Immunodeficiencies and autoimmune diseases

1. Immunodeficiencies andautoimmune diseases Martin Liška

2. Immunodeficiencies • Humoral – innate immunity - complement, MBL acquired immunity – immunoglobulins (B lymphocytes) • Cell mediated immunity – innate immunity – phagocytes - acquired immunity – T lymphocytes • Primary – congenital, genetically defined, symptoms predominantly at an early age • Secondary – the onset of symptoms at any age chronic diseases the effects of irradiation immunosuppression surgery, injuries stress

3. Immunodeficiencies – critical life periods in respect to symptoms onset • Newborn age - severe primary disorders of cell mediated immunity • 6 mth. – 2 yrs. – severe humoral immunodeficiencies cong./transient • 3 - 5 yrs. – transient and selective humoral immunodeficiencies, secondary immunodeficiencies • 15 – 20 yrs. – hormonal instability, thymus involution, life-style changes, some typical infections first symptoms of CVID • Middleage – often excessive workload, stress first symptoms of autoimmune disorders (also immunodeficiency) • Advanced and old age – rather symptoms of severe secondary immunodeficiencies, repercussion of functional disorders

4. Immunodeficiencies – major clinical features • Antibodies - microbial infections (encapsulated bacterias) respiratory - pneumonia, sinusitis, otitis GIT – diarrhea • Complement – microbial infections (pyogenic), sepsis various systems affection edema (HAE) – C1-INH deficiency • T lymphocytes - bacterial, fungal, viral GIT – diarrhoea respiratory – pneumonia, sinusitis • Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammations

5. I. Primary immunodeficiencies – phagocytic cell defects 1/ Quantitative – decreased numbers of granulocytes –neutrophil elastase mutation Congenital chronic agranulocytosis Cyclic agranulocytosis (neutropenia)

6. I. Primary immunodeficiencies – phagocytic cell defects 2/ Qualitative – phagocytes functional disorders, various enzyme deficits, inability of phagocytes to degrade the ingested material a/ Chronic Granulomatous Disease (CGD) • Approximately in 60% X-linked • Enzymatic inability to generate toxic oxygen metabolites (H2O2) during oxygen consumption) - result of defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase) • Inability to kill bacteria such as Staph.aureus, Pseud.aeruginosa that produce the enzyme catalase • Clinical features: granulomas in many organs • Treatment: long-term ATB administration

7. I. Primary immunodeficiencies – phagocytic cell defects b/Myeloperoxidase deficiency • Susceptible to Staph.aureus or C.albicans infections c/Chédiak-Higashi syndrome • Clinical features: recurrent, severe, pyogenic infections (streptococcal, staphylococcal) • Defective intracellular killing of bacteria (neutrophils contain abnormal giant lysosomes d/HyperIgE (Job’s) syndrome • Recurrent “cold” staphylococcal abscesses, chronic eczema, otitis media • Extremely high serum IgE levels

8. II. Primary immunodeficiencies – B cell disorders Bruton’s X-linkedhypogamaglobulinemia • Blockage in the maturation of pre-B lymphocytes into B lymphocytes (tyrosine kinasedefect) • Undetectable or very low serum levels of Ig • Pneumonia, pyogenic otitis,complicated sinusitis,increased occurrence of pulmonary fibrosis • Treatment:life-long IVIG substitution CVID – Common Variable ImmunoDeficiency • B cell functional disorder, mostly low levels of IgG and IgA • Symptoms’ onset between 2ndand 3rddecade • Recurrent respiratory tract infections (pneumonia) • Treatment:IVIG substitution

9. II. Primary immunodeficiencies – B cell disorders Selective IgA deficiency • Disorder of B cell function • Recurrent mild/moderate infections (respiratory, GIT, urinary tract) or asymptomatic • Risk of reaction to live attenuated vaccines or generation of anti-IgA antibodies after a blood transfusion Selective IgG subclasses or specific IgG deficiency • B cell function disorder • Onset of symptoms in childhood, mostly respiratory tract infections caused by encapsulated bacteria (H.influenzae, Pneumococci) Transient hypogammaglobulinemia of infancy

10. III. Primary immunodeficiencies –T cell disorders diGeorge syndrome • Disorder of prethymocytes maturation due to absence of thymus (disorder of development of 3rd and 4th branchial pouch) • Congenital heart diseases • The onset of symptoms after the birth – hypocalcemic spasms and manifestations of cong.heart disease • Immunodeficiency could be only mild, the numbers of T lymphocytes later usually become normal • Treatment symptomatic

11. IV. Primary immunodeficiencies –combined defects of T and B cells SCID – Severe Combined ImmunoDeficiency • X-linked recessive or AR disease, combined disorder of humoral and cell mediated immunity • Severe disorder (patients often die during first 2 years of life), symptoms’ onset soon after the birth (severe diarrhoea, pneumonia, meningitis, BCGitis) • Immunological features: typically lymphopenia and thymus hypoplasia • Forms: AR form – often enzymatic deficiency (ADA, PNP) that leads to accumulation of metabolites toxic to DNA synthesis (lymphocytes) X-linked form – disorder of stem-cell Treatment: ATB, IVIG BMT is of critical significance Wiskott-Aldrich syndrome • trombocytopenia, eczema, recurrent infections (encapsulated microbes), decreased IgM levels

12. V. Primary immunodeficiencies –complement system disorders Hereditary angioedema(HAE) • Absence orfunctional deficiency of C1-inhibitor • Anaphylactoid reactionswith skin and/or mucosal (oral, laryngeal, gut) edemascaused by C3a a C5a • Injuries or surgical/stomatological operations are mostly the triggering factor • Laryngeal edemas could be life-threatening, immediate treatment is necessary ! • Treatment:preventive – androgens, EACA immediate – C1-INH concentrate or fresh frozen plasma administration • Secondary forms also exist !

