AUTOIMMUNE DISEASES

1. AUTOIMMUNE DISEASES

2. Autoimmune Disease • Autoimmunity: acquired immune reaction, against self antigens • Autoimmune diseases: the autoimmune reaction induces lesions in tissues • Auto-antibodies (Auto-Ab): Abs against self Ags (usually IgG or IgM)

3. Autoimmune Reaction • Natural – up to a point • Needed to eliminate unwanted auto-Ags (“old”, “non-efficient”, “alternated”), or to reduce the immune response activated in excess (“anti-idiotyp”) • T ly, by linking to MHC  stimulate B ly to secrete Auto-Abs (there are auto-Ab anti-albumin etc)

4. Immune Tolerance • This Immune tolerance induce either deletion or inactivation of autoreactive T ly • Central Tolerance : immature T and B ly became tolerant to self Ags – clonally deletion (takes place during the thymus maturation, usually an irreversible process. Its is followed by positive or negative selection)

5. Immune Tolerance • Induce deletion or inactivation of autoreactive T ly 2. Peripheral Tolerance: takes placein secondary lymphoid organs (ClonalAnergy) – proliferative functions and secretion one are inhibited by leak of costimulitory mediators/signals

6. Immune Tolerance • Induce deletion or inactivation of autoreactive ly T 3. Activation of some suppressor mechanisms : Ts ly act by inhibating cytotoxic cells; idiotype – anti-idiotype network or death of autoreactive cells)

7. Autoimmunity Hypothesis • Theory of the hidden Ags (in Nervous System, crystalline, thyroid, sperm cells, bile) • Theory of forbidden clone (some error in deletion of autoreactive ly during fetal life). Forbidden clones might appear also after somatic mutation (normally they are eliminated)

8. Autoimmunity Hypothesis • Theory of clonal anergy: another form of forbidden clones. Clones which encounter the self Ag are not eliminated, they are just temporally suppressed (they recover at high quantities of Ags, or long persistent of them)

9. Autoimmunity Hypothesis • Theory of immune deficiency: there is functional inhibition of suppressor cells (CD8+ T ly) which do not block anymore auto-aggressive phenomenon

10. Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000 Bach, J.-F. N Engl J Med 2002;347:911-920

11. CD25 CTLA-4 IL-10 TGF-b IgG4, IgA Fibroblasts, epithelial cells Regulatory and repair responses TGF-b FOXP3 Treg IgE Eosinophil Immediate-type responses IL-4 IL-5 CRTH2 IL-4 GATA-3 Th2 Naive IgG1 Antigen-presenting cells Inflammatory responses IFN-g TIM-3 IL-12 T-BET Th1 Schmidt-Weber, Blaser; Curr Opinion Immunol 2004; 16:709–716

12. Treg Th2 Th1 IL-4 IL-10 IgG4, IgA IL-12 IgE IgG1

13. Immune Recognition • High organ Specificity • Without organ Specificity (systemic reactions)

14. Auto-Abs • Anti-molecule Immune Complexes (CI) deposition in vessel, glomeruls (colagenosis; SLE) • Anti-cells (Ag in membranes) cytotoxicity (C’ activation) or cell-mediated cytotoxicity (CCAD) or phagocytosis • Anti-receptor (cell receptor) stimulation of function or neutralization of receptor (myasthenia, hypertiroiditis)

15. Pathogenic Effects of Auto-Abs • Cytotoxic (dependent of C’, mediated by cells) • Blocking, agglutination or masking (of some cell function) • Activation of phagocytosis (oposonization and activation of macrophages)

16. Autoreactive T Lymphocytes • Present in experimental encephalitis in mice • NK Cells – usually suppressed (they lose their regulatory role of down-regulation of immune responses)

17. Predisposing Factors • Genetic Factors: HLA-B27 with Ankylosis spondylitis - in other diseases, the importance of genetic factors is lesser

18. Association of the Autoimmune diseases and HLA

19. Predisposing Factors • Age: frequent in old age, but colagenosis are seen in young people (SLE, RA) • Sex: female (SLE – ratio F/M = 10/1; Grave’s disease: 7/1; spondylitis – mostly in male)

20. Predisposing Factors • Infection (“antigenic mimetism”) : virus (vi: Epstein-Barr, Cocksakie); bacteria (mycoplasma, Klebsiella, Borrelia burgdorferi etc) • Drugs: procainamide, hidralazine (phenomenon lupus-like)

