Autoimmune polyglandular syndrome type 1

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


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


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


SEMINARS IN LIVER DISEASE/VOLUME 29, NUMBER 3 2009


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



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


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


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


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


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


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


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


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


MANAGEMENT

MANAGEMENT

Hormone replacement : endocrinopathies

insulin in type 1 diabetes mellituscalcium and vitamin D in hypoparathyroidism thyroid hormone in hypothyroidism



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



MANAGEMENT If asplenism is identified, vaccinations against

Streptococcus pneumoniae (pneumococcus) Neisseria meningitides (meningococcus) and Hemophilus influenzae


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


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


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



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


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

Health & Medicine

Autoimmune polyglandular syndrome type 1