ahlgren…lobell et al increased il-17a secretion in response to candida albicans in autoimmune...

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Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J Immunol 2011, 41:235-245 Kisand…Meager et al Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 2010 207:299-308 Puel….Casanova et al Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 2010, 207:264-265. “Th17” Anti-Cytokine Autoantibodies (IL- 17A, IL17F, IL-22) and abnormal Th17 T cell function Associated with Mucocutaneous Candidiasis of APS-1 Anti-Cytokine Autoantibodie s

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Page 1: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J Immunol 2011, 41:235-245

Kisand…Meager et al Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 2010 207:299-308

Puel….Casanova et al Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 2010, 207:264-265.

“Th17” Anti-Cytokine Autoantibodies (IL-17A, IL17F, IL-22) and abnormal Th17 T cell function Associated with Mucocutaneous Candidiasis of

APS-1

Anti-Cytokine Autoantibodies

Page 2: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

80%Multiplex

Simplex

Control

Baker et al. Haplotype Analysis discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease. JCEM 2010 95:E263-E270.

Multiplex Addison’s Families Greater DR3/4-B8

Less Complete DR3-B8-A1 Extended Haplotype

Page 3: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

General Paradigm

• Identify Genetic Susceptibility

• Detect Initial Autoantibodies

• Monitor Metabolic Decompensation

• Treat Overt Disease Prior to

Morbidity/Mortality

• Basic/Clinical Research to Allow Prevention

Page 4: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Associated Autoimmune IllnessesCeliac Disease: Diarrhea, weight loss, growth

failure, abdominal pain, osteoprorosis, anemia

Hyperthyroid: Hypothyroid:

Weight loss, feeling warm, anxiety, bulging eyes Weight gain, feeling cold

Pernicious Anemia: Anemia, movement problems

Addison’s Disease: Darkening of skin, loss of weight, dizziness, nausea

Ovarian Failure: Premature menopause, hot flashes, infertility

Myasthenia Gravis: Muscle weakness, double vision

Diabetes Mellitus: Increased urination, thirst, appetite, weight loss, coma

Page 5: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Premature Mortality in Patients with Addison’s Disease: A Population-Based Study

J clin endocrinol Metab 91:4859, 2006

0

5

10

15

20

25

30

Addison's Expected

Percent Dying 6.7 yr follow-up; mean start age 52.8

N=507 deaths of 1675 patients N=199 deaths

Page 6: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Autoimmune Polyendocrine Syndromes• APS-II (Autoimm Polyendocrine)

• APS-I (AIRE mutation)

• XPID: (Scurfy Mutation)

• Anti-insulin Receptor Abs + “Lupus”

• Hirata (Anti-insulin Autoantibodies)

• POEMS (Plasmacytoma,..)

• Thymic Tumors + Autoimmunity

• Congenital Rubella + DM +Thyroid

Page 7: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Polyendocrine non-Autoimmune Syndromes

• Wolfram’s Syndrome – DIDMOADDiabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (WFS1 gene mutation on Chromosome 4)

• Kearns-Sayre SyndromeExternal Ophthalmoplegia, Retinal Degeneration, Heart Block- Diabetes, Hypoparathyroidism, Thyroiditis reported (Mitochondrial deletions, rearrangments)

Page 8: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

APS-SyndromesBetterle et al. Endocrine Reviews 2002

Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine Disorders

• APS-I:>=2 of Candidiasis, Hypopara,Addison’s

• APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes (Addison’s must be present)

• APS-III: Thyroid Autoimmune + other autoimmune [not Ad, hypopara, candidiasis]

• APS-IV: Two or more organ-specific autoimmune, not I,II, or III.

Page 9: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Comparison APS-I and APS-II APS-I APS-II

• Onset Infancy• Siblings

AIRE gene mutated• Not HLA Associated• Immunodeficiency

AsplenismMucocutaneous Candidiasis

• 18% Type 1 DM

• Older Onset• Multiple Generations• DR3/4 Associated• No Defined

Immunodeficiency• 20% Type 1 DM

BDC

Page 10: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

APS-I• Autoimmune Polyendocrine Syndrome Type

1• Autosomal Recessive mutations AIRE

(Autoimmune Regulator) gene• Mucocutaneous Candidiasis/Addison’s

Disease/Hypoparathyroidism• 18% Type 1 Diabetes• “Transcription Factor” in Thymus

BDC

Page 11: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Diagnosis

• Classic criterion – At least two:

