74 AUTOIMMUNE DISEASES Autoimmune disease Results from a

74. AUTOIMMUNE DISEASES

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

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

Central tolerance in T cells § Central tolerance of T cells is the result of highaffinity 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 CD 4+ lineage develop into regulatory T cell that supress self reactivity in the periphery

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

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)

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

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

AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY § disorders are characterized by chronicity and usually are irreversible § 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)

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 Ig. G class § autoantibodies against intracelular proteins and nuclear acid, cytoplasmatic molecules participating in protein synthesis and expression and regulation of genes § Ig. M and Ig. G 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

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

Type IV hypersensitivity reaction § T cell- mediated diseases are caused by Th 1 -mediated delayed-type hypersensitivity reactions or Th 17 mediated inflammatory reactions, or by killing of host cells by CD 8+ CTLs (cytotoxic lymphocytes). § Diabetes mellitus (insulin-dependent), Rheumatoid arthritis, Multiple sclerosis, Inflammatory bowel disease

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 with development or function

75. EXAMPLES OF SYSTEMIC AUTOIMMUNE DISEASES § examples § autoantibodies

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

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

DIAGNOSTIC TESTS § a elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leukopenia, hemolytic anemia, depresed levels of complement (C 4, C 3), elevated serum gamma globulin levels, immune complexes in serum

AUTOANTIBODIES § Autoantibodies: ANA, ds. DNA (doublestranged), ENA (SS-A/Ro, SS-A/La), Sm, against histones, phospholipids

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 Ig. G = rheumatoid factor (RF), a-CCP (cyclic citrulline peptid), ANA - X-rays of hands and legs- show a periarticular porosis, marginal erosion

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

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

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

Immunological findings § ANA, ENA - anti-Scl-70 (fluorescence of nucleolus), anti-centromers

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-U 1 -RNP antibody (ENA)

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 Heliotrope rash is a violaceous erythematous, scaly eruption on the upper eyelids, occurring in symmetric fashion often with swelling over the MCP and interphalangeal joints

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)

Antiphospholipid syndrome § autoimmune disease characterized by vein and arterial thrombosis, repeated abortions § accompanied by anti-phospholipid autoantibodies (APA) and antibodies against β 2 -glykoprotein I

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 organnecrosis, granulomas, angiography

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)

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

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

Sarcoidosis § multisystem disorder characterized by noncaseating 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)

76. EXAMPLES OF ORGANSPECIFIC AUTOIMMUNE DISEASES § diseases § autoantibodies

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

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

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 against Saccharomyces cerevisiae (ASCA), a- pancreas

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

§ 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 § p. ANCA

AUTOIMMUNE HEPATITIS § type I – association with autoantibodies against smooth muscles SMA, 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

Pulmonary fibrosis § is associated with SLE, RA, systemic sclerosis, polymyositis § autoantibodies nonspecific- RF, ANA, others autoantibodies in according with associate disease § biopsy, spirometry, X-ray

ORGAN SPECIFIC AUTOIMMUNE DISEASES § § § Autoimmune endocrinopathy Autoimmune neurological diseases Autoimmune cytopenia Autoimmune cutaneous diseases Autoimmune eye diseases

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

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)

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

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

Diabetes mellitus (insulindependent) § 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

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

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

Pernicious anemia § the deficiency of the intrinsic factor results in inadequate and abnormal formation of erythrocytes and failure to absorb vitamin B 12 § clinical feature- atrophic gastritis, macrocytic anemia § autoantibodies against parietal cells of gastric mucose, against intristic factor (transport vit. B 12)

AUTOIMMUNE NEUROPATHY § Guillain-Barré syndrome (acute idiopathic polyneuritis) § Myasthenia gravis § Multiple sclerosis

Guillain-Barre syndrome § inflammatory demyelinate peripheral neuropathy 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 ganglioside membrane (cross-react with Campylobacter jejuni lipopolysacharids)

Myasthenia gravis § chronic disease resulting from faulty neuromuscular transmission § characterized by muscle weakness and fatigue § the muscle weakness and neuromuscular dysfunction result from blockage and depletion of acetylcholin receptors at the myoneural junction § immunological findings: autoantibodies against Ach receptors § ptosis of the eye

