Advertisement

Autoimmune Polyglandular Syndrome Type 2

  • George J. Kahaly
  • Manuela Dittmar
Part of the Contemporary Endocrinology book series (COE)

Summary

The nature of autoimmune polyglandular syndrome type 2 (APS-2) has been based on the presence of lymphocyte infiltration in the affected gland, organ-specific antibodies (Abs) in the serum, cellular immune defects, and an association with the human leukocyte antigen (HLA)-DR/DQ genes or immune-response genes. Autoantibodies to the various endocrine and non-endocrine tissues not only offer a diagnostic clue to the autoimmune nature of diseases but also can be used to identify asymptomatic individuals who are at risk of developing other component diseases of the syndrome. Although target tissues or glands differ, several common threads link the diseases of the APS. The autoimmune destruction of most target glands appears to be a slow process with a long preclinical prodrome that may last for years. During this period, autoantibodies, lymphocyte abnormalities, and subclinical endocrine defects are usually present. As knowledge of target antigens has progressed, it appears that despite polyendocrine disease, within each gland, specific antigens are the targets of the autoimmune process. A defect resides in one of the genes of the HLA locus, which, in concert with other gene(s), results in susceptibility. Genetic susceptibility is necessary but not sufficient to produce the disorder. This is illustrated by the lack of 100% concordance of disease in identical twins. When the genetic defects and environmental influences of organ-specific autoimmunity are better understood, it may be possible to devise specific replacement or corrective therapies. Given the similar features of many of the organ-specific autoimmune disorders, it is likely that if immunotherapeutic modalities are successful in one disease, they may be of benefit in related disorders. With respect to the significant morbidity and potential mortality of the disease, the main diagnostic objective is to detect APS-2 at an early stage, with the advantage of less frequent complications, effective therapy, and better prognosis. This requires that patients at risk be regularly screened for subclinical endocrinopathies before clinical manifestation occurs. Regarding the possible large time interval between manifestation of the first and further endocrinopathies, regular and long-term follow-up of patients with endocrine autoimmune disorders is warranted. Considering the high incidence of one or more endocrinopathies in first-degree relatives of patients with APS-2, family members of patients should be regularly screened, because they may develop autoimmune endocrinopathies in the future.

