Autoimmune polyglandular syndrome type 1

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Autoimmune polyglandular syndrome type 1

Presented by Suparat Sirivimonpan, MD.

October26, 2012

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  • Dx at least 2/3
  • presentation profile associated with APECED for several years, together with some less common manifestations,before the endocrinopathies developfingernails are more commonly affected than toenails
  • AADC : amino acid decarboxylase
  • TPH tryptopanhydroxylaseHDC Histidinedecarboxylasehypocalcemia prevents secretion of cholecystokinin by the duodenal mucosa in response to a meal
  • Jew : low CMC
  • interferon-ω-reactive autoantibodies present in 100% of patients
  • The septicemia case occurred during immunosuppressive treatment, but all of the other infections described were unrelated to either immunosuppression or asplenia.
  • Autoimmune polyglandular syndrome type 1

    1. 1. Suparat Sirivimonpan, MD. 26/10/2012
    2. 2.  Introduction Clinical manifestation Diagnosis Molecular basis Management
    3. 3.  Autoimmune polyglandular syndrome type 1 (APS-1) also known as Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED) rare autosomal recessive disease (OMIM 240300) with a complex picture discovered over decades disease of immune dysregulation mutations in a particular autoimmune regulator (AIRE) gene (21q22.3) Horm Res Paediatr 2010;73:449–457
    4. 4.  The term ―polyendocrine‖ itself is a misnomer not all patients have multiple endocrine disorders many have nonendocrine autoimmune diseases N Engl J Med 2004;350:2068-79
    5. 5.  APECED appears to occur worldwide common only in Iranian Jews, Sardinians, and Finns  Iranian Jews (1:9,000)  Sardinians (1:14,000)  Finns (1:25,000) J Clin Endocrinol Metab 91: 2843–2850, 2006 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    6. 6.  The first description with hypoparathyroidism and CMC was reported by Thorpe and Handley in 1929 In 1938, Söderlund reported a patient with insulin- dependent diabetes mellitus and candidiasis Subsequent case reports confirmed the association of endocrine disorders such as hypoadrenalism, hypoparathyroidism, and hypothyroidism with chronic mucocutaneous candidiasis  triad J Clin Immunol (2008) 28 (Suppl 1):S11–S19
    7. 7.  Whitaker’s triad of symptoms— 1. chronic mucocutaneous candidal infections 2. hypoparathyroidism 3. adrenocortical failure (Addison’s disease) is pathognomonic for APECED CMC is the first sign (75–93%) followed by Hypoparathyroidism, (peak age 4-5 yr) then by Addison’s disease (also in childhood) Ann. N.Y. Acad. Sci. 1246 (2011) 77–91 Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
    8. 8.  Other early manifestations that can present prior to the symptoms and/or diseases described above include  hepatitis, keratoconjunctivitis, periodic rashes with fever, chronic diarrhea, severe obstipation, alopecia, or vitiligo Additional clinical manifestations develop up to the fifth decade of life of these patients Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    9. 9.  mucocutaneous candidiasis : oral, ungual, esophagial and vaginal mucosa and nails  Oral candidiasis  Candidal esophagitis esophageal stricture or squamous cell carcinoma  Perianal candidal eczema  intestinal mucosal candidiasis  Infection of skin of the hands ,face and nails  Candidal vulvovaginitis (after puberty) Ann. N.Y. Acad. Sci. 1246 (2011) 77–91 Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
    10. 10.  course and severity varies significantly  mild and remittent infection VS  chronic hypertrophic and/or atrophic lesions Generalized candidiasis has only been reported in patients on immunosuppressive medication Humoral immunity against Candida develops normally Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
    11. 11.  Apartfrom hypoparathyroidism and Addison’s disease,  hypergonadotropic hypogonadism  type 1 diabetes  autoimmune thyroid diseases  pituitary defects  gastric parietal cell atrophy autoimmune origin oftenassociated with a specific set of organ- specific autoantibodies Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    12. 12. Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    13. 13. J Clin Immunol (2008) 28 (Suppl 1):S11–S19