Multiple sclerosis § chronic demyeline 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 demyelination § The cerebrospinal fluid is tested for oligoclonal bands, can provide evidence of chronic inflammation of the central nervous system

AUTOIMMUNE DISORDERS OF REPRODUCTIVE ORGANS § Autoimmune men‘s infertility = autoimmune orchitis - autoantibodies against sperms § Premature Ovarian Failure = lymphocytic oophoritis - autoantibodies against enzymes participate in steroidogenesis - autoantibodies against 17 -hydroxylase,

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

EYE DISEASE § Uveitis - the autoreactive T cells react with retinal S autoantigen

Bullous pemphigoid § an autoimmune bullous disease of the skin and mucosa § the blisters form beneath the epidermis at the dermal- epidermal junction § lesions demonstrate deposition of antibody and complement along skin basement membrane § circulating antibasement membrane antibodies also can be detected

Pemphigus vulgaris § an erosive disease of the skin and mucous membranes characterized by intraepidermal blisters § skin lesions show antibody (mainly Ig. G) deposition and complement components in squamous intercellular spaces (when examined by imunofluorescence)

Dermatitis herpetiformis (Duhring) § autoimmune disease affect skin, associate with coeliac disease § autoantibodies against endomysium, more specific against tissue transglutaminaze § biopsy of skin: Ig. A deposition on the dermal papilles § biopsy of jejunum/duodenum: atrophy of the intestine villi

Psoriasis § Disorder which affects the skin and joints, commonly causes red scaly patches to appear on the skin § T cells become active, migrate to the dermis and trigger the release of cytokines which cause inflammation and the rapid production of skin cells § It is not known what initiates the activation of the T cells

77. IMMUNOSUPRESSION § non-specific treatment §examples of drugs §indication §risks

Immunosuppressants § are drugs that inhibit or prevent activity of the immune system § They are used in immunosuppressive therapy to: § Prevent the rejection of transplanted organs and tissues (bone marrow, heart, kidney, liver) § Treat autoimmune diseases or 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 inflammatory diseases (allergic asthma, atopic eczema).

Glucocorticoids § suppress the cell-mediated immunity- act by inhibiting genes that code for the cytokines IL 1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, the most important of which is the IL-2 § Smaller cytokine production reduces the T cell proliferation. § suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors- this diminishes both B cell clone expansion and antibody synthesis.

Glucocorticoids § leads to diminished eicosanoid production, supression of the cyclooxygenase expression § Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits : epithelial adhesion, migration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators from neutrophils, macrophages, and mastocytes. § side-effects: hypertension, dyslipidemia, hyperglycemia, peptic ulcers, osteoporosis, disturbed growth in children

Drugs affecting the proliferation of both T cells and B cells § Cyclophosphamide -very efficient in therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosis § high doses cause pancytopenia and hemorrhagic cystitis § Methotrexate is a folic acid antagonist, acts during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle; used in the treatment of autoimmune diseases (RA, Crohn's disease, psoriasis) and in transplantations.

Drugs affecting the proliferation of both T cells and B cells § Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leukocytes; SLE, RA, sclerosis multiplex, transplantation § Mycophenolate mofetil – affects the enzyme that controls the purine synthesis § Used in transplantation of solid organ

Drugs blocking the activation of lymphocytes § Tacrolimus - prevents the cell from transitioning from the G 0 into G 1 phase of the cell cycle § Used to prevent rejection reactions, atopic eczema § Sirolimus - affects the signal transduction of T cells and their clonal proliferation § Cyclosporin A- inhibits calcineurin, which is responsible for activating the transcription of interleukin-2; inhibits cytokines production and interleukin release § Used to prevent rejection reactions § Side effects: nephrotoxicity, neurotoxicity, hypertension, dyslipidemia, hyperglycemia

Monoclonal antibodies § Monoclonal antibodies are directed towards exactly defined antigens § Daclizumab - acts by binding the IL-2 a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival § used in the prophylaxis of the acute organ rejection after the bilateral kidney transplantation

Immunosuppressionkidney transplantation § Prevent the acute kidney rejection, tend to eliminate side effects § Induction by daclizumab § Therapy: Glucocorticoids + mycophenolate mofetil + tacrolimus (or cyclosporin A)