AUTOIMMUNE DISEASES

1. AUTOIMMUNE DISEASES Martina Vachová Department ofImmunologyandAllergology FacultyofMedicineandFacultyHospital in Pilsen

2. 27. 11. 2014 MUDr. Martina Vachová 54. Non-organ-specific autoantibodies and their diagnostic significance. 55. Autoantibodies in organ specific autoimmune diseases. Organ-localized autoimmune diseases with non-organ specific autoantibodies. 56. Autoimmune diseases - pathophysiology, division, laboratory diagnostics, treatment. 57. Examples of systemic autoimmune diseases. 58. Examples of organ-specific autoimmune diseases. 59. Immunosupressive treatment - examples of drugs, indications, risks.

3. AUTOIMMUNE DISEASES • chronic and usually irreversible • incidence: 5%-7% of population, higher frequencies in women, increases with age

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

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

6. AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY Factors contributing to autoimmunity: - internal (HLA association, polymorphism of cytokine genes, defect in genes regulating apoptosis, polymorphism in genes for TCR and H immunoglobulin chains, association with immunodeficiency, hormonal factors) - external (infection, stress by activation of neuroendocrinal axis and hormonal dysbalance, drug and ionization through modification of autoantigens) Mechanismoftissuedamage: - Type II, III and IV hypersensitivityreactions

7. Type II hypersensitivity reaction • IgMand IgGAb promote the phagocytosis of cells which they bind, induce inflammation 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, Myasthenia gravis, Acute rheumatic fever, Goodpasture‘s syndrome, Pemphigusvulgaris, Autoimmune hemolytic anemia or thrombocytopenicpurpura

8. Type III hypersensitivity reaction • Ab may bind to circulating antigens to form immune complexes, which deposit in vessels and cause tissue injury • Injury is mainlydue to leukocyte recruitment and inflammation • Systemic lupus erythematosus, Polyarteritisnodosa, Poststreptococcalglomerulonephritis

9. Type IV hypersensitivity reaction • T cell- mediateddiseases are caused by Th1-mediateddelayed-type hypersensitivityreactionsor Th17- mediatedinflammatoryreactions, or by killingof host cells by CD8+ CTLs (cytotoxiclymphocytes). • Diabetes mellitus (insulin-dependent), Rheumatoid arthritis, Multiple sclerosis, Inflammatoryboweldisease

10. Autoimmunediseases • Organ-specific • Systemic • Organ-localised

11. CLINICAL CATEGORIES • systemic - affect many organs and tissue - organ non-specificautoantibodies • organ specific - affect one organ - organ specificautoantibodiesorautoreactive T lymphocytes • organlocalised - affect predominantly one organ accompanied by affection of other organs (inflammatory bowel diseases, coeliac disease, AI hepatitis, pulmonary fibrosis) - organ non-specificautoantibodies

12. EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES examples autoantibodies

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

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

16. DIAGNOSTIC TESTS • an elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leucopenia, hemolytic anemia, decreased levels of complement compounds(C4, C3), elevated serum Ig levels, immune complexes in serum

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

18. https://www.youtube.com/watch?v=WgfFcpAD9XQ

19. RHEUMATOID ARTHRITIS • chronic, inflammatory disease with systemic involvement • 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 - autoantibodiesagainst IgG = rheumatoid factor (RF), a-CCP (cyclic citrullinepeptid) - X-rays of hands and legs- show a periarticular porosis, marginal erosion

20. SJÖGREN‘S SYNDROME • chronic inflammatory disease affecting 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 • secondary syndrome – is associated with other AI diseases (SLE, RA, sclerodermia, polymyositis, primary biliarycirhosis,AIthyroiditis) • autoantibodies against ENA (SS-A, SS-B), ANA • The Schirmer test - measures the production of tears

21. Dermatopolymyositis • a connective-tissue disease 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

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

23. Systemic sclerosis • sclerosis in the skin or other organs • Diffuse scleroderma(progressive systemic sclerosis) is the most severe form, involves skin, will generally cause internal organ damage (specifically the lungs and gastrointestinal tract) • The limited formis much milder • 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, Sclerodactyly, Telangiectasia

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

25. Mixed connective tissue disease • combines features of polymyositis, systemic lupus erythematosus, scleroderma, and dermatomyositis(overlap syndrome) • features : 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 anti-U1-RNP antibody (ENA)