• Chronic recurrent mucocutaneous candidiasis• Hypoparathyroidism• Addison’s disease• Prevalence of these criterion by 30 years is only 94%

– High index of suspicion with individuals presenting with multiple autoimmune disease

– In siblings one autoimmune disease is required for diagnosis

• Mutation analysis– Three most common mutations may miss 5%

Page 12: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

AIRE (Autoimmune Regulator) and Percentage Mutations APS-I: Halonen JCEM 87:2568,2002

0 100 200 300 400 500

Homogeneously StainingDomain

SAND DomainPlextrin

Homology 1

Plextrin

Homology 2

LX

LL

LX

LL

LX

LL

LX

LL

NL

S

0

10

20

30

40

50

60

C322fsX372

Page 13: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Mutations in the AIRE gene causing APS1 (She et al)

Exon/Intron Mutation Change in coding sequence No of Alleles Population

Exon 6 769C>T R257X 170 Multiple

Exon 8 967-979del13bp C322fsX372 85 Multiple

Exon 2 254A>G Y 85C 26 Iranian J ews

Exon 3 415C>T R139X 21 Egyptian, Sardinian

Exon 8 1085-1097del13bp P367>X 22 Norwegian

Exon 8 1094-1106del13bp G374>X 9 American

Exon 8 969 9̂70insCCTG L323fsX372 6 Italian

Exon 5 607C>T R203X 6 Italian

Exon 1 30-52dup23bp R15fsX19 2 Hispanic, Australian

Exon 1 44G>T R15L 1 British

Exon 1 47C>T T16M 1 Russian

Exon 1 83T>C L28P 2 American, British

Exon 1 86T>C L29P 1 J apanese

Intron 1 IVS1_IVS4 Deletion of Exons 2-4 2 Russian

Exon 2 232T>A W78R 1 Russian

Exon 2 238G>T V80L 1 Italian

Exon 2 247A>G K 83E 1 French

Exon 2 269A>G Y 90C 1 British

Exon 2 191-226del36bp Del67-75&D76Y 1 American

Exon 2 208 2̂09insCAGG D70fsX216 2 Arabian

Exon 2 278T>G L93R 1 French Canadian

Intron 3 IVS3+2T>C GT>GC 1 American

Exon 4 508 5̂09ins13bp A170fsX219 1 German

Exon 4 517C>T Q173X 2 Hispanic, Italian

Exon 6 682G>T G228>W 1 Italian

Exon 8 901G>A V301M 1 Norwegian

Exon 8 931delT C311fsX376 2 French

Exon 8 932G>A C311Y 2 Finnish

Exon 8 977C>A P326Q 2 Finnish, French

Intron 9 IVS9G>C G>C skip exon 10 60aa 1 J apanese

Intron 10 IVS9G>A G>C skip exon 10 60aa 1 Hispanic

Exon 10 1103 1̂104insC P370fsX370 1 J apanese

Exon 10 1163 1̂164insA M388fsX422 2 Finnish

Exon 10 1189delC L397fsX478 2 French

Exon 10 1193delC P398fsX478 4 French, Italian

Exon 10 1242 1̂243insA H415fsX422 2 Norwegian

Exon 10 1244 1̂245insC L417fsX422 1 German

Exon 10 1249delC L417fsX478 1 British

Exon 10 1264delC P422fsX478 2 American

Exon 11 1295insAC C434fsX479 1 American

Exon 11 1296delGinsAC R433fsX502 1 American

Exon 11 1344delCinsTT C449fsX502 1 J apanese

Intron 11 IVS11+1G>A GT>AT, X476 1 J apanese

Exon 13 1513delG A502fsX519 1 K orean

Exon 14 1638A>T X564C+59aa 5 Finnish

Page 14: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

TCR

MHC + Peptide

Autoreactive thymocyte

Self-peptides from "peripheral"

antigens

Tolerization of autoreactive thymocyte

MODEL AIRE Role in Preventing Autoimmunity

Thymic MedullaryEpithelial Cells

AIRE

Mathis/Benoist

Page 15: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Highly variable expression of tissue-restrictedself-antigens in human thymus: Implications forself-tolerance and autoimmunity

Richard Taubert, Jochen Schwendemann and Bruno KyewskiDivision of Developmental Immunology, Tumor Immunology Program, German CancerResearch Center, Heidelberg, Germany

