1. General Pathology Basic Principles of Cellular and Organ Pathology Inflammation - IV Jaroslava Dušková Inst. Pathol.,1st Med. Faculty, Charles Univ. Prague http://www1.lf1.cuni.cz/~jdusk/ CD3

2. Immune Disorders Diseases – table of contents  decreased – immunodeficiency  vascular - DM, ischemia - atherosclerosis  primary – inborn  NG disorders  thymic hypoplasia  T-lymphopenia  Bruton´s agamaglobulinemia  isolated IgA deficiency  complement deficiency  secondary – acquired  HIV-AIDS  neutropenia  leukemia   increased – hypersensitivity – alergy  anaphylactic  cytotoxic  immune complexes  cell mediated (delayed) T- cell mediated cytotoxicity  self oriented – autoimmune diseases  Autoimmunity – definition, function  Mechanisms of autoimmune reaction prevention  Autoimmune diseases – representatives  systemic  organ related

3. Defenses Against Infection – 1. Surface barriers: skin, conjunctiva, mucous membranes mechanical removal: shedding, tears, mucus, ciliary action, coughing, salivation, swallowing, urination, defecation normal bacterial flora chemical inhibitors: gastric acid, lactic acid, fatty acids,bile salts.. antimicrobial substances: lysozym, secretory IgA

4. Defenses Against Infection – 2. Nonspecific resistance factors fever, interferon, complement, lysozyme, C-reactive protein, lactoferrin, α1- antitrypsin Inflammation- soluble factors clotting system –Hageman fc. (XII) complement system: chemotactic fc, anaphylatoxins kinin system: bradykinin Inflammation- phagocytes circulating: neutrophils, eosinophils, monocytes, macrophages fixed: alveoli, spleen, liver, bone marow

5. Defenses Against Infection – 3. Immune response humoral: B-cells, plasma cells, immunoglobulins cell-mediated: T-cells, lymphokins

6. Inflammation – immunity Nonspecific antibodies v immunocomplexes on dendritic cells v long lasting antigen presentation

7. Hypersensitivity 1. anaphylactic astmaIgE 2. cytotoxicerythroblastosis IgG, IgM 3. immune complexes SLE, GNAg+AB+C 4. cell mediated (delayed) tbc, contact dermatitis – T-cell mediated cytotoxicity

8. Autoimmunity lack of self-tolerance

9. Autoimmunity constant activity in v organogenesis v regeneration v metalaxia

10. Autoimmune Diseases Def.: loss of self-tolerance resulting into damage of organ /tissue

11. Self x non-self Three mechanisms of self-tolerance clonal deletion - thymus clonal anergy – APC „off signal“ peripheral suppresion – Ts CD8+

12. Mechanisms Preventing Antiself Reactivity: clonal deletion (thymus) clonal anergy (thymus) peripheral clonal supression by T supressor cells (B,T helpers ) Protection from protectors….

13. Inflammation – autoimmune Systemic autoimmune diseases DISEASE SLE RA Sjögren dis. Syst. sclerodermia Dermato–polymyositis Prim. vasc. syndromes ANTIBODY ANA, ENA collag. II, F c –Ig (rheum. factor) ANA,ENA ENA (Scl–70) ENA (Jo–1) ANCA

14. Lupus erytematodes disseminatus VASCULITIS skin – butterfly rash, discoid erythema mucose membranes ulcers heart- Liebman-Sacks endocarditis arthritis serositis hemopoietic disorders – hemolytic anemia, leuco-lympho- thrombocyto- penia kidney – glomerulonephritis CNS – seizures, psychosis (vascular etiology?) SLE

15. Rheumatoid arthritis - polyarthritis progressiva primaria chronica adult women mainly small joints morning stiffness dysfigering, pain, ankylosis + tendovaginitis, iridocyclitis, vasculitis, lung fibrosis serum rheumatoid factor – IgM x Fc IgG – immunocomplexes complication (potentially killing)

16. Def.: a group of autoimmune conditions characterized by T-lymphocyte mediated sialo- & dacryoadenitis ---------- women predilection sicca (dry) syndrome Sjögren´s syndrome

17. Classification: primary: keratoconjunctivitis sicca, no co- existing systemic a-i diseases secondary: accompanying rheumatoid arthritis, SLE, dermatomyositis…. Sjögren´s syndrome

18. T.E.Daniels, Th.B. Aufdemorte, J.S.Greenspan: Histopathology of Sjögren´s syndrome. s. 41-52, in: N. Talal, H.M. Moutsopoulos, S.S.Kassan: Sjögren´s syndrome. Clinical and immunological aspects. Springer Vrlg, Berlin, Heidelberg, New York, London, Paris, Tokyo 1987, 299ss.

19. Focus Score Morphometric representation of focally accented chronic sialoadenitis focus – agregate of 50 and more lymphocytes (defined 1968)

21. meandr scaning FS ≥ 1

22. Focus Score morphometry result table

23. Lichen planus fibrinogen Ab in BM Mucous Membrane Pemphigoid IgG, C3 along BM Pemphigus vulgaris IgG Erythema multiforme IgM,C3 deep dermis - perivascular J.P.Sapp et al. Contemporary maxillofacial pathology. 2nd ed. Mosby 2004

24. Inflammation – autoimmune Organ autoimmune diseases – skin ANTIBODY intercel. epith. matrix basal membraneof epidermis DISEASE pemphigus pemphigoid

25. Inflammation – autoimmune Organ autoimmune diseases – GIT ANTIBODY against mitochondrie membr. hct., cytosol gliadin DISEASE prim. bill. cirrhosis CAH gluten enteropathy

26. man 27 yrs B 2138/06 4 pieces from D3 announced 3 pieces diam. 1-2mm found clin. dg. susp. celiakia, diff. dg. lambliasis

27. Histopathology Report mild shortening & widening of villi intraepit. lymphocytes > 40/100 enterocytes lamblie not found Conclusion: histopathology changes supporting clinical dg. suggested - celiac sprue - type 3a of Marsh´ - Oberhuber´s classification

28. Marks, DJB, Harbord, MWN, Mac Allister R. et al.: Impotent immune System: An Underlying Problem in Crohn´s Disease. Lancet 2006, 367, 668-78 in patients with Crohn´s an impaired acute inflammatory response – 79% reduction in the number of neutrophils and interleukin 8 in ulcerative colitis initiation of inflammation normal, resolution delayed

29. Inflammation – autoimmune Organ autoimmune diseases – endocrine ANTIBODY TGB, microsomes pancreas  cells insulin ins. receptors adrenal microsomes TSH rec. DISEASE GB, HT DM I I–res. DM Adison dis. GB

30. Inflammation – autoimmune Organ autoimmune diseases – CNS ANTIBODY acetylcholin rec. basic myelin protein DISEASE myasthenia gravis disseminated sclerosis

31. Sclerosis cerebrospinalis multiplex disseminata - virus infection influence (morbilli, herpes, EB) …bacteria?... Pathogenesis interaction of the macroorganism and virus – limited antibody production (only 10-20% produced viruses are virulent) virus mutation & immunosupresion (age, pregnancy, stress, other diseases….)

32. MS – viral influence (2) Pathogenesis infection of endothelia – microangiitis blood-brain- barrier disorder serum & CSF CD4, CD8 (miror image to AIDS) Sclerosis cerebrospinalis multiplex disseminata - virus infection influence 2.

33. Immune Disorders Diseases Morphology alteration up to necrosis NG + lymphoplasmocellular infiltration fibrosis Prognosis important in terms of both morbidity and mortality – possible lethal outcome