26. Vasculitis • characterized by inflammatory destruction of vessels leading to thrombosis and aneurysms • affect mostly lung, kidneys, skin • diagnostic tests: elevated ESR, CRP, leucocytosis, biopsy of affected organ (necrosis, granulomas), angiography, ANCA (antineutrophilcytoplasmicantibodies)

27. Vasculitis • p- ANCA (myeloperoxidase) positivity (Polyarteritisnodosa, Churg- Strauss) • c- ANCA (serinproteinase) positivity(Wegener granulomatosis)

28. Classification • Large vessel vasculitis(Takayasuarteritis, Giant cell (temporal) arteritis) • Medium vessel vasculitis(Polyarteritisnodosa, Wegener's granulomatosis, Kawasaki disease) • Small vessel vasculitis(Churg-Strauss arteritis, Microscopic polyarteritis, Henoch-Schönleinpurpura) • Symptoms:fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

29. https://www.youtube.com/watch?v=A4b_-uUNv7w

30. EXAMPLES OF ORGAN LOCALISED AUTOIMMUNE DISEASES diseases autoantibodies

31. ORGAN LOCALIZED AUTOIMMUNE DISEASES • Ulcerative colitis • Crohn‘s disease • Autoimmune hepatitis • Primary biliarycirhosis • Pulmonary fibrosis

32. Ulcerative colitis • chronic inflammation of the large intestine mucosa and submucosa • features: diarrhea, bloody and mucusstools • extraintestinal features (arthritis, uveitis) • autoantibodiesagainst pANCA, a- large intestine

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

34. Primary biliarycirhosis autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts; can lead to cirrhosis AMA= antimitochondrialautoantibodies

35. AUTOIMMUNE HEPATITIS • typeI – association with autoantibodies against smooth muscles SMA, ANA, ANCA, SLA • type II –autoantibodies against microsomesLKM-1 = liver-kidney microsomes • type III – autoantibodies against SLA (solubile liver antigen)

36. ORGAN SPECIFIC AUTOIMMUNE DISEASES • Autoimmune endocrinopathy • Autoimmune neurological diseases • Autoimmune cytopenia

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

38. 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 thyroglobulin (a-TG)

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

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

41. 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

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

43. Pernicious anemia • autoantibodies against parietal cells of gastric mucose, against intrinsic factor (transportation of B12 vitamin) • 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

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

45. Guillain-Barré syndrome • inflammation demyelinates peripheral nerves that causes progressive muscle weakness and paralysis • the cause is the loss of myelin • occurs often 1-3 weeks after infection (Campylobacter jej.) • features: progressive weakness and paresthesia of the lower and later upper extremitas and respiratory muscles, weakness can leads to paralysis and respiratory failure • immunologic findings: autoantibodies against gangliosidemembrane

46. Myasthenia gravis • chronic disease with impaired neuromuscular transmission • characterized by muscle weakness and fatigue • the muscle weakness and neuromuscular dysfunction result from blockageand depletion of acetylcholine receptors at the myoneural junction • immunological findings: autoantibodies against Ach receptors • ptosis of the eye

47. Multiple sclerosis • chronic demyelinizing disease with abnormal reaction T cells to myeline protein on the base of mimicry between a virus and myeline protein • features: weakness, ataxia, impaired vision, urinary bladder dysfunction, paresthesias, mental abberations • autoantibodies against MOG (myelin-oligodendrocyte glycoprotein) • Magnetic resonance imaging of the brain and spine shows areas of demyelinization • The cerebrospinal fluid is tested for oligoclonal bands, can provide evidence of chronic inflammation of the central nervous system

48. AUTOIMMUNE CYTOPENIA • AI hemolytic disease- autoantibodies against membrane erythrocyte antigens • AI trombocytopenia - autoantibodies against trombocyte antigens (GPIIb/IIIa) • AI neutropenia - autoantibodies against membrane neutrofil antigens

49. IMMUNOSUPPRESSION non-specific treatment examples of drugs indication risks

50. Immunosuppressants • Drugs that inhibit or prevent activity of the immune system • They are used to: • Prevent the rejectionof transplanted organs and tissues (bone marrow, heart, kidney, liver) • Treat autoimmune diseasesor diseases that are most likely of autoimmune origin (rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, pemphigus, ulcerative colitis). • Treat some other non-autoimmune inflammatorydiseases (allergic asthma, atopic eczema).