Autoimmune Diseases

1. Autoimmune Diseases Systemic autoimmunity (#03) Organ-specific autoimmunity (#04) Allergic diseases (#05)

2. - intro - • Key feature of immune responses: • -target the pathogen • -orchestrate the local/regional* inflammatory reaction, eliminating the antigen without extensively damaging the host’s tissue • -manage the repair

3. Extensive deleterious effects => hypersensitivity (allergy) • SPECIFIC IMMUNTY: • sensitization phase (abnormal immune response in terms of type, taget, clearance) • (memory induction) • elicitation phase

4. The four types of hypersensitivity reactions, PGH Gell and RRA Coombs (Kuby 5th Edition 2002, Fig. 16-1)

5. IgE-mediated TYPE I • (cytotoxic/cytolytic) antibody-mediated TYPE II • immune complex-mediated TYPE III • delayed-type hypersensitivity TYPE IV

6. Antibody-mediated Hypersensitivity, Type II • Detrimental effects: • - lysis via Complement System activation • -ADCC • -phagocytosis (Fc/C3b and others) • Classical models: transfusion reactions, hemolytic disease of the newborn, drug-induced hemolytic anemia

7. Antibody-mediated Hypersensitivity, Type II (Kuby 5th Edition 2002, Fig. 16-13)

8. Antibody-mediated Hypersensitivity, Type II (Kuby 5th Edition 2002, Fig. 16-14)

9. Immune complex-mediated Hypersensitivity, Type III • Detrimental effects: • - deposition of immune complexes formed either in the bloodstream, or locally • -complement activation, neutrophils involvement (regurgitation of organelle components) • Classical models: local forms: alveolitis, pneumonitis due to bacterial spores, fungi, dried fecal proteins of parasites - Arthus reaction, farmer’s lung; systemic forms: serum sickness due to horse antitetanus or antidiphteria serum • SLE, RA, Goodpasture syndrome, Allergies to penicillin and sulfonamides, poststreptococcal glomerulonephritis, meningitis, hepatitis, mononucleosis, malaria, trypanosomiasis

10. Immune complex-mediated Hypersensitivity, Type III (Kuby 5th Edition 2002, Fig. 16-15, 16)

11. Delayed-Type Hypersensitivity, Type IV • Detrimental effects: • - local recruitment of monocytes/macrophages • -Langerhans cell, Th (in some instances Tc): TDTH, Th1 • granuloma formation; cytokines (MCAF, monocyte chemotactic and activating factor, MIF, migration-inhibition factor; IFNgamma, TNFbeta); NO • Classical models: contact dermatitis; tuberculous reaction

12. Delayed-Type Hypersensitivity, Type IV (Kuby 5th Edition 2002, Fig. 16-15, 20)

13. Autoimmune Diseases • (AID): immune responses mounted against self components that result in pathology. • Prevalence: higher with age, in developed countries (~3-5%); major cause of death for women under age 65. • 1890s: Paul Ehrich ‘horror autotoxicus’ concept • 1900s: reports of autoreactivity (anti-self agglutinins, J.Donath & K.Landsteiner; rabbit anti-self ocular proteins as immunogens; cross-reaction of human anti-Treponema pallidum with self antigens - later cardioipin; rheumatoid factor, in 1930s, as being able to agglutinate indicator - coated with IgG - sheep RBCs) • 1950s: WJ Harrington: platelet depletion effect of serum from patients with idiopathic thrombocytopenic purpura (=> autoantibodies); Peter Miescher and Henry Kunkel: antibodies against self DNA, RNA and various nuclear proteins; Noel Rose: immunization of the rabbit with self thyroid induces thyroiditis. • 1960s: New Zealand, Marianne and Feliz Bieloschowsky: NZB inbred mice that died prematurely of an AID similar to autoimmune hemolytic anemia; further breeding: kidney, thymus

14. Autoimmune Diseases • 1960/70s: clarification of T and B lymphocytes, MHC; fluorescence microscopy for detection of autoantibodies on cell surfaces and serum; GF Bottazo, WJ Irvine independently demonstration of anti-pancreatic beta-islet cell antibodies in IDDM • 1990s: DC subsets, Th subsets; PCD (apoptosis and other forms) mechanisms. • Currently more than 80 distinct disorders (previously considered as ‘idiopathic’):