Page 16: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Insulin Message but not GAD67 thymic meduallary epithelial expression is tremendously variable and

correlates with AIRE message

Log scale100-fold differences

Continuous not step-wise variation

Taubert et al, 2007 EJI

Page 17: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Gene Dosage-limiting Role of Aire in Thymic Expression, Clonal Deletion, and Organ-Specific Autoimmunity

Liston et al. J. Exp Med 200:1015, 2004

0

0.1

0.2

0.3

0.4

0.5

Aire+/+ Aire+/- Aire-/-

Mature Transgenic Thymocytes

0

10

20

30

40

50

60

70

Aire+/+ Aire+/- Aire-/-

Percent Diabetic

Rip-HEL Antigen+CD4 T Cell Receptor anti-HEL Model

X107 CD4+Cd8-1G12-CD69-

Page 18: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Halonen JCEM 87:2568,2002104 APS-I International Series Patients

Greater % Addison’s and Candidiasis with R257XNonsense (X) Mutation

0

20

40

60

80

100

R257X/R257X R257X/n n/n

Addison's Candidiasis

Page 19: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

0

13 66

25

DiabetesNot Diabetic

DQB1*0602+

DQB1*0602-

APS-I Patients Protected from Diabetes by DQB1*0602

Halonen et al JCEM 87:2574, 2002

16.4%

P=.03

Page 20: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

NALP5:HypoparathroidismNACHT leucine-rich-protein 5

• >>Expression Parathyroid and Ovary

• 41% Hypopara+APS-1 Positive 0% Not

• APS-1 Animal Model “Have Abs”

• 68% Hypogonad+; 29% not Hypogonad

• Day 3 Thymectomy model +

Kampe et al NEJM 358:1018, 2008

Page 21: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

A. 6 Month Evaluation APS-I (Perheentupa)

• Check oral Candida, Autontibodies, Ca,Pi,Na,K,Mg, Alkaline phosphatase,ACTH,TSH, HCG,renin, HbA1c, Howell-Jolly smear, platelets

• Autoantibodies: 21-hydroxylase (Addison’s), GAD65 (Diabetes), 17-OH, CYP450scc (hypogonadism/Addison’s); Tryptophane hydroxylase (intestine chromaffin cell loss), H/K ATPase and Intrinsic factor (Pernicious anemia), Thyroid peroxidase (hypothyroidism)

• If hypoparathyorid: every 6 to 8 weeks check Ca• Intense control oral candida (e.g. amphotericin lozenge, fluconazole or

ketoconazole if needed) with prompt biopsy suspicious lesion. Careful mouth hygiene with elimination of sharp points of teeth and plastic materials from mouth.

• No live virus immunization• Patient web site: http://www.empower.org.nz

Page 22: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

B. 6 Month Evaluation APS-I (Perheentupa)

• Carry written warning of disease symptoms/complications• If Howell-Jolly bodies on smear, ultrasound spleen• Asplenic patients need meningococcal and hemophilus

influenza type b immunization and pneumococcal vaccine with measured response. If no response to pneumococcal vaccine, prophylactic daily antibiotics

• Keratoconjunctivitis: Topical steroid and vitamin A• Potential immunosuppression for hepatitits, refractory

diarrhea and other refractory disorders

Page 23: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Check List APS-I Visit

New Symptoms History

New Signs Physical

Oral Candidiasis

New Antibodies (21-OH, GAD, IA-2)

Ca, Pi, Mg

Na, K

ALT

ACTH, TSH, (LH, FSH)

HbA1c

Blood Smear (Howell-Jolly)

Platelet Count

Other

Page 24: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Oral Cancer Prevention APS-I

• Aggressive Therapy Oral CandidiasisAmphoteracin Lozenges for early infectionFluconazole/Keotoconazole(2-3 weeks)Itaconazole (4-6 months) for nail candida

• Prompt biopsy of suspicious oral lesion

BDC

Page 25: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Immunodeficiency APS-I

• Live virus vaccination avoided

• If splenic atrophy present (Howell-Jolly bodies of blood smear, ultrasound)-Pneumococcal vaccine with Antibody response monitoring(6-8 weeks)-If no antibody response daily antibiotic prophylaxis

BDC

Page 26: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Gastrointestinal disease

• Pernicious anemia

• Autoimmune hepatitis• Diarrhea

– Hypocalcemia from hypoparathyroidism– Celiac disease– Intestinal infection (candida)– Autoimmune destruction of endocrine cells of duodenal

mucosa

• Severe constipation

Page 27: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Table 8.5Unusual manifestations of disease – APS-I

