Autoimmune polyglandular syndrome type 1 Presented by Suparat Sirivimonpan, MD. October26, 2012

1. Suparat Sirivimonpan, MD.
26/10/2012

2.  Introduction
 Clinical
manifestation
 Diagnosis
 Molecular basis
 Management

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.  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.  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.  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

8.  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

9.  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

10.  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

11.  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

12.  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

13. Ann. N.Y. Acad. Sci. 1246 (2011) 77–91

14. J Clin Immunol (2008) 28 (Suppl 1):S11–S19

15.  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

16.  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

17.  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

18.  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

19.  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

20.  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

21. SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009

22. 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;74:275–284
J Clin Endocrinol Metab, April 2012, 97(4):1114–1124

23. J Clin Endocrinol Metab, April 2012, 97(4):1114–1124

24.  The presence and sequence of symptoms vary to
a great extent in each patient
Finnish 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

25. Sardinian J Clin Endocrinol Metab 97: 1114–1124, 2012

26. Finn J Clin Endocrinol Metab 91: 2843–2850, 2006

28.  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

29.  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

30.  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

32.  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

33.  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)

34.  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

36.  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

37. negative selection of
autoreactive T cells
autoantibodies
to cytokines
respond to self antigens
Candidiasis
Tolerance
Nat. Rev. Endocrinol. 7, 25–33 (2011)

38.  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)

39.  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

40.  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

41.  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

42. Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition

43.  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

44.  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

45.  Anticytokine autoantibodies
 Anti IL-22 and/or IL-17

46. 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)

47. SEB
J. Exp. Med. 207, –

48.  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

49. 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

50.  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

51. 7/19 patients
Horm Res Paediatr 2010;74:275–284

52.  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

53.  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

55.  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)

56.  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)

57.  If asplenism is identified, vaccinations against
 Streptococcus pneumoniae (pneumococcus)
 Neisseria meningitides (meningococcus) and
 Hemophilus influenzae
Nat. Rev. Endocrinol. 6, 270–277 (2010)

58.  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)

59.  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)

60. 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)

61. SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009

62.  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

63. Nat. Rev. Endocrinol. 6, 270–277 (2010)

64.  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

65.  mutations in AIRE gene  tolerance
 more studies are required to completely
evaluate its contribution
 Treatment
 Hormone replacement
 Rx infection
 Immunosuppressive drug