathyroidism may occur as a sporadic disease or as the major endocrine disorder of autoimmune polyendocrine syndrome type 1 (APS1). In idiopathic hypoparathyroidism, lymphocytic infiltration of and autoantibodies against the parathyroid gland have been reported, although it is as yet unclear what proportion of patients have an autoimmune basis for their condition. In addition, there is a strong association of HLA-A*26:01 with idiopathic hypoparathyroidism, suggesting an important role in its pathogenesis for major histocompatibility complex (MHC) class I-mediated presentation of autoantigenic peptides to CD8+ cytotoxic T cells. Furthermore, MHC class II HLA-DRB1*01 and HLA-DRB1*09 alleles are more frequent in patients with idiopathic hypoparathyroidism than in controls, and this too supports an autoimmune basis for the disease. In APS1, a monogenic disease caused by mutations in the AIRE (autoimmune regulator) gene, autoantibodies against parathyroid-expressed targets including the calcium-sensing receptor and NALP5 (NACHT leucine-rich-repeat protein 5) are prevalent. T cell reactivity against the parathyroid in APS1 is less well studied, although autoreactive T lymphocytes that have escaped clonal deletion due to the lack of AIRE gene expression in thymic medullary epithelial cells may target and damage the parathyroid leading to hypoparathyroidism, the hallmark of APS1.


Autoantibody Autoantigen Autoimmune hypoparathyroidism Autoimmune polyendocrine syndrome Calcium-sensing receptor NALP5 Parathyroid 


  1. 1.
    Schmidt MB (1926) Eine biglandulare Erkrankung (Nebennieren und Schilddrüse) bei Morbus Addisonii. Verh Dtsch Ges Pathol 21:212–221Google Scholar
  2. 2.
    Leifer E, Hollander W Jr (1953) Idiopathic hypoparathyroidism and chronic adrenal insufficiency: a case report. J Clin Endocrinol Metab 13:1264–1269CrossRefPubMedGoogle Scholar
  3. 3.
    Blizzard RM, Chee D, Davis W (1966) The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Clin Exp Immunol 1:119–128PubMedPubMedCentralGoogle Scholar
  4. 4.
    Spinner MW, Blizzard RM, Gibbs J, Abbey H, Childs B (1969) Familial distributions of organ specific antibodies in the blood of patients with Addison’s disease and hypoparathyroidism and their relatives. Clin Exp Immunol 5:461–468PubMedPubMedCentralGoogle Scholar
  5. 5.
    Neufeld M, MacLaren NK, Blizzard RM (1981) Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine 60:355–362CrossRefPubMedGoogle Scholar
  6. 6.
    Perheentupa J (2006) Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 91:2843–2850CrossRefPubMedGoogle Scholar
  7. 7.
    Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, Furcas M, Rosatelli MC, Cao A, Congia M (2012) Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab 97:​1114–1124CrossRefPubMedGoogle Scholar
  8. 8.
    Kisand K, Peterson P (2011) Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome. Ann N Y Acad Sci 1246:77–91CrossRefPubMedGoogle Scholar
  9. 9.
    Betterle C, Dal Pra C, Mantero F, Zanchetta R (2002) Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease. Endocr Rev 23:327–364CrossRefPubMedGoogle Scholar
  10. 10.
    Goswami R, Marwaha RK, Goswami D, Gupta N, Ray D, Tomar N, Singh S (2006) Prevalence of thyroid autoimmunity in sporadic idiopathic hypoparathyroidism in comparison to type 1 diabetes and premature ovarian failure. J Clin Endocrinol Metab 91:4256–4259CrossRefPubMedGoogle Scholar
  11. 11.
    Rose NR, Bona C (1993) Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today 14:426–430CrossRefPubMedGoogle Scholar
  12. 12.
    Lupuleseu A, Potorac E, Pop A, Heitmanek C, Merculiev E, Chisiu N, Oprisan R, Neacsu C (1968) Experimental investigations on immunology of the parathyroid gland. Immunology 14:475–482Google Scholar
  13. 13.
    Jancovic BD, Isvaneski M, Ljuhjana P, Mitrovic K (1965) Experimental allergic thyroiditis (and parathyroiditis) in neonatally thymectomized and bursectomized chickens. Int Arch Allergy 26:18–33CrossRefGoogle Scholar
  14. 14.