• Pituitary hormone deficiency (diabetes insipidus, growth hormone, gonoadotropic, ACTH deficiency)

• Autoimmune disease (hyperthyroidism, rheumatoid arthritis, Sjogren’s syndrome, periodic fever with rash, antisperm autoimmunity, hemolytic anemia)

• Hemetologic manifestations (pure red cell aplasia, autoimmune hemolytic anemia, splenomegaly and pancytopenia, Ig A deficiency)

• Ocular disease (iridocyclitis, optic nerve atrophy, retinal degeneration)

• Other organ system involvement (nephritis, cholelithiasis, Bronchiolitis obliterans organizing pneumonia, Lymphocytic myocarditis)

• Hypokalemia with or without hypertension• Metaphyseal dysostosis

Page 28: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea

• Other NamesIPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linkedXLAAD: X-Linked Autoimmunity Allergic Dysregulation

• Foxp3 Gene Mutation

• Loss of Regulatory T LymphocytesBone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man

BDC

Page 29: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Mutations for XPID Syndrome Scurfy/Foxp3/JM2 Gene

Fork Head HomologyZn Zip

X

X

Scurfy

D

ORF

XLAAD-100

XLAAD-200

Zn = Zinc-finger domain, Zip = Zip Motif

ORF = Predicted Open Reading Frame

Modified from Review by Patel, JCI, 2000

Page 30: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Type II Syndrome DiseasesDISEASE HLA ASSOCIATION

Graves’ DR3, DQ2 Type 1A DM DR3,DQ2; DR4,DQ8 Celiac DQ2 (DR5/7 or DR3) and

DR4,DQ8 Addison’s DR3,DQ2; DR4,DQ8

Thyroiditis DQB1*0201; DQA1*0301

Insulin Autoimmune

DR4, DRB1*0406

BDC

Page 31: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Addison’s: DR3/4 DQ8 DRB1*0404

05

1015202530354045

Per

cent

Wit

h G

enot

ype

Addison'sUSA

USAPopulation

Addison'sNorway

NorwayPopulation

3/4 DQ8 3/4 DQ8 (DRB1*0404)

U.S. Odds Ratio: 3/4 DQ8= 32; 3/4 DQ8 DRB1*0404 = 98

U.S. Risk= 1/200 Addison’s with 3/4 DQ8 DR0404 (1/500 Norway)

Information from Yu et al JCEM, 84:328-335, Myhre et al JCEM, 87:618-623,2002

Page 32: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

PTPN22 Lymphoid Tyrosine Phosphatase R620W Allele

in Graves’ and Addison’s Disease

0

10

20

30

40

50

60

70

80

90

CC TC TT

Graves'Addison'sControls

Odds ratio T allele Graves=1.88

Odds ratio T Addison’s=1.69

Velaga et al The codon 620 Tryptophan Allele of Lymphoid Tyrosine Phosphase (LYP) Gene is a major determinant of Graves’ Disease JCEM 89:5862, 2004

Page 33: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

MIC-AMHC Class I Chain-related Genes

• Near HLA B

• No Classical Binding Groove

• Predominantly expressed in intestine

• NK cell Receptor; gamma delta cells

• Addison’s Association Sanjeevi et al.

• Triplet repeat within gene, and allele 5.1 has 1 extra nucleotide=frameshift, no transmembrane

BDC

Page 34: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

0

10

20

30

40

50

60

70

MH30 G +49 G CT60 G JO31 G JO30 G JO27_1 T

CTLA-4 Polymorphisms - Allele FrequenciesBlomhoff JCEM 2004, 89:3474

Norway Add Norway Ctrl UK Add UK Ctrl

JO30 G: Odds ratio 1.5 for combined

Page 35: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Percent 21-OH Autoantibody Positive/ Patients with type 1 DM

0

1

2

3

4

5

6

DQ2/DQ8 0501/0301:X DQ2/DQ2 DQ8/DQ8 Other

N=208 53 57 55 307

Yu et al, JCEM, 1999 BDC

Page 36: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

21-Hydroxylase Autoantibodies

0.5

1

1.5

2

Levels of autoantibodies

Healthy Controls Negatives PositivesType I Diabetics

n= 241 n= 817 n= 13

Figure 2

KnownAddison's

Yu et al, JCEM, 1999

Page 37: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Stages Adrenal Function 21-hydroxylase Positive Patients: Modified from Betterle

