74. AUTOIMMUNE DISEASES

1. 74. AUTOIMMUNE DISEASES

2. Autoimmune disease • Results from a failure of self-tolerance • Immunological tolerance is specific unresponsiveness to an antigen • All individuals are tolerant of their own (self) antigens

3. Central and peripheral tolerance • Central tolerance is induced by the death of or other changes in immature lymphocytes that encounter antigens in the generative lymphoid organs • Peripheral tolerance results from the recognition of antigens by mature lymphocytes in peripheral tissues

4. Central tolerance in T cells • Central tolerance of T cells is the result of high-affinity recognition of antigens in the thymus • Some of these self-reactive T cells die (negative selection), thus eliminating the potentially most dangerous T cells, which express high-affinity receptors for self antigens. • Other Tcells of the CD4+ lineage develop into regulatory T cell that supress self reactivity in the periphery

5. Peripheral tolerance in T cells • Peripheral tolerance in T cells is induced by multiple mechanisms • Anergy results from the recognition of antigens without innate immunity and costimulators • The mechanisms of anergy include a block in TCR signaling and engagement of inhibitory receptors • Self reactive regulatory T cells supress potentially pathogenic T cell • Deletion may occure when T cell encounter self antigens

6. Central tolerance in B cells • central tolerance in B lymphocytes occurs when immature cells recognize self antigens in the bone marrow – some of the cells change their receptors and others die by apoptosis (negative selection)

7. Peripheral tolerance in B cells • Is induced when mature B cells recognize self antigens without T cell help - this results in anergy and death of the B cells

8. Autoimmunity • is defined as an immune respons against self antigens • The principial factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections • Most autoimmune diseases are polygenic and are asssociated wih multiple gene loci, the most important of which are the MHC genes • Infections may activate self-reactive lymphocytes, thereby triggering the development of autoimmune diseases

9. AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY • disorders arecharacterized by chronicity and usually areirreversible • incidence: 5%-7% of population, higher frequencies in women, increases with age • factors contribute to autoimmunity: - internal (HLA association, polymorfism in genes for cytokines, defect in genes regulating apoptosis, polymorphism in genes for TCR a H immunoglobulin chains, association with immunodeficiencies, hormonal factors) - external (infection, stress by activation of neuroendocrine‘s line and hormonal disbalance, drug and ionization through modification of autoantigens)

10. Type II hypersensitivity reaction • Ab against cell and tissue antigens may cause tissue injury and disease • autoantibodies characterized by a high afinity to antigens, present in a high level in serum, predominantly in the IgG class • autoantibodies against intracelular proteins and nuclear acid, cytoplasmatic molecules participating in protein synthesis and expression and regulation of genes • IgM and IgG Ab promote the phagocytosis of cells which they bind, induce inflamation by complement – and Fc receptor- mediated leukocyte recruitment , and may interfere with the functions of cells by binding to essential molecules and receptors. • Graves‘ disease, Pernicious anemia, Myastenia gravis, Acute rheumatic fever, Goodpasture‘s syndrome, Pemphigus vulgaris, Autoimmune hemolytic anemia or trombocytopenic purpura

11. Type III hypersensitivity reaction • Ab may bind to circulating antigens to form immune complexes, which deposit in vessels and cause tissue injury. • Injury is due mainly to leukocyte recruitment and inflammation. • Systemic lupus erythematosus, Polyarteritis nodosa, Poststreptococcal glomerulonephritis

12. Type IV hypersensitivity reaction • T cell- mediated diseases are caused by Th1-mediated delayed-type hypersensitivity reactions or Th17- mediated inflammatory reactions, or by killing of host cells by CD8+ CTLs (cytotoxic lymphocytes). • Diabetes mellitus (insulin-dependent), Rheumatoid arthritis, Multiple sclerosis, Inflammatory bowel disease

13. CLINICAL CATEGORIES • systemic - affect many organs and tissue • organ localised - affect predominantly one organ accompained by affection of other organs (nonspecific bowel diseases, celiatic disease, AI hepatitis, pulmonary fibrosis) • organ specific - affect one organ or group of organs connected withdevelopment or function

14. 75. EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES examples autoantibodies

15. SYSTEMIC AUTOIMMUNE DISEASES • Systemic lupus erythematosus • Rheumathoid arthritis • Sjögren‘s syndrome • Dermatopolymyositis • Systemic sclerosis • Mixed connective tissue disease • Antiphospholipid syndrome • Vasculitis • Sarcoidosis

16. SYSTEMIC LUPUS ERYTHEMATOSUS • chronic, inflammatory, multiorgan disorder • predominantly affects young women • autoantibodies react with nuclear material and attack cell function, immune complexes with dsDNA deposit in the tissue • general symptoms: include malaise, fever, weight loss • multiple tissueare involved including the skin, mucosa, kidney, joints, brain and cardiovascular system • characteristic features: butterfly rash, renal involvement, CNS manifestation, pulmonary fibrosis