    14. 14.  correlation of autoantibodies is purely statistical prevalence of the antibodies is higher in the group of patients presenting with the certain manifestation compared to patients without this manifestation In certain cases, the antibodies can be predictive of future disease manifestations Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    15. 15.  variable etiology Chronic atrophic gastritis and pernicious anemia  autoantibodies specific for parietal cells and intrinsic factor Autoimmune hepatitis  autoantibodies specific for liver-expressed antigens P450 1A2 and AADC  In most cases chronic and without symptoms, it may lead to cirrhosis or be fulminant and lethal Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    16. 16.  chronic diarrhea  result of hypocalcemia (hypoparathyroidism)  Diarrhea alternates with obstipation  Malabsorption and steatorrhea can be the result of exocrine pancreatic failureintestinal endocrine cells : targets of autoimmune attack  intestinal dysfunction ≈ endocrinopathy Autoantibodies to TPH and HDC  destruction of serotonin-producing enterocromaffin and endocromaffin-like cells, respectively Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    17. 17.  Autoimmune skin diseases, such as vitiligo and alopecia Keratoconjunctivitis Dental enamel hypoplasia (permanent or decidual teeth) Pitted nail dystrophy (DDX : onychomycosis) Tympanic membrane calcification aberrations are not present at birth but develop over time Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    18. 18.  enamelhypoplasia ≠ hypoparathyroidism  not always present together dental defects may be secondary to recurrent oral infections and malnutrition Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    19. 19.  Asplenia  20% of patients  impaired immune responses to encapsulated bacteria  septicemia  Pathogenesis : unknown Tubulointestinal nephritis Obstructive lung disease Vasculitis Sjogren’s syndrome Hemolytic anemia scleroderma, Metaphyseal dysplasia celiac disease autoimmune in origin Horm Res Paediatr 2010;73:449–457 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    20. 20. SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
    21. 21. France Finn Sardinia 2006 n 2012 87% 77% 68% 68% 8% 9% 22% 4% 20% 0% 4% 22% 31% 18% 27% 39% 40% 30% 20% 100% 95% J Clin Endocrinol Metab 91: 2843–2850, 2006 Horm Res Paediatr 2010;74:275–284J Clin Endocrinol Metab, April 2012, 97(4):1114–1124
    22. 22. J Clin Endocrinol Metab, April 2012, 97(4):1114–1124
    23. 23.  The presence and sequence of symptoms vary to a great extent in each patientFinnish study 1 median age of onset of the first component was 3.3 years (0.2 to 18 years of range) median age of diagnosing APECED was 7.5 years (range, 0.6 to 45.2 years) Typically, manifestations of APECED begin with a resistant and recurrent candidiasis in the first 5 years of life 1JClin Endocrinol Metab 91: 2843–2850, 2006 SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
    24. 24. Sardinian J Clin Endocrinol Metab 97: 1114–1124, 2012
    25. 25. Finn J Clin Endocrinol Metab 91: 2843–2850, 2006
    26. 26.  Classical diagnosis  2/3 major components or  only one component if a sibling has already been diagnosed complete triad develops in up to two-thirds of patients diagnostic criterion of having at least two elements of this triad would leave many cases missed In some cases the rare components dominate with none of the triad present SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91 Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
    27. 27.  clinical picture varies in severity and in the number of disease components  —with up to 10 abnormalities per patient frequencies of phenotype components vary from one population to another Factors contributing to the complexity of the disease are not yet understood If APECED is suspected, genetic analysis of the AIRE gene may be helpful to confirm diagnosis ,esp. atypical clinical presentations SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    28. 28.  autoantibodies specific for type I interferons (especially IFNα- and IFN-ω)  diagnostic tool for APECED especially in cases where mutational analysis is complicated (for example, large deletions, duplications, or mutations in regulatory or intronic regions) Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    29. 29.  AIRE gene is localized on chromosome 21q22.3 highest concentration in thymus but also found in lymph nodes, spleen, and fetal liver SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    30. 30.  transcriptional regulator located primarily in nucleus can influence the expression of several thousand genes of tissue-specific proteins Ann. N.Y. Acad. Sci. 1246 (2011) 77–91 Nat. Rev. Endocrinol. 7, 25–33 (2011)