Endocrine Reviews 23:327-364,2002Stage ACTH Cort 0 Cort 60 Renin Aldos Sign

0’ 0’ 60’ 0’ O’ Addis

0(Potential) normal normal normal normal normal No

1 (Subclin) normal normal normal Incr +/- No

2 (Subclin) normal normal Decr Incr +/- No

3(Subclin) N/Incr Decr Decr Incr Decr No

4(Clinical) Incr Decr Decr Incr Decr yes

Page 38: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

SerositisTucker WS, et al. Serositis with Autoimmune Endocrinopathy:

Clinical and Immunogenetic Features. Medicine. 1987.– Retrospective review of 20 pts presenting with serositis and

autoimmune endocrinopathies between 1967 and 1984 at Vanderbilt University

– Could include: Thyroiditis, Grave’s, Addison’s, 1o hypogonadism, Type 1 DM, 1o Hypoparathyroidism

– Serositis = idiopathic pleuritis, pleural effusion, pericardial effusion, peritonitis or ascites

– Checked Abd: microsomal, thyroglobulin, TSH receptor, islet cells, adrenal cortical cells and ovarian follicular cells

– Extensive Rheumatologic tests

– Immunogenetic tests (HLA antigens)

Tucker WS. Medicine. 1987.

Adochio slide

Page 39: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Results:– 7 pts with APS-II– 4 pts with SLE (?)– No pt with hypopara or candidiasis– 45 total episodes of serositis– 25 episodes in the hospital = 10% of all inpatient cases of

idiopathic/rheumatologic serositis– 4 episodes of pericardial tamponade– Fevers, pleuritis, dyspnea, pericarditis– Some episodes occurred simultaneously with onset of

endocrinopathy

Serositis

Tucker WS. Medicine. 1987.

Adochio slide

Page 40: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

15 unrelated Caucasian pts:

• 80% HLA-B8 (17% controls)

• 73% HLA-DR3 (22% controls)

17 pts phenotyped for C4:

• 52% C4AQ0 phenotype (all B8 & DR3)

Serositis

Tucker WS. Medicine. 1987.

Adochio slide

Page 41: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

A family of diseases occurring in families

Type 1A Diabetes

Celiac Disease

Addison’s Disease

BDC

Page 42: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

DP DQ DR B C A

+++? +++ ? ? +

WHICH HLA LOCI ARE INVOLVED APS-II?

Modified from Noble

MIC-A

Page 43: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Major DR/DQ Associations• Type 1 Diabetes

DR3: DRB1*0301/DQA1*0501/DQB1*0201DR4: DRB1*0401/DQA1*0301/DQb1*0302

• Celiac DiseaseThe same as Type 1 DM plusDR5/DR7 = DQA1*0501/DQB1*0201 in trans

• Addison’s DiseaseThe same as Type 1 DM but DRB1*0404 preference (Yu, JCEM 84:328,1999)

BDC

Page 44: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Known Initiators

DISEASE INITIATOR ASSOCIATIONCeliac Gliadin/wheat

glutenPredominant

InsulinAutoImmune

SH-Drugsmethimizole

Predominant

Type 1 DM Cong Rubella RareThyroiditis Iodine “Common”Graves’ Anti-CD52 RareMyasthenia Penicillamine Rare

Page 45: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with

alemtuzumab (Campath-1H)

Joanne L. Jones, et al JCI 119:2052-2061, 2009

Page 46: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Mediator/Autoantigen(s)

Graves’ Antibody TSH ReceptorMyasthenia Antibody ACh ReceptorInsulin Auto Antibody InsulinCeliac ? TransglutaminaseType 1 DM T Cell Insulin/GAD/

ICA512Addison’s T Cell 21-OHThyroiditis T Cell Thyroglobulin

Peroxidase

Page 47: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Celiac Disease

• Intestinal Autoimmune Disorder

• Anti-Transglutaminase (EMA)

• 1/200 General Population U.S./Europe1/20 Patients with Type 1 DM1/6 Patients Type 1 DM who are DR3/DR3

• Gliadin Induction

• Hypothesis: transglutaminase+gliadin

Page 48: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

Celiac disease introduction

• Also known as “gluten sensitive enteropathy”

• Celiac disease is considered an autoimmune disease, mediated by T cells

• Associated with other autoimmune diseases– Type 1 diabetes, autoimmune thyroid

• Autoantibodies to tissue transglutaminase are one of the hallmark features of celiac disease

