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Organ-specific autoimmune diseases

Prof Peter Gergely

Slide 2 Ssystemic autoimmune diseases

systemic lupus erythematosus (SLE)

antiphospholipid syndrome (APS)

rheumatoid arthritis (RA)

Sjögren’s syndrome (SS)

scleroderma group

mixed connective tissue disease (MCTD)

myositis group

UCTD and overlap

Organ-specific

Slide 3 1. ENDOCRINE SYSTEM1. ENDOCRINE SYSTEM

thyroidthyroidparathyroidparathyroidpancreaspancreasadrenalsadrenalsgonadsgonadshypophysishypophysis

2. DIGESTIVE SYSTEM2. DIGESTIVE SYSTEMstomachstomachintestinesintestinesliverliver

3. EYE3. EYE4. NERVOUS SYSTEM4. NERVOUS SYSTEM5. HEART5. HEART6. KIDNEY6. KIDNEY7. LUNG7. LUNG8. SKIN8. SKIN9. BLOOD9. BLOOD

Slide 4 Pure (genetic) autoinflammatory diseases (e.g.,

FMF) Inflammatory disease without signs of

autoimmunity, and infection (e.g., osteoarthritis) Inflammatory diseases without signs of

autoimmunity, infection likely (e.g., sarcoidosis) Inflammatory disease with signs of

autoimmunity, infection likely (e.g., Crohn’s) Autoimmune diseases (e.g., SLE) Pure (genetic) autoimmune diseases (e.g.,

APECED)

Slide 5 Autoantigens in organ-specific autoimmune diseases

Thyreoiditis thyroglobulin, TPO (thyroid peroxidase)Gastritis H+/K+ ATP-ase, intrinsic factorCeliac d. (tissue) transglutaminaseGraves TSH receptorVitiligo tyrosinase, TRP (tyrosinase-related

protein)TI diabetes m insulin, GAD (glutamate dehydrogenase)Multiple sclerosis MBP (myelin basic protein)Myasthenia acetylcholin receptor Pemphigus desmogleinsHepatitis cytochrom P450 (CYP2D6)PBC 2-oxoacid dehidrogenase complex (2-

OADC)

Slide 6 Prevalence (/100,000)

1) Graves’ disease 1151.52) thyreoiditis 791.63) vitiligo 400.24) diabetes (TIDM) 1925) pernicious anaemia 150.96) muliple sclerosis 58.37) glomerulonephritis 40________________________* Jacobson et al. Clin Immunol Immunopathol 1997; 84:223-43

Slide 7 1. ENDOCRINE SYSTEMthyroid: Hashimoto’s thyroiditis and primary

(idiopathic) myxedema, Graves’ disease and endocrineophthalmopathy

parathyroid: hypoparathyroidismpancreas: Type I diabetes mellitus (TIDM)adrenals: Addison’s diseasegonads: early menopausa, female infertility,

azoospermiahypophysis: autoimmune hypophysitis (with

hypofunction)

Slide 8 Graves’ disease

Thyroid hyperfunction with suppressed TSH

Goiter

Exophthalmos

Pretibial myxoedema

presence of antibodies against TSH

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Exophthalmos in Graves’ disease

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Lymphocytic infiltration in Hashimoto thyroiditis

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Thyroid antibodies in Hashimoto’s thyroiditis:a) anti-microsomal or anti-thyroid peroxidase (TPO) antibodyb) anti-thyroglobulin (anti-TG)

a b

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Islet cell antibodies (ICA) in T1D. Other antibodies: anti-insulin, anti-GAD,anti-IA-2Ab)

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Pathomechanism of T1D: 1) viruses activate APCs; 2) they attract and 3) activate T cells; 4) activated T cells and APCs kill islet cells

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Autoantibodies in autoimmune (idiopathic) Addison’s disease: antigens are: 17α-hydroxylase and 21-hydroxylase enzymes

Slide 15 Polyglandular autoimmune syndromes

Type I: Addison’s + hypoparathyreoidism + chr. mucocutan candidiasis

Type II: Graves’ + Addison’ or TIDM or myasthenia

POEMS syndrome = polyneuropathia +organomegalia (hepatosplenomegalia) +endocrinopathia (hypogonadism) + M protein + skin alterations (hyperpigmentation)

