1. AUTOIMMUNITY Johan van Rensburg

2. What goes wrong? • Tissue damage due to • antibodies • T cells • Etiology multi-factorial • environmental • genetic • specific HLA genotypes Self antigens HLA II > HLA I

3. Tolerance • Tolerance to self-antigens • deletion of self-reactive B and T cells • during maturation in the bone marrow and thymus • Recognition of peptide/MHC complexes by peripheral T cells • In the absence of costimulatory signals No activation of potentially self-reactive T cells Anergy

4. Tolerance • Regulatory(suppressor) T cells • Immunologically privileged sites • eye • brain TGFB IL-10 IL-4 Clonal expansion of autoreactive cells Do not normally encounter immunocompotent cells Self antigen inaccessible or in to low quantities

5. Autoimmune disease • Lack of tolerance • Triggered by • Infection • Other environmental factors • Unknown Increased/ aberrant expression of costimulatory molecules Changing antigenicity of infected tissue (now a target) Molecularmimicracy(eg. Rheumatic fever) Superantigens Stimulates families of T cells expressing a particular TCR-Vß segment

6. GENETIC PREDISPOSITION MHC-class II genes Other MHCgenes Multiple non-MHC genes Environmental factors CD4+ T cell driving force (autoreactive) Autoreactive B cells CD8+ T-cells IgG autoantibodies Non T cell effector cells Cell-mediated organ damage Autoantibody mediated organ damage

7. SYSTEMIC CONNECTIVE TISSUE DISEASE

8. Systemic connective tissue disease

9. Systemic Lupus Erythematosis (SLE)

10. In general • Most common of multisystem connective tissue disease • Geographical • Racial • Caucasians • 30/100 000 • Afro-caribians • 200/100 000 • Gender • 90% Women • Age • Peak • 2nd to 3rd decades

11. Etiology and pathogenesis • Polyclonal B and T cell activation • Circulating auto-antibodies • Multi-organ involvement • Wide variety of clinical presentation • ~50 autoantigens identified • Hidden from Immune system in health • Intranuclear • Intra-cellular • Possible mechanisms • Environmental factors • Apoptosis • Autoantigens expressed on cell surface • Induce flares of SLE • Pregnancy • Infection • Sunlight

12. Diagnosis • Revised ACR criteria for SLE • 4/11 in present or past • 4 mucocutaneous • 4 Systems • 1 pleura/pericardial/peritoneum (PPP) • 2 Auto-antibody • Anti-dsDNA • 30-50% of patients • ANA negative unlikely for SLE • Unless (Ro) positive • Most have skin rashes

13. 4 mucocutaneous • Malarrash • Erythema • Fixed • Flat • Raised • Sparing nasolabial folds • Discoid rash • Erythematous • Raised patches • Adherent • Keratotic scaring • Follicular plugging • Photosensitivity • Skin rash • Sun burn areas • Oral ulcers • May be painless

14. MALAR RASH

15. SUBACUTE CUTANEOUS LUPUS

16. DISCOID LUPUS LESIONS

17. ALOPECIA

18. ALOPECIA

19. MOUTH ULCERS

20. MOUTH ULCERS

21. EARLY VASCULITIC LESIONS

22. 4 Systems • Arthritis/arthralgia • Non-erosive • 2 or more peripheral joints • (Jaccoudarthropathy) • Renal • Proteinuria • Persistent • >0.5g/day • Cellular casts • Red cell • Granular • Tubular • Neurological • Seizures • Psychosis • Absence • Offending drugs • Metabolic derangement • Hematological • In absence of offending drugs • Hemolytic anemia • Leucopenia • <4000/mm3 • 2 separate occasions • Lymphopenia • <1500/mm3 • 2 separate occasions • Thrombocytopenia • <100 000/mm3 • 2 Separate occasions

23. JACCOUD ARTHRITIS Jaccoud Sigismond, French physician, 1830–1913

24. GLOMERULONEPHRITIS • Minimal change • Mesangeal • Focal proliferative • Diffuse proliferative • Membranous glomerulonephritis • End Stage renal failure • (Typical is that the complement is diminished)

25. MESANGIAL LESIONS

26. FOCAL PROLIFERATIVE GN (WHO CLASS III)

27. 1 pleura/pericardial/peritoneum (PPP) • Serositis • Pleuritis • Pleuritic pain • Rub • Effusion • Pericarditis • ECG • Rub • Effusion

28. 2 Auto-antibody • Immunology • Anti-DNA antibodies • Anti-SM antibodies • Antiphosfolipid antibodies • Antinuclear antibodies (ANA) • Abnormal titer • By immunofluorescence

29. Clinical features(more than criteria) • Raynaud's phenomenon • Musculoskeletal • Mucocutaneous • Renal • Management • Cardiopulmonary • Central nervous system • Hematological • Other

30. Lipmann Sacks Endocarditis

31. GANGRENE OF THE TOE

34. OSTEONECROSIS

35. Polymyositis and Dermatomyositis

36. Classiffication • Adult polymiositis • Adult dermatomyositis • Important • Malignancy • Childhood dermatomyositis

37. Clinical picture • Proximal muscle weakness • Skin manifestations • NOT typically sun exposed areas • Malar rash • Heliotropic rash • V-sign • Shawel sign • Gottron’s nodules • Mechanic hands

38. MALAR AND HELIOTROPIC RASH Upper eyelid Involving nasolabial folds

39. V-sign

40. Gottron’s Nodules

41. Differential diagnosis (NB) • Inclusion body myositis • Other causes of proximal muscle weakness • See Davidson’s

42. Sjogren's disease

43. Clinical features • Risk markers • Common clinical features • Less common features • Auto antibodies • Associated autoimmune disorders

44. Scleroderma

45. Scleroderma (systemic sclerosis) Scleros: hard Derma: skin

46. SYSTEMIC SCLEROSIS Multisystem disorder Fibrosis of the skin, bloodvessels, and viseral organs Affected organs: Lungs Heart Kidneys GIT

47. CLASSIFICATION • Limitedcutaneous disease • Diffusecutaneous disease • Sinescleroderma • Undifferentiated connective tissue disease • Overlapsyndromes

48. Limited cutaneous scleroderma • Skin thickening: Distal to elbow and knee Face and neck • Synonym: CREST Syndrome

49. Diffuse cutaneous scleroderma • Skin thickening includes: Trunk Face Proximal extremities Distal extremities

50. Sine scleroderma • Internal organ manifestations • Vascular abnormalities • Serologic abnormalities • Noclinical detectable skin change