Slide 1. Slide 2. Organ-specific autoimmune diseases. Prof Peter Gergely

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1 Slide 1 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 SYSTEM thyroid parathyroid pancreas adrenals gonads hypophysis 2. DIGESTIVE SYSTEM stomach intestines liver 3. EYE 4. NERVOUS SYSTEM 5. HEART 6. KIDNEY 7. LUNG 8. SKIN 9. BLOOD

2 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 factor Celiac d. (tissue) transglutaminase Graves TSH receptor Vitiligo tyrosinase, TRP (tyrosinase-related protein) TI diabetes m insulin, GAD (glutamate dehydrogenase) Multiple sclerosis MBP (myelin basic protein) Myasthenia acetylcholin receptor Pemphigus desmogleins Hepatitis cytochrom P450 (CYP2D6) PBC 2-oxoacid dehidrogenase complex (2- OADC) Slide 6 Prevalence (/100,000) 1) Graves disease ) thyreoiditis ) vitiligo ) diabetes (TIDM) 192 5) pernicious anaemia ) muliple sclerosis ) glomerulonephritis 40 * Jacobson et al. Clin Immunol Immunopathol 1997; 84:223-43

3 Slide 7 1. ENDOCRINE SYSTEM thyroid: Hashimoto s thyroiditis and primary (idiopathic) myxedema, Graves disease and endocrine ophthalmopathy parathyroid: hypoparathyroidism pancreas: Type I diabetes mellitus (TIDM) adrenals: Addison s disease gonads: early menopausa, female infertility, azoospermia hypophysis: autoimmune hypophysitis (with hypofunction) Slide 8 Graves disease Thyroid hyperfunction with suppressed TSH Goiter Exophthalmos Pretibial myxoedema presence of antibodies against TSH Slide 9 Exophthalmos in Graves disease

4 Slide 10 Lymphocytic infiltration in Hashimoto thyroiditis Slide 11 a b Thyroid antibodies in Hashimoto s thyroiditis: a) anti-microsomal or anti-thyroid peroxidase (TPO) antibody b) anti-thyroglobulin (anti-tg) Slide 12 Islet cell antibodies (ICA) in T1D. Other antibodies: anti-insulin, anti-gad, anti-ia-2ab)

5 Slide 13 Pathomechanism of T1D: 1) viruses activate APCs; 2) they attract and 3) activate T cells; 4) activated T cells and APCs kill islet cells Slide 14 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)

6 Slide DIGESTIVE SYSTEM mouth: aphtha, periodontitis stomach: chronic atrophic gastritis and pernicius anemia intestines: ceeliac disease, chronic non-specific inflammatory bowel disease (IBD): ulcerative colitis and Crohn s disease liver: chronic autoimmune hepatitis, primary biliary cirrhosis Slide 17 a b Autoantibodies in autoimmune liver diseases: a) antimitochondrial antibodies (AMA) in primary biliary cirrhosis b) smooth muscle antibodies (SMA) in autoimmune hepatitis Slide 18 c) Liver-kidney microsomal (LKM-1) antibodies in type 2 autoimmune hepatitis. Antigen: cytochrome P450, CYP2D6

7 Slide 19 a parietal cell antibodies in chronic autoimmune gastritis with pernicious anemia (rat stomach substrate) Slide EYE sympathetic ophthalmia, phacogenic uveitis, Vogt-Koyanagi-Harada syndrome, endogenous or idiopathic uveitis 4. NERVOUS SYSTEM parainfectious encephalitis, idiopathic polyneuritis and/or Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis Slide 21

8 Slide 22 Acetylcholin receptor antibodies in myasthenia on striated muscle substrate Slide 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, eosinophilic pneumonia, idiopathic pulmonary fibrosis, sarcoidosis 8. SKIN vesicobullous skin diseases (pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, herpes gestationis), psoriasis, vitiligo, alopecia Slide 24 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 countries 2/100,000 in developed countries

9 Slide 25 Cross-reacting epitopes between streptococcus N- terminal M5 protein and heart antigens M5 epitope sequence antigen 1 20 TVTRGTISDPQRAKEALDKY heart muscle QRAKEALDKYELENH heart muscle DKLKQQRDTLSTQKET heart muscle LKQQRDTLSTQKETLEREVQN mitral/aortic valve 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 marginatum b) 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-A strain. Diagnosis can be established in the presence of 2 major or 1 major + 2 minor criteria. The presence of streptococcal infection is mandatory! Slide 27 Histology of Aschoff body (inflammatory nodule)

10 Slide 28 Mitral stenosis Slide 29 Erythema marginatum Slide 30 Erythema marginatum

11 Slide 31 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

12 Slide 34 Pemphigus vulgaris Slide 35 Bullous pemphigoid Slide 36 Dermatitis herpetiformis

13 Slide 37 Herpes gestationis Slide 38 a b 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

14 Slide 40 Alopecia areata - sometimes totalis (1-2%) - lymphocytes attack hair follicles Slide BLOOD red blood cells: autoimmune hemolytic anaemia, drug-induced immune-hemolytic anemia, isoimmune hemolytic anemia, autoimmune aplastic anemia, Diamond-Blackfan s syndrome thrombocyte: idiopathic (immune) thrombopenic purpura (ITP), drug-induced immune thrombocytopenia, posttransfusion purpura granulocyte: immune neutropenia, drug-induced autoimmune neutropenia 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.

15 Slide 43 Slide 44 Slide 45 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

16 Slide 46 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 Dr Gergely Péter ANTIPHOSPHOLIPID SYNDROME (APS) 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), and b) secondary APS (associated with other autoimmune disease (most frequently SLE, AIHA, ITP. etc)

17 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

18 Slide 52 Multiple infarctions in SLE APS (MRI) Slide 53 Livedo reticularis Slide 54 Healed ulcers and postthrombotic syndrome in APS

19 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, OR b) 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, OR c) 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 plateletaggregation inhibitor) CAPS: heparin, high-dose corticosteroid, IVIG, apheresis