    Altenähr E, Jenke W (1974) Experimental parathyroiditis in the rat by passive immunisation. Virchows Arch A Pathol Anat Histol 363:333–342CrossRefPubMedGoogle Scholar
  15. 15.
    Kössling FK, Emmrich P (1971) Demonstration eines Falles von Kindlichem Morbus Addison mit Hypoparathyreoidismus. Verh Dtsch Ges Pathol 55:155–160PubMedGoogle Scholar
  16. 16.
    Van de Casseye M, Gepts W (1973) Primary (autoimmune?) parathyroiditis. Virchows Arch A Pathol Anat 361:257–261CrossRefPubMedGoogle Scholar
  17. 17.
    Talat N, Diaz-Cano S, Schulte KM (2011) Inflammatory diseases of the parathyroid gland. Histopathology 59:897–908CrossRefPubMedGoogle Scholar
  18. 18.
    Wortsman J, McConnachie P, Baker JR Jr, Mallette LE (1992) T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism. Am J Med 92:352–356CrossRefPubMedGoogle Scholar
  19. 19.
    Irvine WJ, Scarth L (1969) Antibody to the oxyphil cells of the human parathyroid in idiopathic hypoparathyroidism. Clin Exp Immunol 4:505–510PubMedPubMedCentralGoogle Scholar
  20. 20.
    Brandi ML, Aurbach GD, Fattorossi A, Quarto R, Marx SJ, Fitzpatrick LA (1986) Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism. Proc Natl Acad Sci U S A 83:8366–8369CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fattorossi A, Aurbach GD, Sakaguchi K, Cama A, Marx SJ, Streeten EA, Fitzpatrick LA, Brandi ML (1988) Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism. Proc Natl Acad Sci U S A 85:4015–4019CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Betterle C, Caretto A, Zeviani M, Pedini B, Salviati C (1985) Demonstration and characterization of anti-human mitochondria autoantibodies in idiopathic hypoparathyroidism and in other conditions. Clin Exp Immunol 62:353–360PubMedPubMedCentralGoogle Scholar
  23. 23.
    Posillico JT, Wortsman J, Srikanta S, Eisenbarth GS, Mallette LE, Brown EM (1986) Parathyroid cell surface autoantibodies that inhibit parathyroid hormone secretion from dispersed human parathyroid cells. J Bone Miner Res 1:475–483CrossRefPubMedGoogle Scholar
  24. 24.
    Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580CrossRefPubMedGoogle Scholar
  25. 25.
    Brown EM, Pollak M, Hebert SC (1995) Sensing of extracellular Ca2+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca(2+)-sensing receptor. Am J Kidney Dis 25:506–513CrossRefPubMedGoogle Scholar
  26. 26.
    Li Y, Song YH, Rais N, Connor E, Schatz D, Muir A, Maclaren N (1996) Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 97:910–914CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gylling M, Kääriäinen E, Väisänen R, Kerosuo L, Solin ML, Halme L, Saari S, Halonen M, Kämpe O, Perheentupa J, Miettinen A (2003) The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex. J Clin Endocrinol Metab 88:4602–4608CrossRefPubMedGoogle Scholar
  28. 28.
    Söderbergh A, Myhre AG, Ekwall O, Gebre-Medhin G, Hedstrand H, Landgren E, Miettinen A, Eskelin P, Halonen M, Tuomi T, Gustafsson J, Husebye ES, Perheentupa J, Gylling M, Manns MP, Rorsman F, Kämpe O, Nilsson T (2004) Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 89:557–562CrossRefPubMedGoogle Scholar
  29. 29.
    Goswami R, Brown EM, Kochupillai N, Gupta N, Rani R, Kifor O, Chattopadhyay N (2004) Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 150:9–18CrossRefPubMedGoogle Scholar
  30. 30.
    Tomar N, Gupta N, Goswami R (2013) Calcium-sensing receptor autoantibodies in idiopathic hypoparathyroidism. J Clin Endocrinol Metab 98:3884–3891CrossRefPubMedGoogle Scholar
  31. 31.
    Mayer A, Ploix C, Orgiazzi J, Desbos A, Moreira A, Vidal H, Monier JC, Bienvenu J, Fabien N (2004) Calcium-sensing receptor autoantibodies are relevant markers of acquired hypoparathyroidism. J Clin Endocrinol Metab 89:4484–4488CrossRefPubMedGoogle Scholar
  32. 32.