Liu

Page 49: Ahlgren…Lobell et al Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J

• Gluten is the environmental trigger– Comes from a group of plant storage proteins

called prolamins• Found in wheat (gliadin), rye (secalin), and barley

(hordien)

– Treatment is lifelong dietary avoidance of gluten (gluten-free diet, GFD)

• Found in pastas, bread, most marinated meats, salad dressings, beer

Celiac disease introduction

Liu

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A brief historical perspectiveEarly 19th century Dr. Mathew Baillie described a chronic diarrheal disorder causing

malnutrition characterized by a gas-distended abdomen. “Some patients have appeared to derive considerable advantage from living almost entirely upon rice.”

75 years later Samuel Gee sensed that “if the patient can be cured at all, it must be by means of diet.” Described a child “who was fed upon a quart of the best Dutch mussels daily, throve wonderfully, but relapsed when the seasons for mussels was over.”

1918 Sir Frederick Still, Royal College of Physicians "Unfortunately one form of starch which seems particularly liable to aggravate the symptoms is bread. I know of no adequate substitute.“

1924 Haas Cornerstone of therapy: the high-banana diet. Specifically excluded bread, crackers and all cereals. Decades of success.

Professor Dicke 1950 Bread shortages in Netherlands coincided with improvements in children with celiac disease. When Allied plans dropped bread into the Netherlands, they quickly deteriorated. Doctoral thesis reported that celiac children benefited dramatically when wheat, rye and oats flour were excluded from the diet

1950’s Charlotte Anderson extracted wheat starch and determined that the resulting “gluten mass” was the harmful component of wheat. Formed the basis of today’s “gluten-free diet”

Liu

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• diarrhea

• distention

• vomiting

• abdominal pain

• weight loss

• malnutrition

Celiac disease in London, 1938

Liu

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Clinical Presentations

• Intestinal– diarrhea, distention, vomiting, abdominal pain, weight

loss

• Extra-intestinal– rash, pubertal or growth delay, anemia, osteopenia

• Asymptomatic– Type 1 diabetes, relative with CD or diabetes

Liu

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1:5000Clinical symptoms

The Celiac Iceberg:

Liu

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Antibodies and Celiac Disease• Anti-Gliadin antibodies – Less Specific/Less Sensitive ?

Utility• Calreticulin antibodies – calcium binding protein

– Not disease specific– No studies to correlate with degree of intestinal injury

• Anti-actin antibodies - against cytoskeletal structure– Correlation with degree of intestinal injury– Needs further study

• EMA – Endomysial antibody– Immunofluorescent test human umbilical cord– Probably = high TG autoantibodies (highly specific/ less

sensitive)

• Transglutaminase autoantibodies (TG)

Liu

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Diagnosis of celiac disease

Endoscopic findings suggestive of celiac disease (CD) include loss of duodenal folds, scalloped folds

Normal Celiac

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NormalNormal

Villous atrophy

IELsIELs

Histologic Features of CD

Liu

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Role of transglutaminase in celiac disease

• Transglutaminase (TG) is required for:– Deamidation of Glutamine (Q) to Glutamic Acid (E)

on gliadin peptides• Enhances the immunogenicity of gliadin

– Crosslinks proteins (ie TG-gliadin complexes)

• Similar to deimination of arginine to citrulline by peptidylarginine deiminase (PAD) to create citrullinated antibodies in RA and MS

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Ovalbumin vs wheat gliadinSelective deamidation of Glutamine (Q) to Glutamic Acid (E)