Slide 16 2. DIGESTIVE SYSTEMmouth: aphtha, periodontitisstomach: chronic atrophic gastritis and pernicius anemiaintestines: ceeliac disease,

chronic non-specific inflammatory bowel disease (IBD): ulcerative colitis and Crohn’s disease

liver: chronic autoimmune hepatitis, primary biliarycirrhosis

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Autoantibodies in autoimmune liver diseases:a) antimitochondrial antibodies (AMA) in primary biliary cirrhosisb) smooth muscle antibodies (SMA) in autoimmune hepatitis

a b

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c) Liver-kidney microsomal (LKM-1) antibodies in type 2autoimmune hepatitis.Antigen: cytochrome P450, CYP2D6

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parietal cell antibodies in chronic autoimmune gastritis with pernicious anemia (rat stomach substrate)

Slide 20 3. EYE sympathetic ophthalmia, phacogenic

uveitis, Vogt-Koyanagi-Harada syndrome, endogenous or

idiopathic uveitis

4. NERVOUS SYSTEM

parainfectious encephalitis, idiopathic polyneuritis and/or Guillain-Barrésyndrome, multiple sclerosis,myasthenia gravis

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Acetylcholin receptor antibodies in myasthenia on striated muscle substrate

Slide 23 5. HEART rheumatic fever, postinfarction syndrome,

autoimmune cardiomyopathies (myocarditis)

6. KIDNEY anti-GBM nephritis or Goodpasture syndrome,idiopathic or primary glomerulonephritis, amyloidosis

7. LUNG extrinsic allergic pneumonitis, eosinophilicpneumonia, idiopathic pulmonary fibrosis, sarcoidosis

8. SKIN vesicobullous skin diseases (pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, herpes gestationis), psoriasis, vitiligo, alopecia

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Rheumatic fever (febris rheumatica)

Rheumatic fever (RF) develops following Group A Streptococcus (usually throat) infection in 3-4% of genetically susceptible children, not treated by antibiotics. The disease can be detected in cca. 30% of patients within 3- 4 weeks after infection.The basis of disease is an immune reaction between heart antigens and cross-reacting streptococcal antigens.

Prevalence: 100/100,000 in non-developed countries2/100,000 in developed countries

Slide 25 Cross-reacting epitopes between streptococcus N-

terminal M5 protein and heart antigens

M5 epitope sequence – antigen_______________________________________________1–20 TVTRGTISDPQRAKEALDKY – heart muscle11–25 QRAKEALDKYELENH – heart muscle81–96 DKLKQQRDTLSTQKET – heart muscle

83–103 LKQQRDTLSTQKETLEREVQN – mitral/aortic valve

163–177 ETIGTLKKILDETVK - valve

Slide 26 Diagnostic Criteria for RF:The diagnosis of RF may be established by the modified Jones criteria (AHA, 1992): a) Major criteria: carditis, polyarthritis, Sydenham’s chorea, subcutaneous nodules, erythema marginatumb) Minor criteria:- clinical: fever, arthralgia - laboratory: high ESR, high CRP, prolonged PR distance on ECG (in the absence of manifest carditis)c) Essential to prove underlying infection:- High or increasing ASO, or- Positive culture or bacterial quick-test for Streptococcus-Astrain.Diagnosis can be established in the presence of 2 major or 1 major + 2 minor criteria. The presence of streptococcal infection is mandatory!

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Histology of Aschoff body (inflammatory nodule)

Slide 28 Mitralstenosis

Slide 29 Erythema marginatum

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Erythema marginatum

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Subcutaneous nodules

Slide 32 Treatment and Prevention

Antibiotics (penicillin or macrolid) – prophylaxis for at least 10 years

Nonsteroid antiinflammatory drugs

Slide 33 b

GBM antibodies in Goodpasture syndrome

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Pemphigus vulgaris

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Bullous pemphigoid

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Dermatitis herpetiformis

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Herpes gestationis

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a) Pemphigus vulgaris – antibodies against keratinocytes (desmoglein 3)b) Bullous pemphigoid – antibodies against skin basal membrane

Slide 39 Vitiligo

- frequent 1-16%- autoimmune raction against melanocytes- genetic predisposition

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Alopecia areata- sometimes totalis (1-2%)- lymphocytes attack hair follicles