17. DIAGNOSTIC TESTS • a elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leukopenia, hemolytic anemia, depresed levels of complement (C4, C3), elevated serum gamma globulin levels, immune complexes in serum

18. AUTOANTIBODIES • Autoantibodies: ANA, dsDNA (double-stranged), ENA (SS-A/Ro, SS-A/La), Sm, against histones, phospholipids

19. RHEUMATOID ARTHRITIS • chronic, inflammatory joint disease with systemic involvement • predominantly affects women • characterized by an inflammatory joint lesion in the synovial membrane, destruction of the cartilage and bone, results in the joint deformation • clinical features: arthritis, fever, fatigue, weakness, weight loss • systemic features: vasculitis, pericarditis, uveitis, nodules under skin, intersticial pulmonary fibrosis • diagnostic tests: elevated C- reactive protein and ESR, elevated serum gammaglobulin levels - autoantibodies against IgG = rheumatoid factor (RF), a-CCP (cyclic citrulline peptid), ANA - X-rays of hands and legs- show a periarticular porosis, marginal erosion

20. Rtg: symmetrical destruction of proximal joints, erosion of carpal bones, distal radioulnar joints

21. SJÖGREN‘S SYNDROME • chronic inflammatory disease that affects the exocrine glands • the primary targetsare the lacrimal and salivary gland duct epithelium • general features: malaise, weakness, fever • primary syndrome - features: dry eyes and dry mouth, swollen salivary glands, dryness of the nose, larynx, bronchi and vaginal mucosa, involvement kidney, central and periferal nervous system, artritis • secondary syndrome – is associated with others AI diseases (SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis) • autoantibodies against ENA (SS-A, SS-B), • ANA, RF • The Schirmer test - measures the production of tears

22. Systemic sclerosis • sclerosis in the skin or other organs • Diffuse scleroderma (progressive systemic sclerosis) is the most severe form - it has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (specifically the lungs and gastrointestinal tract • The limited form is much milder • The scleroderma may be limited to the fingers - known as sclerodactyly. • The limited form is often referred to as CREST syndrome "CREST" is an acronym for the five main features: Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyy, Telangiectasia

23. Immunological findings • ANA, ENA - anti-Scl-70 (fluorescence of nucleolus), anti-centromers

24. Mixed connective tissue disease • combines features of polymyositis, systemic lupus erythematosus, scleroderma, and dermatomyositis, and is thus considered an overlap syndrome • Causes : joint pain/swelling, malaise, Raynaud phenomenon, muscle inflammation and sclerodactyly (thickening of the skin of the pads of the fingers) • Distinguishing laboratory characteristics: a positive, speckled anti-nuclear antibody (ANA) and an anti-U1-RNP antibody (ENA)

25. Dermatopolymyositis • a connective-tissue disease related to polymyositis (PM) that is characterized by inflammation of the muscles and the skin. Gottron's sign is an erythematous, scaly eruption occurring in symmetric fashion over the MCP and interphalangeal joints Heliotrope rash is a violaceous eruption on the upper eyelids, often with swelling

26. Dermatopolymyositis • Elevated creatine phosphokinase (CPK) • muscle biopsy (a mixed B- and T-cell perivascular inflammatory infiltrate, perifascicular muscle fiber atrophy) • EMG (electromyogram) • autoantibodies - ENA (Jo-1)

27. Antiphospholipid syndrome • autoimmune disease characterized by vein and arterial thrombosis, repeated abortions • accompanied by anti-phospholipid autoantibodies (APA) and antibodies against β2-glykoprotein I

28. Vasculitis • characterized by inflammatory destruction of the bloodstream leads into thrombosis and aneurysma • proliferation of the intimal part of blood-vessel wall and fibrinoid necrosis • affect mostly lung, kidneys, skin • diagnostic tests: elevated ESR, CRP, leukocytosis, biopsy of affected organ- necrosis, granulomas, angiography

29. Vasculitis • p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyartheritis nodosa, Good- Pasture‘s syndrome, Kawasaki syndrome) • c- ANCA (serin. proteinase) positivity (Wegener granulomatosis, Churg- Strauss syndrome)

30. Classification • Large vessel vasculitis (Takayasu arteritis, Giant cell (temporal) arteritis) • Medium vessel vasculitis (Polyarteritis nodosa, Wegener's granulomatosis, Kawasaki disease) • Small vessel vasculitis (Churg-Strauss arteritis, Microscopic polyarteritis, Henoch-Schonlein purpura) • Complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

31. Giant cell (temporal) arteritis Angiography of a.temporalis • Temporal artery tenderness or decreased pulsation Biopsy showing vasculitis with mononuclear cell infiltrate, usually with multinucleated giant cells