QXP into EXP and other algorithms

1 MGSIGAASME FCFDVFKELK VHHANENIFY CPIAIMSALA MVYLGAKDST RTQINKVVRF

61 DKLPGFGDSI EAQCGTSVNV HSSLRDILNQ ITKPNDVYSF SLASRLYAEE RYPILPEYLQ

121 CVKELYRGGL EPINFQTAAD QARELINSWV ESQTNGIIRN VLQPSSVDSQ TAMVLVNAIV

181 FKGLWEKAFK DEDTQAMPFR VTEQESKPVQ MMYQIGLFRV ASMASEKMKI LELPFASGTM

241 SMLVLLPDEV SGLEQLESII NFEKLTEWTS SNVMEERKIK VYLPRMKMEE KYNLTSVLMA

301 MGITDVFSSS ANLSGISSAE SLKISQAVHA AHAEINEAGR EVVGSAEAGV DAASVSEEFR

361 ADHPFLFCIK HIATNAVLFF GRCVSP

1 MKTFLILALL AIVATTATTA VRVPVPQPQP QNPSQPQPQR QVPLVQQQQF PGQQQQFPPQ

61 QPYPQPQPFP SQQPYLQLQP FPQPQPFPPQ LPYPQPPPFS PQQPYPQPQP QYPQPQQPIS

121 QQQAQQQQQQ QQQQQQQQQQ QQILPQILQQ QLIPCRDVVL QQHNIAHARS QVLQQSTYQP

181 LQQLCCQQLW QIPEQSRCQA IHNVVHAIIL HQQQQQQQPS SQVSLQQPQQ QYPSGQGFFQ

241 PSQQNPQAQG SVQPQQLPQF EEIRNLALQT LPRMCNVYIP PYCSTTTAPF GIFGTN

Proline content ~ 14% of gliadinGlutamine/Glutamic acid content ~ 46% of gliadin

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Significance of TG autoantibodies

• Data controversial 2 suggest inhibition of enzymatic activity, 2 suggest insufficient inhibition– Latest study by Schuppan suggests that patient’s

TG autoantibody is insufficient to block TG enzymatic activity

• Pathogenic role?– Celiac disease common in selective IgA

deficiency– No evidence to suggest pathogenic role in

enteropathy

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Proposed formation of TG autoantibodies

Gliadin-reactiveT cell

T cell help

TG-reactiveB cell

TG

Gliadin

Gliadin peptides

DQ2

1. TG crosslinks to gliadin2. Gliadin-TG complexes taken up by B

cells– Function as a hapten

3. Prossessed and presented4. DQ2-gliadin recognized by gliadin-

reactive T cell5. T cell help to B cells to make TG

autoantibodiesAdapted from Sollid L, Gut 1997

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Population Based Swedish Celiac Cohort1964-1993: 10,032

0-4 5-19 20-39 40-59 60-69 >=701

10

100

1000No. Deaths

Excess Deaths

Age at Death

Num

ber D

eath

s/Ex

cess

Num

ber 828 Deaths

Intest malignancy 21

Non-Hodg Lymph 33

Peters, Arch Int Med 163:1566-1572

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Prevalence of TGA by HLA-DR amongst patients with type 1 DM, relatives of DM patients and

general population

0%

5%

10%

15%

20%

25%

DR3+ DR3-

IDDMRelativesPopulation

Prevalence

HLA-DR

BDC

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Liu E et al. Clin Gastroenterol Hepatol 2003

TG Index 0.05 0.1 0.25 0.5 0.75

PPV 0.76 0.80 0.89 0.96 1NPV 1 1 0.75 0.65 0.39

Higher TG levels are more predictive of villous atrophy

(Marsh Score) Increasing villous atrophy

0 1 2 30.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

TG

In

dex

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Pre GFD Post GFD First Positive Last F/U0.001

0.01

0.1

1

10

TG

AA

ind

ex

p < 0.001

ns

p < 0.001

Pre GFD Post GFD First Positive Last F/U

0

50

100

150

200

DG

P u

nit

s

p < 0.001

ns

p < 0.001

GFD Regular diet

DGP antibodies resolved sooner than TG on GFD (mean follow-up was 2 years)

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Clinical Features of Children With Screening-Identified Evidence of Celiac Disease

Hoffenberg et al, Pediatrics 113:1254, 2004

• 13/18 (2.3-7.3 years old) of Transglutaminase autoantibody+ abnormal small bowel biopsy

• Decreased Z-score weight for height (-0.3)

• Decreased BMI Z-score (-0.3)

• Zinc concentration inversely correlated with intestinal biopsy

• Post antibody increased symptoms (irritability/lethargy; distention/gas; poor weight gain)

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Bone Mass Subclinical Celiac Disease Corazza Bone 18:525,1996

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

Controls Subclinical Classical-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5Z-Scores

Before

Gluten Free

DietMedian age 28.5, 7/11 relatives CD patients

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Nature 456, 534-538 (27 November 2008)

The role of HLA-DQ8 57 polymorphism in the anti-gluten T-cell response in coeliac diseaseZaruhi Hovhannisyan, Angela Weiss, Alexandra Martin, Martina Wiesner, Stig Tollefsen, Kenji Yoshida, Cezary Ciszewski, Shane A. Curran, Joseph A. Murray, Chella S. David, Ludvig M. Sollid, Frits Koning, Luc Teyton & Bana Jabri