    Kifor O, Moore FD Jr, Delaney M, Garber J, Hendy GN, Butters R, Gao P, Cantor TL, Kifor I, Brown EM, Wysolmerski J (2003) A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 88:60–72CrossRefPubMedGoogle Scholar
  33. 33.
    Kifor O, McElduff A, LeBoff MS, Moore FD Jr, Butters R, Gao P, Cantor TL, Kifor I, Brown EM (2004) Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 89:548–556CrossRefPubMedGoogle Scholar
  34. 34.
    Gavalas NG, Kemp EH, Krohn KJ, Brown EM, Watson PF, Weetman AP (2007) The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 92:2107–2114CrossRefPubMedGoogle Scholar
  35. 35.
    Kemp EH, Gavalas NG, Akhtar S, Krohn KJE, Pallais JC, Brown EM, Watson PF, Weetman AP (2010) Mapping of human autoantibody binding sites on the calcium-sensing receptor. J Bone Miner Res 25:132–140CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kemp EH, Gavalas NG, Krohn KJE, Brown EM, Watson PF, Weetman AP (2009) Activating autoantibodies against the calcium-sensing receptor in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 94:4749–4756CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerström G, Westin G, Scott HS, Holländer GA, Kämpe O (2008) Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med 358:1018–1028CrossRefPubMedGoogle Scholar
  38. 38.
    Tomar N, Kaushal E, Das M, Gupta N, Betterle C, Goswami R (2012) Prevalence and significance of NALP5 autoantibodies in patients with idiopathic hypoparathyroidism. J Clin Endocrinol Metab 97:1219–1226CrossRefPubMedGoogle Scholar
  39. 39.
    Cheng MH, Fan U, Grewal N, Barnes M, Mehta A, Taylor S, Husebye ES, Murphy EJ, Anderson MS (2010) Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N Engl J Med 362:764–766CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Cervato S, Morlin L, Albergoni MP, Masiero S, Greggio N, Meossi C, Chen S, del Pilar Larosa M, Furmaniak J, Rees Smith B, Alimohammadi M, Kämpe O, Valenzise M, Betterle C (2010) AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED. Clin Endocrinol (Oxf) 73:630–636CrossRefGoogle Scholar
  41. 41.
    Eisenbarth G (2008) Do NALP5 antibodies correlate with hypoparathyroidism in patients with APS-1? Nat Clin Pract Endocrinol Metab 4:544–545CrossRefPubMedGoogle Scholar
  42. 42.
    Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, Allahabadia A, Armitage M, Chatterjee KV, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA (2010) Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med 123:183.e1–9CrossRefGoogle Scholar
  43. 43.
    Weetman AP (2011) Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol (Oxf) 74:411–418CrossRefGoogle Scholar
  44. 44.
    Goswami R, Gupta N, Ray D, Rani R, Tomar N, Sarin R, Vupputuri MR (2005) Polymorphisms at +49A/G and CT60 sites in the 3′ UTR of the CTLA-4 gene and APECED-related AIRE gene mutations analysis in sporadic idiopathic hypoparathyroidism. Int J Immunogenet 32:393–400CrossRefPubMedGoogle Scholar
  45. 45.
    Goswami R, Singh A, Gupta N, Indian Genome Variation Consortium, Rani R (2012) Presence of strong association of the major histocompatibility complex (MHC) class I allele HLA-A*26:01 with idiopathic hypoparathyroidism. J Clin Endocrinol Metab 97:E1820–E1824CrossRefPubMedGoogle Scholar
  46. 46.
    Laakso SM, Kekäläinen E, Rossi LH, Laurinolli TT, Mannerström H, Heikkilä N, Lehtoviita A, Perheentupa J, Jarva H, Arstila TP (2011) IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Immunol 187:​2023–2030CrossRefPubMedGoogle Scholar
  47. 47.
    Ray D, Tomar N, Gupta N, Goswami R (2006) Protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene R620W variant and sporadic idiopathic hypoparathyroidism in Asian Indians. Int J Immunogenet 33:237–240CrossRefPubMedGoogle Scholar
  48. 48.
    Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398CrossRefPubMedGoogle Scholar
  49. 49.
    Zuklys S, Balciunaite G, Agarwal A, Fasler-Kan E, Palmer E, Holländer GA (2000) Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Immunol 165:1976–1983CrossRefPubMedGoogle Scholar

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© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Department of Human Metabolism, Faculty of Medicine, Dentistry and HealthUniversity of Sheffield, The Medical SchoolSheffield South YorkshireUK

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