32. Sarcoidosis • multisystem disorder characterized by non-caseating granulomas • granulomas most often appear in the lungs or the lymph nodes • cause of sarcoidosis is not known • fatigue, weight loss, arthralgia, shortness of breath, a dry cough, skin lesions, bilateral hilar lymphadenopathy • Hypercalcemia, high level of ACE (angiotensin converting enzyme)

33. 76. EXAMPLES OF ORGAN- SPECIFIC AUTOIMMUNE DISEASES diseases autoantibodies

34. ORGANOLEPTIC AUTOIMMUNE DISEASES • Ulcerative colitis • Crohn‘s disease • Coeliac disease • Autoimmune hepatitis • Primary biliary cirhosis • Primary sclerotic cholangoitis • Pulmonary fibrosis

35. Ulcerative colitis • chronic inflammation of the large intestine mucose and submucose • features: diarrhea mixed with blood and mucus • extraintestinal features (artritis, uveitis) • autoantibodies against pANCA, a- large intestine

36. Crohn‘s disease • the granulomatous inflammation of all intestinal wall with ulceration and scarring that can result in abscess and fistula formation • the inflammation of Crohn's disease the most commonly affects the terminal ileum, presents with diarrhea and is accompanied by extraintestinal features - iridocyclitis, uveitis, artritis, spondylitis • antibodies againstSaccharomyces cerevisiae (ASCA), a- pancreas

37. Coeliac disease • a malabsorption syndrome characterized by marked atrophy and loss of function of the villi of the jejunum • inflammatory bowell disease arise from gliadin exposition • autoantibodies against endomysium, the most specific = tissue transglutaminaze; antibodies against gliadin are nonspecific • biopsy of the jejunum with findings of the villi atrophy

38. Primary biliary cirhosis autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts; can lead to cirrhosis AMA= antimitochondrial autoantibodies Primary sclerotic cholangoitis a chronic disorder of the liver in which the bile ducts become inflamed, thickened, scarred (sclerotic), and obstructed process can in time destroy the bile ducts and lead to cirrhosis pANCA

39. AUTOIMMUNE HEPATITIS • typeI – association with autoantibodies against smooth muscles SMA, ANA, ANCA, SLA • type II – autoantibodies against microsomes LKM-1 = liver-kidney microsomes • type III – autoantibodies against SLA (solubile liver antigen) • type IV – overlap syndrome with PBC – autoantibodies against mitochondries AMA

40. Pulmonary fibrosis • isassociated with SLE, RA, systemic sclerosis, polymyositis • autoantibodies nonspecific- RF, ANA, others autoantibodies in according with associate disease • biopsy, spirometry, X-ray

41. ORGAN SPECIFIC AUTOIMMUNE DISEASES • Autoimmune endocrinopathy • Autoimmune neurological diseases • Autoimmune cytopenia • Autoimmune cutaneous diseases • Autoimmune eye diseases

42. AUTOIMMUNE ENDOCRINOPATHY • Hashimoto‘s thyroiditis • Graves-Basedow disease • Postpartum thyroiditis • Diabetes mellitus I. type • Addison‘s disease • Autoimmune polyglandular syndrome • Pernicious anemia

43. Hashimoto‘s thyroiditis • thyroid disease result to hypothyroidism on the base of lymphocytes and plasma cells infiltrate • autoantibodies against thyroidal peroxidase (a-TPO) and/or against thyroglobulinu (a-TG)

44. infiltrate of plasma cells and lymphocytes with germinal center formation is seen in this thyroid

45. Grave‘s disease • thyrotoxicosis from overproduction of thyroid hormone (patient exhibit fatigue, nervousness, increased sweating, palpitations, weight loss, exophtalmos) • autoantibodies against thyrotropinreceptor, autoantibodies cause thyroid cells proliferation

46. Diabetes mellitus (insulin- dependent) • characterized by an inability to process sugars in the diet, due to a decrease in or total absence of insulin production • results from immunologic destruction of the insuline- producing β-cells of the islets of Langerhans in the pancreas • autoantibodies against GAD- glutamic acid decarboxylase = primary antigen), autoantibodies anti- islet cell, anti- insulin • islets are infiltrated with B and T cells

47. Addison‘s disease • a disorder involving disrupted functioning of the adrenal cortex, this resullt in decreased production of cortisol and aldosterone • features malaise, pain of muscle and joint, hyperpigmentation • autoantibodies against adrenal cortex and/or 21-hydroxylase, autoantibodies against 17-hydroxylase

48. Polyglandular autoimmune syndrome • combination of several different AI endocrinopathies • autoantibodies appear in according with the connected disorders

49. Pernicious anemia • the deficiency of the intrinsic factor results in inadequate and abnormal formation of erythrocytes and failure to absorb vitamin B12 • clinical feature- atrophic gastritis, macrocytic anemia • autoantibodies against parietal cells of gastric mucose, against intristic factor (transport vit. B12)

50. AUTOIMMUNE NEUROPATHY • Guillain-Barré syndrome (acute idiopathic polyneuritis) • Myasthenia gravis • Multiple sclerosis