Department of Medicine, Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USADepartment of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USADepartment of Immunohematology and Blood Transfusion, Leiden University, 2300 RC, Leiden, The NetherlandsCentre for Immune Regulation, Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, NorwayThe Scripps Research Institute, La Jolla, California 92037, USADepartment of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USACentre for Immune Regulation, Institute of Immunology, University of Oslo, 0027 Oslo, Norway

J COHEN

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Celiac Disease

Antigen is a gliadin, a proline/glutamine rich protein in wheat, barley and rye. There are several gliadins, which combine with glutenins to form gluten, the crosslinked elastic protein which allows bread to rise.

All gliadin-specific CD4 T cells from the intestines of adult patients see an immunodominant gluten peptide on HLA-DQ2 or HLA-DQ8.MHC →40% of risk.

The immunogen studied here is α2 gliadin 219-242:QQPQQQYPSGQGSFQPSQQNPQAQ

From which the epitope (DQ8-α-I) recognized by many HLA-DQ8-

restricted CD4 cells is: QGSFQPSQQ “Q”while most see a deamidated version, EGSFQPSQE “E” [Gln 229 and 237 are targets of tissue transglutaminase.] J COHEN

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Glutamine (Gln, Q) Glutamic acid (Glu, E)

Tissue Transglutaminase (TG2) is activated during gut inflammation, and converts many gliadin Q residues to E.

J COHEN

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From Fig 4. of: A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.Henderson KN, Tye-Din JA, Reid HH, Chen Z, Borg NA, Beissbarth T, Tatham A, Mannering SI, Purcell AW, Dudek NL, van Heel DA, McCluskey J, Rossjohn J, Anderson RP.Immunity. 2007 Jul;27(1):23-34.

The basic P9 pocket (blue)

J COHEN

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Previous/Supplemental: Can get strong responses to native peptides thatcannot be demonstrated to bind to HLA-DQ8! They should have a negative charge to bind to the strongly positive P9 pocket in DQ8. But they don’t.

Can these peptides can be stabilized in the MHC Class IIcleft if the TCR has a negative amino acid at CDRβ3 position 3?

J COHEN

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Conclusions and speculation:1.Because of high glutamine (Q) and proline (P) content, gluten peptides are difficult to digest fully, so immunogenic peptides may linger.2.If absorbed, they associate poorly with HLA-DQ8 because its positive P9 pocket interacts weakly with their uncharged Q.3.However, the structure of the peptide – DQ8 complex can be stabilized by a TCR with a negative amino acid in CDR3β position 3.4.Most responsive clones respond as well or better on deamidated peptides where Q → E.5.TTG is activated in inflammation, causing more Q → E.6.T cell clones responding to deamidated peptides have no special restrictions on CDR amino acids, so many more clones are recruited.7.So things go from bad to worse.

J COHEN

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Barbara Davis Center• New Onset Patients

Anti-Islet Autoantibodies ½ Hispanic/African American Children not 1A

• All type 1A patients periodic TSH, transglutaminase and 21-OH Abs

21-OH autoantibody positive: Annual ACTH, cortrosyn

Tg+: Biopsy when level >0.5: Diet Rx if + Biopsy

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Demyelinating Neuropathy in Diabetes Mellitus

Sharma et al. Arch Neurol 2002:758-765CIDP: Chronic Inflammatory Demyelinating Polyneuropathy

• Sensory symptoms, limb weakness, pain, poor balance (Type 1 and Type 2 DM)

• Conduction block, prolonged distal motor latency, slowed conduction, delayed or absent F waves

• Odds ratio 11 fold re diabetes present with CIDP than other neurologic disorders

• Treatment response to IV immunoglobulin

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Disruption of Intestinal Motility by a Calcium Channel-Stimulating Autoantibody in Type 1

DiabetesJackson, Gordon, Waterman Gastroenterology 2004:126:819

• “Functional” autoantibody bioassays in vitro and in vivo (note also Narcolepsy-cholinergic: Lancet 2004:364)

• Type 1 DM: 8/16 patients: Antibodies (Protein A Purified) mouse colon and vas deferens)

• L-type channel Voltage Gated Calcium Channels apparent target (block DHP-dihydropyridine antagonist)

• Clinical GI Correlates: Unknown