13. Secondary immunodeficiencies • Acute and chronic viral infections – infectious mononucleosis, influenza • Metabolic disorders– diabetes mellitus, uremia • Autoimmune diseases– autoantibodies against immunocompetent cells (neutrophils, lymphocytes); autoimmune phenomena also after administrationof certain drugs (e.g. oxacilin, quinidine) • ChronicGIT diseases • Malignant diseases(leukemia) • Hypersplenism/asplenia • Burn, postoperative status, injuries • Severe nutritional disorders • Chronic infections • Ionizing radiation • Drug induced immunodeficiencies(chemotherapy) • Immunosupressive therapy • Chronic stress • Chronic exposureto harmfulchemical substances

14. Secondary immunodeficiencies Chronic fatigue syndrome • First, it is necessary to exclude all chronic diseases which can lead to fatigue: • autoimunity • malignancy • focal infection • neurological disorders • metabolic disorders • depression

15. Secondary immunodeficiencies - A.I.D.S. • Caused by retrovirus HIV 1 or HIV 2 • Virus has a tropism for cells bearing CD4 surface marker(Th CD4+ lymphocytes);also affects macrophagesand CNS cells • Viral genome transcribes into human DNA and infected cell provides viral replication • Transmission: sexual intercourse contact with blood endouterine(mother – fetus, breast milk) • Phases: acute (flu-like sy) asymptomatic – several years, viral replication symptomatic – infections, autoimmune disorders, malignancy, allergy final –systemic breakdown, opportune infections

16. A.I.D.S. - Treatment • Reverse transcriptase inhibitors (e.g.zidovudine) • Protease inhibitors - block the viral protease enzyme • Combined drug therapy • Antimicrobial agents

17. AUTOIMMUNE DISEASES

18. 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

19. AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY • the diseases are chronic and usually irreversible • incidence: 5%-7% of population, higher frequencies in women, increases with age • factors contribute to autoimmunity: - internal (HLA association, polymorphism of cytokine genes, defect in genes regulating apoptosis, polymorphism in genes for TCR a H immunoglobulin chains, association with immunodeficiency, hormonal factors) - external (infection, stress by activation of neuroendocrine axis and hormonal dysbalance, drug and ionization through modification of autoantigens)

20. CLINICAL CATEGORIES • systemic - affect many organs and tissue • organoleptic - affect predominantly one organ accompanied by affection of other organs (inflammatory bowel diseases, celiac disease, AI hepatitis, pulmonary fibrosis) • organ specific - affect one organ or group of organs connected withdevelopment or function

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

22. SYSTEMIC LUPUS ERYTHEMATOSUS • chronic, inflammatory, multiorgan disorder • 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

23. DIAGNOSTIC TESTS • a 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

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

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

26. 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, involvement kidney, central and periferal nervous system, arthritis • 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

27. 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

28. 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)

29. 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 form is 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

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

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

32. Vasculitis • characterized by inflammatory destruction of vessels leading to thrombosis and aneurysms • proliferation of the intimal part of blood-vessel wall and fibrinoid necrosis • affect mostly lung, kidneys, skin • diagnostic tests: elevated ESR, CRP, leucocytosis, biopsy of affected organ (necrosis, granulomas), angiography

33. Vasculitis • p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa) • c- ANCA (serin proteinase) positive (Wegener granulomatosis, Churg- Strauss syndrome)

34. 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-Schönlein purpura) • Symptoms: fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

35. ORGANOLEPTIC AUTOIMMUNE DISEASES • Ulcerative colitis • Crohn‘s disease • Autoimmune hepatitis • Primary biliary cirhosis • Pulmonary fibrosis

36. Ulcerative colitis • chronic inflammation of the large intestine mucosa and submucosa • features: diarrhea, bloody and mucus stools • extraintestinal features (arthritis, uveitis) • autoantibodies against pANCA, a- large intestine

37. Crohn‘s disease • the granulomatous inflammation of whole 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

38. 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

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

40. 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)

41. 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

42. 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

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

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

45. 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 demyelination • The cerebrospinal fluid is tested for oligoclonal bands, can provide evidence of chronic inflammation of the central nervous system

46. 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

47. Immunosuppressive drugs • 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 inflammatorydiseases (allergic asthma, atopic eczema).

48. Glucocorticoids • suppress the cell-mediated immunity- act by inhibiting genes that code for various cytokines (e.g.IL-2) • decrease cytokine production reduces the T cell proliferation. • suppress the humoral immunity • side-effects: hypertension, dyslipidemia, hyperglycemia, peptic ulcers, osteoporosis, disturbed growth in children

49. Drugs affecting the proliferation of both T cells and B cells • Cyclophosphamide -very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias • 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) and in transplantations.

50. Drugs affecting the proliferation of both T cells and B cells • Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leucocytes; SLE, RA, sclerosis multiplex, transplantation