21. With organ specificity Autoimmune Diseases Hashimoto’s Thyroiditis Autoimmune atrophic Gastritis Pernicious Anemia Addison’s disease Myasthenia gravis Goodpasture’s Sd. Diabetes Autoimmune hemolytic Anemia Thrombocytopenia idiopathic Purpura Sjőgren’s Sd. Ulcerative Colitis Primitive Biliary Cirrhosis Systemic Lupus erythematous Dermatomiositis Sclerodermia Rheumatoid Arthritis Systemic

22. Hashimoto’s autoimmune Thyroiditis • Mechanism: humoral and cellular • thyroid Cell • Auto-Ab anti-tireoglobuline; - anti-peroxidaza from thyroid • La female (F/M = 5/1) • 30-60 years • Diffuse infiltration with ly, eosinophils, atresia of parenchimatous cells • Hypothyroidism

23. Grave’s disease • Auto-Ab anti-receptor TSH (stimulatory hormone of thyroid) - mechanism HS type II • Hyperthyroidism • Gointre (hyperplasic, diffuse) • Extrathyroid signs (exophthalmia, peritibial mixedema)

24. Myasthenia gravis • Auto-Ab anti-receptor for acetylcholine • Neuromuscular: post-synaptic block of nervous influx transmition to motor plate • Rare: incidence 2-6 cases in 1 million of persons • Muscular fatigue – very severe: ocular, extension up to respiratory insufficiency) • Treatment: extirpation of hypertrofiated thymus (sometimes might work)

25. Myasthenia gravis: - neuron-muscular junction - Acetylcholine (Ach) Auto-Ab anti receptor for Ach Receptors for Ach

26. Other autoimmune disease - organ-spf • Pancytopenia (H, L, Tr) autoimmune • Anemia pernicious (Biermer) – intrinsec factor • Diabetes (insulin-dependent) (B cells from pancreas) • Addison’s Disease (receptors for ACTH and microsoms) • Systemic Sclerosis (basic myelin protein from brain, bown marrow) • Guillain-Barré Sd (peripheral nerves – ganglioside) • Pemfigus – keratinocytes

27. SYSTEMIC LUPUS ERITHEMATOUS Diana Dumitrascu

28. Definition • Affection with unknown etiology, where the tissues are damaged by Auto-antibodies and Immune Complexes

29. Ethiology 

30. Epidemiology • 90% are Female, aged 20-30 years • More frequent in blacks, followed by Hispanic populations, and Asiatic populations • Prevalence 15-50/100,000 (SUA)

31. Pathology • Lesions induced by AutoAb, IC • Hyperreactivity of T, B lymphocytes • Genetic Induce • Environment factors: viruses, bacteria, drugs

32. Pathology GeneticInduce : - more frequent in monozigots (25 - 58%) vs dizigots (0-6%) - more frequent in families with one patients - more frequent in pts with defects or deletion of allele of classes III C4AQO (40-50% pts) - more frequent in homozygote with defects of C’ (C1q, C2, C4) (< 5% pts) - haplotype B8.DR3.DQw2.C4AQO predispose to SLE in population from north of Europe • Genetic Predisposition for SLE induce by drugs: dependence of the acetilation of the drug

33. Pathology • Associated with HLA-DR2 or –DR3 (“gene for autoimmunity”) • Cz 1 (1q23) has gene for FcγRIIA; and 1q41-42 has poli gena (DNA-ribosil) polymerase (PARP) and them may produce defects of the way DNA is repaired and defects of apoptosis • AutoAb are associated with some symptoms in SLE: • AutoAb to Ro/La (SS-A/SS-B) in sub acute SLE • normal Allele of FcγRIIA or FcγRIIIA which bound to IgG2/IgG3 are more frequent in nephritis (CI are not eliminated from circulation)

34. Pathology Immunological Factors:  • IFN – type I (cz 9p21): -there are 13 isoforms of IFN-1 - they activate the “program” of T ly for IFN-2 secretion (former γ) • TollReceptors (role in innate immune sist and allows the formation of acquired immunity; stimulatory and inhibitory functions) • Dendritic plasmocitoideCells (they secrete IFN- 1) – receptors to identified BDCA-2 si BDCA-4

35. Pathology Environmental Factors:  • UV-B and UV-A (70% pts have photosensitivity) • Chemical Substances (hidralazine, isoniazide, clorpromazin, D-penicilamin, practolol, metildopa, quinidin, IFN-, hidantoine, etosuximide, contraceptive oral) • Infections viruses/retroviruses  • Sexual hormones (female, in child bearing period)