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9. BLOODred blood cells: autoimmune hemolytic anaemia, drug-induced

immune-hemolytic anemia, isoimmunehemolytic anemia, autoimmune aplastic anemia,Diamond-Blackfan’s syndrome

thrombocyte: idiopathic (immune) thrombopenic purpura (ITP),drug-induced immune thrombocytopenia, post-transfusion purpura

granulocyte: immune neutropenia, drug-induced autoimmuneneutropenia

hemostasis: antiphospholipid syndrome (APS)

Slide 42 Immune thrombocytopenia (ITP)

A nonblanching, nonpalpable petechial rash in a patient with immune thrombocytopenia. ITP is the most frequent cause of acquired thrombocytopenia in children. It is caused by platelet destruction by autoantibodies. An episode may be preceded by a viral infection. Thrombocytopenia is not associated with significant lymphadenopathy and hepatosplenomegaly. Anemia and neutropenia are absent. Approximately 80% to 90% of cases of acute ITP resolve without recurrence.

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Thrombocytopenia and large platelets in a patient with ITP. The increased platelet size is thought to reflect increased megakaryopoiesis. Giant platelets and thrombocytopenia are also observed in Bernard-Soulier syndrome, a hereditary bleeding disorder with defective platelet glycoprotein Ib/IX surface receptors

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A normal or increased number of megakaryocytes in the bone marrow of patients with ITP. Megakaryocytes are easily identified as the largest cell type in the bone marrow and by their finely granular cytoplasm and multilobed nuclei. A low megakaryocyte count, decreased cellularity, and the presence of abnormal cells suggests a diagnosis other than ITP. In typical cases of ITP, a bone marrow aspirate is not mandatory

Slide 47

ANTIPHOSPHOLIPID SYNDROMEANTIPHOSPHOLIPID SYNDROME(APS)(APS)

Dr Gergely Péter

Slide 48 APS is a thrombophilic disorder caused by antiphospholipid (APL) antibodies (actually the antibodies are directed against phospholipid –glycoprotein complexes); characterised by arterial and/or venous thrombosis and/or pregnancy loss.

There are two forms:

a) primary APS (without underlying disease), andb) secondary APS (associated with other autoimmune disease (most frequently SLE, AIHA, ITP. etc)

Slide 49 Epidemiology:No reliable data.

Antibodies occur in 1-5% of normal population (increases with age)

APS is more frequent in females (ratio 4-10:1). In SLE the occurrence of APS is 20-30%. The APS (i.e. positive LA and/or ACL) in other thromboembolic diseases (e.g. stroke, AMI) varies around 10%. In pregnancy loss the likelihood of APS is 10-20%.

Slide 50 Pathomechanism:a) endothel and thrombocyte activation → thrombus

formation

b) inhibition of binding of endogenous anticoagulants (e,g,: activated protein C, protein S, annexin V, etc)

Slide 51 Clinical Signs

Venous thromboses (e.g. extremities), Arterial thromboses (e.g. stroke, AMI) Pregnancy loss (recurrent abortions,

intrauterine death, premature birth, preecclampsia)

Less common signs: livedo reticularis, thrombocytopenia, pulmonary hypertension, etc

Catastrophic APS (CAPS): multiple thromboses – multiorgan failure

Slide 52 Multiple infarctions inSLE –APS (MRI)

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Livedo reticularis

Slide 54 Healed ulcers andpostthromboticsyndrome in APS

Slide 55 Classification criteria of APS (2006) Clinical criteria Vascular thrombosis:

One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ .

Pregnancy Morbidity:a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, ORb) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, ORc) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation .

Laboratory criteria a) Lupus anticoagulant present in plasma, on 2 or more occasions at least

12 weeks apart, OR b) Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in

medium or high titer, on 2 or more occasions, at least 12 weeks apart, OR c) Anti-beta2-glycoprotein I antibody of IgG/IgM isotype in blood, present

in>99% percentile titre, on 2 or more occasions at least 12 weeks apart.

For a definitive APS diagnosis the presence of at least 1 clinical and at least 1 laboratory criterion is required.

Slide 56 Therapy Acute: heparin, then long-term warfarin (coumarine)

Long-term: warfarin - INR between 2-3

Pregnancy: NO warfarin, LMW heparin (+ low-dose aspirin

In milder cases: aspirin alone (or other platelet-aggregation inhibitor)

CAPS: heparin, high-dose corticosteroid, IVIG, apheresis