    31. 31.  AIRE protein contains a combination of functional domains:  the N-terminal CARD (caspase-recruitment) domain  the SAND (SP100, AIRE, Nuc p41/75, DEAF) domain, located in the middle  two PHD (plant homeo domain) fingers at the C- terminal region of the protein Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    32. 32.  mainly expressed by medullary thymic epithelial cells (mTECs)  presentation of the self- antigens (tissue specific antigen) to developing thymocytes  self tolerance Negative selection Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    33. 33. negative selection ofautoreactive T cells autoantibodies to cytokines respond to self antigens Candidiasis Tolerance Nat. Rev. Endocrinol. 7, 25–33 (2011)
    34. 34.  In medullary thymic epithelial cells (mTECs), AIRE has been suggested not to act as a direct regulator of gene expression  regulator of existing mechanisms of gene expression—both as an enhancer and suppressor basis of the expression of tissue-restricted antigens, in particular antigens from endocrine tissues by mTECs is not well understood Ann. N.Y. Acad. Sci. 1246 (2011) 77–91 Nat. Rev. Endocrinol. 7, 25–33 (2011)
    35. 35.  current AIRE function model  using T cell receptor (TCR) transgenic mouse models self-reactive T cells are naive and in low numbers in the setting of nonmanipulated TCR repertoire The tolerization of potential autoreactive T cells is more likely to occur by multiple peripheral tolerogenic back-up mechanisms Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    36. 36.  The activation of naive self-reactive T cells in the periphery  depend on multiple predisposing and triggering factors  different between individuals The validity of the current and emerging models of disease pathogenesis in APECED should be further evaluated by any means available for human studies  transgenic mouse models cannot be directly applied to human disease Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    37. 37.  Over 60 APECED-associated mutations have been reported in the AIRE gene Most of these mutations, distributed throughout the coding region  Nonsense mutations  Frameshift mutations  Missense mutations  Large genomic deletions affect either AIRE transcriptional activity or its localization to nuclear bodies Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    38. 38. Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
    39. 39.  Most prevalent mutation  R257X mutation in exon 6  13 base-pair deletion (967-979del13bp) in exon 8 R257X – Finnish , European 967-979del13bp - North American, British, and Norwegian Y85C - Iranian Jews R139X - Sardinian Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    40. 40.  different AIRE mutations lead to different phenotypes clinical phenotypes of different mutations overlap Significant variation in clinical presentations of APECED has been described for patients carrying a homozygous R257X mutation, and intrafamilial differences have been reported between siblings of the identical AIRE genotype correlations with respective genotypes are far from clear Nat. Rev. Endocrinol. 7, 25–33 (2011) Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    41. 41.  Anticytokine autoantibodies Anti IL-22 and/or IL-17
    42. 42. Anti IL-22 , IL-17 autoantibodies against the Th17- related cytokines (IL-22, IL-17F, and IL-17A) IL-17A and IL- 22 synergistically exert their function on epithelial cells by inducing the production of chemokines and antimicrobial peptides (S100A7, S100A8, S100A9, β-defensins, and histatins) - direct antifungal activity In contrast to several other syndromes associated with CMC,the PBMCs of APECED patients produce normal or even increased amounts of IL-17A but are deficient in IL-22 and IL-17F secretion Acad. Sci. 1246 (2011) 77–91 Ann. N.Y. Nat. Rev. Endocrinol. 7, 25–33 (2011)
    43. 43. SEB J. Exp. Med. 207, –