36. Discoid Lupus Histopathology • Lesions of basal membrane (epidermis) • Discontinuing of dermal-epidermal junctions • Infiltration with monocytes around the vessels • Hyperkeratosis • IgG and C’ deposits (80-100%) – may be presents in normal tissues (50%) • Leucocytoclastic vasculitis • Glomerulonephritis - IC deposits or the might be generated in situ in mesangiumor in glomerular basal membrane (if Ig and C’ deposits are out of mesangium– severe prognostic)

37. Clinical forms • Systemic lupus erithematous • Discoidlupus erithematous – skin lesions (skin atrophy) – 20% • Subacute lupus erithematous – skin lesions - vasculitis type

38. Symptoms Onset • One organ (after that  systemic) • Systemic (most frequent: fatigue, malaise, fever, anorexia, loss in weight) Severity: mild severe

39. Symptoms • Muscular, joint, bone: • mialgia, arthralgia (most of the pts):  intermittent arthritis, usually symmetric: small joints: hand, foot, sometimes knee etc  tenosinovitis  inflammatory myopathy (or after treat: K , GCS, hidroxiclorochin)  ischemic necrosis in the bone: pelvic joint, knee, shoulder (post-GCS)

40. Symptoms • Skin and mucosa: • Rash - “butterfly” on the face • without scarf lesion (only in discoid lupus) • Rare: urticaria, vesicles, erithema multiform, lichen plan, paniculitis (= profound lupus) • Vasculitis lesions (SLE systemic, discoid, subacute): purpura, subcutaneous nodules, infarctation at nails, ulcers, vasculitic urticaria, paniculitis, necrosis of fingers • Mucosa: Ulcer on oral, nasal mucosa

41. Symptoms • Renal: • ½ pts - glomerulonephritis (most of the pts have Ig deposits in glomeruls) • Focal glomerulonefritis renal sclerosis • Without symptoms or nephrotic edema • haematuria, proteinuria, renal failure

42. Symptoms • Neurological symptoms: • meningitis, spine cord, central and peripheral nerves • Unique or multiples • Associated with another organ lesions • Mild cognitive dysfunction (most frequent), headache (migraine or unspecific headache), muscular contraction • Rare: psychosis, acute confusion, cerebro-vascular disease, aseptic meningitis, mielopathy, mono or polineuropathy, Guillan-Barré polineuropathy, depression, anxiety

43. Symptoms • Vascular symptoms: • thrombosis in the vessel (anti fosfolipidic antibodies: anticoagulant (LA), anticardiolipid induce coagulation without vasculitis) • Vasculitis • Cerebral embolus (Libman-Sacks endocarditis) • Vascular and cerebral lesions - IC and hyperlipidemia (induced by GCSs) – in chronic disease

44. Symptoms • Hematological: • Anemia – chronic disease in most of the pts - hemolytic anemia – rare, with Coombs Test + • Low Leucocytes (and lymphocytes) • Low platelets (sometimes with purpura) • Seldom – Abs anti - factors for coagulation (VIII, IX) hemorrhage

45. Symptoms • Heart and lungs: • Pericarditis • Myocarditis dysrhithmias • Endocarditis (Libman-Sacks) • Pleuritis – • Lung involvement: most frequent infections, lupic Pneumonitis, lung fibrosis, PHT (rare)

46. Symptoms • Gastrointestinal: • Nausea, diarrhea, abdominal pain • Peritonitis • Vasculitis • Pseudo-obstruction of the bowel • Lesion like scleroderma (motility disorder) • Acute pancreatitis (disease, therapy with corticosteroid, azathioprine) • High level of enzymes (ASAT, ALAT) (without significant hepatic lesions)

47. Symptoms • Eyes: • Retinian vasculitis blindness • Conjunctivitis • Episcleritis • Optic nerve lesion • Sicca sd.

48. Acut Lupus Lupus Paniculitis Discoid lupus

50. Investigation • Antinuclear antibodies (ANA): human substrate (WIL-2 or Hep-2) - + on > 95% (there are false + in normal subjects, other immune disease, viral infections, chronic infections, drugs). Negative ANA does not exclude, but is less probable • Ab anti –ADN double strain (Ab anti –dsDNA) and anti Sm - +, but not specific.