Keywords

Autoimmune polyglandular syndrome type 2 polyglandular autoimmunity epidemiology diagnosis genetics pathogenesis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350: 2068–2079.PubMedCrossRefGoogle Scholar
  2. 2.
    Neufeld M, MacLaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann 1980;9: 154–162.PubMedGoogle Scholar
  3. 3.
    Jenkins RC, Weetman AP. Disease associations with autoimmune thyroid disease. Thyroid 2002;12: 977–988.PubMedCrossRefGoogle Scholar
  4. 4.
    Betterle C, Greggio NA, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998;83:1049–1055.PubMedCrossRefGoogle Scholar
  5. 5.
    Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune polyglandular syndrome type 1. Clin Rev Allergy Immunol 2000;18:167–183.PubMedCrossRefGoogle Scholar
  6. 6.
    Ten S, New M, MacLaren N. Clinical review 130: Addison’s disease 2001. J Clin Endocrinol Metab 2000; 86:2909–2922.CrossRefGoogle Scholar
  7. 7.
    Förster G, Krummenauer F, Kühn I, Beyer J, Kahaly G. Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation; in German. Dtsch Med Wschr 199;124:1476–1481.CrossRefGoogle Scholar
  8. 8.
    Gianani R, Sarvetnick N. Viruses, cytokines, antigens, and autoimmunity. Proc Natl Acad Sci USA 1996;93:2257–2259.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Robles DT, Fain PR, Gottlieb PA, Eisenbarth GS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am 2002; 31:353–368.PubMedCrossRefGoogle Scholar
  11. 11.
    Eisenbarth GS, Wilson P, Ward F, Lebovita H. HLA type and occurrence of disease in familial polyglandular failure. N Engl J Med 1978; 298:92–94.PubMedCrossRefGoogle Scholar
  12. 12.
    Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996; 85:291–297.PubMedCrossRefGoogle Scholar
  13. 13.
    Sanjeevi CB, Lybrand TP, DeWeese C, Landin-Olsson M, Kockum I, Dahlquist G, Sundkvist G, Stenger D, Lernmark A. Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. Diabetes 1995;44:125–131.PubMedCrossRefGoogle Scholar
  14. 14.
    Moghaddam PH, Zwinderman AH, de Knijff P, Roep BO, Schipper RF, Van der Auwera B, Naipal A, Gorus F, Schuit F, Giphart MJ. TNFa microsatellite polymorphism modulates the risk of IDDM in Caucasians with the high-risk genotype HLA DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302. Belgian Diabetes Registry. Diabetes 1997;46:1514–1515.PubMedGoogle Scholar
  15. 15.
    Tandon N, Zhang L, Weetman AP. HLA associations with Hashimoto’s thyroiditis. Clin Endocrinol (Oxf) 1991;34:383–386.Google Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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;84:4656–4664.PubMedCrossRefGoogle Scholar
  18. 18.
    Kotsa K, Watson PF, Weetman AP. A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf) 1997;46:551–554.CrossRefGoogle Scholar
  19. 19.
    Kahaly GJ, Dittmar M. Immunoregulatory genes in thyroid and polyglandular autoimmunity. Abstract band 11th International Symposium on Molecular Thyroidology, Okinawa, Japan, 2004, p. 33.Google Scholar
  20. 20.
    Gambelunghe G, Ghaderi M, Cosentino A, Falorni A, Brunetti P, Falorni A, Sanjeevi CB. Association of MHC Class I chain-related A (MIC-A) gene polymorphism with type I diabetes. Diabetologia 2000;43:507–514.PubMedCrossRefGoogle Scholar
  21. 21.
    Dittmar M, Höhler T, Schneider PM, Adams P, Antunes C, Weber M, Kahaly GJ. Cytokine gene promoter polymorphisms in polyglandular autoimmunity. Exp Clin Endocrinol Diabetes (Heidelberg) 2004;112 (Suppl 1):S14 (Abstract).Google Scholar
  22. 22.
    Siminovitch KA. PTPN22 and autoimmune disease. Nat Genet 2004;36:1248–1249.PubMedCrossRefGoogle Scholar
  23. 23.
    Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004;36:337–338.PubMedCrossRefGoogle Scholar
  24. 24.
    Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, Mc McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004;75:330–337.PubMedCrossRefGoogle Scholar
  25. 25.
    Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004;75:504–507.PubMedCrossRefGoogle Scholar
  26. 26.
    Gomez LM, Anaya JM, Gonzalez CI, Pineda-Tamayo R, Otero W, Arango A, Martin J. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes Immun 2005;6:628–631.PubMedCrossRefGoogle Scholar
  27. 27.
    Aaltonen J, Bjorses P, Sandkuijl L, Perheentupa J, Peltonen L. An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 1994;8:83–87.PubMedCrossRefGoogle Scholar
  28. 28.
    Bjorses P, Aaltonen J, Vikman A, Perheentupa J, Ben-Zion G, Chiumello G, Dahl N, Heideman P, Hoorweg-Nijman JJ, Mathivon L, Mullis PE, Pohl M, Ritzen M, Romeo G, Shapiro MS, Smith CS, Solyom J, Zlotogora J, Peltonen L. Genetic homogeneity of autoimmune polyglandular disease type I. Am J Hum Genet 1996;59:879–886.PubMedGoogle Scholar
  29. 29.
    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. Positional cloning of the APECED gene. Nat Genet 1997;17:393–398.PubMedCrossRefGoogle Scholar
  30. 30.
    Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, Toft AD, Williams G, Kendall-Taylor P. A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Am J Hum Genet 1998;63:1675–1684.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang CY, Davoodi-Semiromi A, Huang W, Connor E, Shi JD, She JX. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1). Hum Genet 1998;103:681–685.PubMedCrossRefGoogle Scholar
  32. 32.
    Chen QY, Lan MS, She JX, Maclaren NK. The gene responsible for autoimmune polyglandular syndrome type 1 maps to chromosome 21q22.3 in US patients. J Autoimmun 1998;11:177–183.PubMedCrossRefGoogle Scholar
  33. 33.
    Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K. APECED mutations in the autoimmue regulator (AIRE) gene. Hum Mutat 2001;18:205–211.PubMedCrossRefGoogle Scholar
  34. 34.
    Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J. AIRE Mutations and Human Leukocyte Antigen Genotypes as Determinants of the Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Phenotype. J Clin Endocrinol Metab 2002;87:2568–2574.PubMedCrossRefGoogle Scholar
  35. 35.
    Skorka A, Bednarczuk T, Bar-Andziak E, Nauman J, Ploski R. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin Endocrinol (Oxf) 2005;62:679–682.CrossRefGoogle Scholar
  36. 36.
    Vogel A, Strassburg CP, Obermayer-Straub P, Brabant G, Manns MP. The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components. J Mol Med 2002;80:201–211.PubMedCrossRefGoogle Scholar
  37. 37.
    Anderson MS Autoimmune endocrine diseases. Curr Opin Immunol 2002;14:760–764.PubMedCrossRefGoogle Scholar
  38. 38.
    Devendra D, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Immunol 2003;111:S624–S636.PubMedCrossRefGoogle Scholar
  39. 39.
    Topliss D, How J, Lewis M, Row V, Volpe R. Evidence for cell-mediated immunity and specific suppressor T lymphocyte dysfunction in Graves’ disease and diabetes mellitus. J Clin Endocrinol Metab 1983;57:700–705.PubMedCrossRefGoogle Scholar
  40. 40.
    Canbay A, Gieseler R, Ella R, Fink H, Saller B, Mann K. Manifestation of adrenal insufficiency after administration of levothyroxine in a patient with polyglandular autoimmune syndrome type II (Schmidt-syndrome); in German. Internist (Berlin) 2000;41:588–591.CrossRefGoogle Scholar
  41. 41.
    Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531–562.PubMedCrossRefGoogle Scholar
  42. 42.
    Shevach EM. Regulatory T cells in autoimmmunity*. Annu Rev Immunol 2000;18:423–449.PubMedCrossRefGoogle Scholar
  43. 43.
    Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 2004;199:1285–1291.PubMedCrossRefGoogle Scholar
  44. 44.
    Luther C, Poeschel S, Varga M, Melms A, Tolosa E. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J Neuroimmunol 2005;164:124–128.PubMedCrossRefGoogle Scholar
  45. 45.
    Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993;75:1169–1178.PubMedCrossRefGoogle Scholar
  46. 46.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004;199:971–979.PubMedCrossRefGoogle Scholar
  47. 47.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expression IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–1164.PubMedGoogle Scholar
  48. 48.
    Lan RY, Ansari AA, Lian ZX, Gershwin ME. Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 2005;4:351–363.PubMedCrossRefGoogle Scholar
  49. 49.
    Dittmar M, Tietz S, Poppe R, Fredenhagen G, Weber M, Kahaly GJ. Impaired DNase activity in patients with endocrine autoimmunity and their healthy relatives. Exp Clin Endocrinol Diabetes 2004;112(Suppl 1):S75 (Abstract).Google Scholar
  50. 50.
    Kumar R, Reddy DV, Unnikrishnan AG, Bhadada SK, Agrawal NK, Singh SK. Polyglandular autoimmune endocrinopathy in type 2 diabetes. J Assoc Physicians India 2004;52:999–1000.PubMedGoogle Scholar
  51. 51.
    Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: Immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003;88:2983–2992.PubMedCrossRefGoogle Scholar
  52. 52.
    Chen S, Sawicka J, Betterle C, Powell M, Prentice L, Volpato M, Smith BR, Furmaniak J. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison’s disease, and premature ovarian failure. J Clin Endocrinol Metab 1996;81:1871–1876.PubMedCrossRefGoogle Scholar
  53. 53.
    Hrdá P, Sterzl I, Matucha P, Korioth F, Kromminga A. HLA antigen expression in autoimmune endocrinopathies. Physiol Res 2004;53:191–197.PubMedGoogle Scholar
  54. 54.
    Devendra D, Franke B, Galloway TS, Horton SJ, Knip M, Wilkin TJ. Distinct idiotypes of insulin autoantibody in autoimmune polyendocrine syndrome type 2 and childhood onset type 1 diabetes. J Clin Endocrinol Metab 2004;89:5266–5270.PubMedCrossRefGoogle Scholar
  55. 55.
    Kahaly GJ, Förster G, Otto E, Hansen C, Schulz G. Diabetes mellitus Typ I als Teil des polyglandulären Autoimmunsyndroms. Diabetes Stoffwechsel 1997;6:19–27.Google Scholar
  56. 56.
    Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004;137:225–233.PubMedCrossRefGoogle Scholar
  57. 57.
    Dittmar M, Kahaly GJ. Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity. Thyroid 2005;15:239–250.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • George J. Kahaly
  • Manuela Dittmar

There are no affiliations available

Personalised recommendations