15. Saunders, Mak, 2006, F 29.1

16. Autoimmune Diseases • Failure of tolerance mechanisms: • -CENTRAL TOLERANCE (the only clear example is APECED, autoimmune polyendochrinopathy candidiasis ectodermal dystrophy, in human, with defects in AIRE function/nuclear localization, and NOD - T1DM non-obese diabetic mice) • -PERIPHERAL TOLERANCE (often associated with certain allelic variation in genes encoding immune defense factors, and revealed by environmental triggers, cytokine context). • In healthy individuals: even when autoreactive clones emerge, intact mechanisms of PT suppress and limit the tissue damage. • Traditionally, based on clinical observation: organ-specific / systemic autoimmunity (paradoxes such as primary biliary cirrhosis, with anti-mitochondrial antibodies, or Sjogren with anti-nuclear antibodies; SLE, with targets at distant sites from the originating antibody-antigen complexes).

17. Autoimmune Diseases • => Saunders, Mak, 2006

18. Systemic Lupus Erythematosus • => idiopathic • large spectrum of clinical manifestations / variability of disease progression with relapses and remissions • targets every organ system; often initially affects the skin, joints, kidney, lung, heart, gastrointestinal tract • more frequently young women (9:1 in adults), Asians; African-Americans; strong concordance rates in monozygotic twins (~50% involving MHCs - DR2, DR3, DRB1*1501, DRB1*1503, DR3 & C4A null, complement - deficiencies in C1q, C4, C2, C1s and C1r; FcRgII-R131 and III genes, apoptosis; IL-1Ra); with alopecia, fatigue, musculoskeletal symptoms, vascular abnormalities, photosensitivity, characteristic rash (red, erythematous, affecting the malar region of the face - wolfish appearance). • Multiple elements of the immune system may be disrupted (including complement, with opportunistic infections). • Incidence ~40 / 100 000. • Antinuclear antibodies (ANA), against dsDNA (fluctuanting with flare-ups), and against small ribonucleoproteins (snRNPs, like Smith -Sm- antigen) exposed by cell necrosis (rather constant in titers).Other targets: histone proteins, RNA-binding proteins, DNA polymerase components, cytoplasmatic and membrane phospholipids, IgG, coagulation factors, complement components

19. Systemic Lupus Erythematosus • These autoantibodies form circulating immune complexes accumulating in target organs; sometimes may be also kidney antigens as targets. • The pattern of autoantibody tends to be conserved for given patients. • B lymphocytes are abnormal: increased numbers in circulation, activated cells of all stages, elevated (beyond basal) levels of cytoplasmatic Calcium; higher responsivity to cytokines. • Higher circulating levels of IL-10 (activatory cytokine for B lymphocyte proliferation and differentiation), sometimes corelating with ANA titers • monocytes/macrophages inefficient producers of IL-12 • defects in AICD of Th • High affinity antibody throughout of the evolution (although both Td and Ti autoantibodies are pathogenic) • unknown positive reactivity for Th cells

20. Systemic Lupus Erythematosus • Mechanisms • genetics • environmental factors NO CAUSATIVE FACTORS, but triggers • UVB=> flares of both cutaneous and internal organ lupus (some antigens, like Ro, La, RNP, but not chromatin antigens and other nuclear components are translocated to keratinocyte cell surface, favorising the immune response); decrease DNA methylation and induces gene expression; increase expression of integrins like LFA-1 • weaker correlation with viral infections (EBV, via CD21, as stimulator of B lymphocytes; mimicry of EBNA II / Sm antigens with partial sequence homology), high-fat and high-caloric diets, cosmetics, trichloretane, but greater with stress, depression, fatigue • contribution of estrogens / low levels of DHEA • drug - induced (procainamide - slow acetylator phenotype due to decreased acethyltransferase activity in p450 cytochrome system, with predominance of anti-histone antibodies)

21. Systemic Lupus Erythematosus • =>

22. Take home topics: • animal (murine) models of SLE • abTCR lymphocytes in SLE • Intrinsic defects of B lymphocytes in SLE • Complement system in SLE