    44. 44.  CMC in APECED is essentially autoimmune Thishas led to the suggestion that gradual immunosuppressive treatments in conjunction with administration of antifungal agents might be (paradoxically) beneficial even in cases of apparent immunodeficiency ?? Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    45. 45. Anti-IFN-ω and Anti-IFN-α present early and persist for years useful diagnostic test for APS-1 functional analysis  ability of anti-IFN antibodies to block the action of IFN in vitro  actual role of the autoantibodies in mediating disease pathology is questionable  in fact, patients with APS-1 are not susceptible to viral infections Nat. Rev. Endocrinol. 7, 25–33 (2011) Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    46. 46.  Specifically,we asked if susceptibility to other infections had been overlooked in these patients several cases of unusual or severe infections Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    47. 47. 7/19 patients Horm Res Paediatr 2010;74:275–284
    48. 48.  Japan : severe HSV-1 stomatitis with viral reactivation occurring 2–3 times per year Italy : 2 of 24 patients reported encephalitis Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
    49. 49.  mechanism may result in a susceptibility to viral and bacterial infections  impaired maturation and intracellular communication in monocytes results in an abnormal communication between lymphocytes and monocytes  Spleen atrophy  Immunosuppressive therapies Horm Res Paediatr 2010;74:275–284
    50. 50.  Hormone replacement : endocrinopathies  insulin in type 1 diabetes mellitus  calcium and vitamin D in hypoparathyroidism  thyroid hormone in hypothyroidism Nat. Rev. Endocrinol. 7, 25–33 (2011) Nat. Rev. Endocrinol. 6, 270–277 (2010)
    51. 51.  Mucocutaneous candidiasis must be treated aggressively and monitored for recurrence  antifungal agents should be started at presentation  anywhere along GI tract  if left untreated  squamous cell carcinoma of the oral cavity or esophagus Nat. Rev. Endocrinol. 7, 25–33 (2011) Nat. Rev. Endocrinol. 6, 270–277 (2010)
    52. 52.  If asplenism is identified, vaccinations against  Streptococcus pneumoniae (pneumococcus)  Neisseria meningitides (meningococcus) and  Hemophilus influenzae Nat. Rev. Endocrinol. 6, 270–277 (2010)
    53. 53.  A high clinical suspicion for other autoimmune disease : individuals with APS-1 and their first- degree relatives (AR) Patients with APS-1 must be followed at a center with experience in monitoring and caring for individuals with this condition Siblings should be followed closely, and screening for anti-interferon-ω autoantibodies should be considered recommendations are to evaluate patients with APS-1 at 6-month intervals and screen for autoantibodies Nat. Rev. Endocrinol. 6, 270–277 (2010)
    54. 54.  Diagnosing APECED is crucial because the detection of the potentially life-threatening Addison’s disease implicates early therapy If autoantibodies are present without the associated disease, functional testing is indicated  antibodies against steroid 21-hydroxylase: ACTH stimulation test  islet-cell autoantibodies (insulin, glutamic acid decarboxylase [GAD], islet antigen 2 [IA-2] and the zinc T8 transporter : home blood glucose monitoring and glucose-tolerance testing Nat. Rev. Endocrinol. 6, 270–277 (2010)
    55. 55. Immunosuppressive agents : autoimmune Cyclosporin to treat  severe failure to thrive, keratoconjunctivitis, intestinal malabsorption and alopecia  pure red cell aplasia and clonal proliferation of large granular  Hypocalcemia  Autoimmune hepatitis Methylprednisolone and methotrexate  malabsorption Nat. Rev. Endocrinol. 7, 25–33 (2011)
    56. 56. SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
    57. 57.  With careful treatment Patients can usually cope with the disease and their life expectancy is only slightly decreased oral squamous cell carcinoma or a sudden onset of the disease by hypocalcemic or Addisonian crisis or acute hepatitis can sometimes be of a fulminant nature
    58. 58. Nat. Rev. Endocrinol. 6, 270–277 (2010)
    59. 59.  rare autosomal recessive disease clinical manifestations associated with APS-1 classically involve mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency, but can vary in scope and timing Clinical phenotypes vary greatly from one patient to another, leading to difficulties in diagnosis mutations in AIRE gene  tolerance more studies are required to completely evaluate its contribution
    60. 60.  mutations in AIRE gene  tolerance more studies are required to completely evaluate its contribution Treatment  Hormone replacement  Rx infection  Immunosuppressive drug

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