· rheumatic fever (febris rheumatica) rheumatic fever (rf) develops following group a...
TRANSCRIPT
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 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
Slide 9
Exophthalmos in Graves’ disease
Slide 10
Lymphocytic infiltration in Hashimoto thyroiditis
Slide 11
Thyroid antibodies in Hashimoto’s thyroiditis:a) anti-microsomal or anti-thyroid peroxidase (TPO) antibodyb) anti-thyroglobulin (anti-TG)
a b
Slide 12
Islet cell antibodies (ICA) in T1D. Other antibodies: anti-insulin, anti-GAD,anti-IA-2Ab)
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)
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
Slide 17
Autoantibodies in autoimmune liver diseases:a) antimitochondrial antibodies (AMA) in primary biliary cirrhosisb) smooth muscle antibodies (SMA) in autoimmune hepatitis
a b
Slide 18
c) Liver-kidney microsomal (LKM-1) antibodies in type 2autoimmune hepatitis.Antigen: cytochrome P450, CYP2D6
Slide 19 a
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
Slide 21
Slide 22
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
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 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!
Slide 27
Histology of Aschoff body (inflammatory nodule)
Slide 28 Mitralstenosis
Slide 29 Erythema marginatum
Slide 30
Erythema marginatum
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
Slide 34
Pemphigus vulgaris
Slide 35
Bullous pemphigoid
Slide 36
Dermatitis herpetiformis
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
Slide 40
Alopecia areata- sometimes totalis (1-2%)- lymphocytes attack hair follicles
Slide 41
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.
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
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
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)
Slide 53
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