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Autoimmune polyglandular syndrome type 1 Presented by Suparat Sirivimonpan, MD. October26, 2012
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AUTOIMMUNE POLYGLANDULA
R SYNDROME TYPE I
Suparat Sirivimonpan, MD.26/10/2012
TOPIC OUTLINES Introduction Clinical manifestation Diagnosis Molecular basis Management
INTRODUCTION 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
INTRODUCTION 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
INTRODUCTION 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)
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91J Clin Endocrinol Metab 91: 2843–2850, 2006
INTRODUCTION 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
CLINICAL MANIFESTATION
CLINICAL MANIFESTATION 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)
Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
CLINICAL MANIFESTATION Other early manifestations that can present prior
to the symptoms and/or diseases described above includehepatitis, 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
CANDIDIASIS mucocutaneous candidiasis : oral, ungual,
esophagial and vaginal mucosa and nails
Oral candidiasisCandidal esophagitis esophageal stricture or
squamous cell carcinomaPerianal candidal eczema intestinal mucosal candidiasis Infection of skin of the hands ,face and nailsCandidal 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
CANDIDIASIS 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
ENDOCRINE MANIFESTATION Apart from hypoparathyroidism and Addison’s
disease, hypergonadotropic hypogonadism type 1 diabetes autoimmune thyroid diseases pituitary defects gastric parietal cell atrophy
autoimmune origin
often associated with a specific set of organ-specific autoantibodies
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
J Clin Immunol (2008) 28 (Suppl 1):S11–S19
ENDOCRINE MANIFESTATION 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
GASTROINTESTINAL MANIFESTATIONS
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
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
GASTROINTESTINAL MANIFESTATIONS
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
ECTODERMAL MANIFESTATIONS
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
ECTODERMAL MANIFESTATIONS enamel hypoplasia ≠ 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
OTHER MANIFESTATIONS 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 Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
Horm Res Paediatr 2010;73:449–457
SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
Horm Res Paediatr 2010;74:275–284
France
95%
77%68%
9%
4%0%4%
27%
31%
40%20%
Sardinian 2012
Finn 2006
87%68%
8%
22%20%
22%
18%39%30%100%
J Clin Endocrinol Metab, April 2012, 97(4):1114–1124
J Clin Endocrinol Metab 91: 2843–2850, 2006
J Clin Endocrinol Metab, April 2012, 97(4):1114–1124
CLINICAL MANIFESTATION 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
1 J Clin Endocrinol Metab 91: 2843–2850, 2006SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
J Clin Endocrinol Metab 97: 1114–1124, 2012Sardinian
J Clin Endocrinol Metab 91: 2843–2850, 2006Finn
DIAGNOSIS
DIAGNOSIS Classical diagnosis
2/3 major components oronly 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
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
DIAGNOSIS 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
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
DIAGNOSIS 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
MOLECULAR BASIS: AIRE
FUNCTION AND MUTATION
AIRE (AUTOIMMUNE REGULATOR)
AIRE gene is localized on chromosome 21q22.3 highest concentration in thymus but also found in lymph nodes, spleen, and fetal
liver
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
AIRE
transcriptional regulator located primarily in nucleus can influence the expression of several thousand
genes of tissue-specific proteins
Nat. Rev. Endocrinol. 7, 25–33 (2011)
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
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
MECHANISMS OF APS-1 PATHOGENESIS
AIRE mainly expressed by
medullary thymic epithelial cells (mTECs)
presentation of the self-antigens (tissue specific antigen) to developing thymocytes
self tolerance
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
Negative selection
negative selection of autoreactive T cells
Tolerance
respond to self antigens
autoantibodies to cytokines
Candidiasis
Nat. Rev. Endocrinol. 7, 25–33 (2011)
AIRE 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
Nat. Rev. Endocrinol. 7, 25–33 (2011)
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
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
MECHANISM 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
AIRE MUTATION
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
Hans D. Ochs,et al.,Primary Immunodeficiency Diseases: A Molecular and Genetic 2nd edition
AIRE MUTATION : GENOTYPE 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
AIRE MUTATION : PHENOTYPE 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
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91Nat. Rev. Endocrinol. 7, 25–33 (2011)
WHY DO THEY HAVE CMC ?? Anticytokine autoantibodies
Anti IL-22 and/or 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
Anti IL-22 , IL-17
Nat. Rev. Endocrinol. 7, 25–33 (2011)
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
J. Exp. Med. 207,299–308 (2010)
SEB
CMC CMC in APECED is essentially autoimmune
This has 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
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
Anti-IFN-ω and Anti-IFN-α
Nat. Rev. Endocrinol. 7, 25–33 (2011)
Ann. N.Y. Acad. Sci. 1246 (2011) 77–91
OTHER INFECTION 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
Horm Res Paediatr 2010;74:275–284
7/19 patients
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
OTHER INFECTION 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
MANAGEMENT
MANAGEMENT
Hormone replacement : endocrinopathies
insulin in type 1 diabetes mellituscalcium and vitamin D in hypoparathyroidism thyroid hormone in hypothyroidism
Nat. Rev. Endocrinol. 6, 270–277 (2010)
Nat. Rev. Endocrinol. 7, 25–33 (2011)
MANAGEMENT
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. 6, 270–277 (2010)
Nat. Rev. Endocrinol. 7, 25–33 (2011)
MANAGEMENT If asplenism is identified, vaccinations against
Streptococcus pneumoniae (pneumococcus) Neisseria meningitides (meningococcus) and Hemophilus influenzae
Nat. Rev. Endocrinol. 6, 270–277 (2010)
MANAGEMENT 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)
MANAGEMENT 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)
MANAGEMENTImmunosuppressive agents : autoimmune Cyclosporin to treat
severe failure to thrive, keratoconjunctivitis, intestinal malabsorption and alopecia
pure red cell aplasia and clonal proliferation of large granular
HypocalcemiaAutoimmune hepatitis
Methylprednisolone and methotrexate malabsorption
Nat. Rev. Endocrinol. 7, 25–33 (2011)
SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009
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
Nat. Rev. Endocrinol. 6, 270–277 (2010)
TAKE-HOME MESSAGES 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
TAKE-HOME MESSAGES mutations in AIRE gene tolerance more studies are required to completely
evaluate its contribution Treatment
Hormone replacement Rx infection Immunosuppressive drug
THANK YOU FOR YOUR ATTENTION
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