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 early age • Secondary – the onset of symptoms at any age chronic diseases effect of irradiation immunosuppression surgical intervention, 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 bacteria) respiratory - pneumonia, sinusitis, otitis GIT – diarrhea • Complement system – microbial infections (pyogenic), sepsis edema (HAE) – C1-INH deficiency • T lymphocytes - bacterial, fungal, viral GIT – diarrhoea respiratory – pneumonia, sinusitis • Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammation

5. I. Primary immunodeficiencies – phagocytic cell defects 1/ Quantitative – decreased numbers of granulocytes 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, some forms AR • Enzymatic inability to generate toxic oxygen metabolites (H2O2) during oxygen consumption) - defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase) • Inability to kill catalase producing bacteria such as Staph.aureus, Pseud.aeruginosa • Clinical features: granulomas of skin, organs • Treatment: long-term ATB prophylaxis, in more severe cases BMT

7. II. Primary immunodeficiencies – B cell disorders X-linked hypogamaglobulinemia (XLA, Bruton’s agammaglobulinemia) • Most common X-linked form • Block of maturation of pre-B lymphocytes into B lymphocytes (Bruton’s tyrosine kinase defect) • Undetectable or very low serum levels of Ig, absence of B cells • Symptoms: pneumonias, pyogenic otitis, increased occurrence of pulmonary fibrosis • Treatment: life-long Ig replacement CVID – Common Variable ImmunoDeficiency • Heterogenous group of B cell functional defects • Low levels of IgG and IgA, B cell counts normal • Symptoms: onset mostly between 2nd and 3rd decade recurrent respiratory tract infections (pneumonia, sinusitis) • Treatment: life-long Ig replacement

8. II. Primary immunodeficiencies – B cell disorders Selective IgA deficiency • Disorder of B cell function: absence of IgA, levels of the other Ig normal • Recurrent mild/moderate infections or asymptomatic • Risk of reaction to live attenuated vaccines or generation of anti-IgA antibodies after blood transfusion Selective IgG subclasses deficiency, specific IgG deficiency • B cell functional disorder • Onset of symptoms in childhood, mostly respiratory tract infections caused by encapsulated bacteria (H.influenzae, Pneumococci) Transitory hypogammaglobulinemia of infancy • Milder and transitory decrease of IgG and IgA

9. III. Primary immunodeficiencies –T cell disorders diGeorge syndrome • Disorder of development of 3rd and 4th branchial pouch → congenital heart disease + absence of thymus + absence of parathyroid glands • Complete or parcial • Symptoms: symptoms of cong.heart dis. – prominent immunodeficency – variable (mild functional → absence of T cells) hypocalcemic spasms – possible mental deficit • Treatment: symptomatic, in complete form BMT

10. 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 until 2nd year of age), onset of symptoms soon after birth (severe diarrhoea, pneumonia, meningitis, BCGitis) • Immunological features: typically lymphopenia, absence of T cells, hypogammaglobulinemia • Forms:X-linked form – the most common, T-B+NK-, defect of common gamma chain shared by receptors of various important cytokines → absence of T cells AR form – T-B-, enzymatic defect (ADA, PNP) → accumulation of metabolites toxic for DNA synthesis → lymphopenia Ommen sy. - defect of recombinases → defect of VDJ recombination → proliferation of one or more clones of autoreactive T cells • Treatment: BMT is of critical significance, in ADA deficiency gene therapy ATB, IVIG

11. V. Primary immunodeficiencies –complement system disorders Hereditary angioedema(HAE) • Absence orfunctional defect of C1-inhibitor • Recurrent swellings of skin or mucosa (oropharynx, gut) triggered by intercurrent infect, trauma or surgery • Uncontroled activation of kinin system • Laryngeal edemas could be life-threatening, immediate treatment is necessary • Treatment:preventive – androgens, EACA, C1 inhibitor concentrate rescue -administration of C1 concentrate (or recombinantly produced) - administration of bradykinin receptor antagonist (icatibant)

12. 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

13. AcquiredImmunoDeficiency Syndrome (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 infects macrophages and CNS cells • Viral genome transcribes into human DNA and infected cell provides viral replication • Diagnosis: serological (3 to 6 weeks after primoinfection, PCR • Transmission: sexual contact contact with blood or blood products mother-to-child – prenatally, delivery, breast feeding • Phases: acute (flu-like symptoms) asymptomatic – months to years, viral replication, loss of Th cells symptomatic – infections, autoimmune disorders, malignancies, allergy final – systemic breakdown, opportune infections (Pneumocystis jirovecii, Cryptococcus neoformans, Toxoplasma gondii, Candida albicans, CMV etc.) - Kaposi’s sarcoma

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

15. AUTOIMMUNE DISEASES

16. 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

17. 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)

18. 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

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

20. 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

21. 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

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

23. 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

24. 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

25. 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

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

27. Vasculitis - 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

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

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

30. 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

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

32. 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)

33. 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

34. 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

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

36. 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

37. 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

38. Treatment of autoimmune diseases • Systemic AI – non-specific immunosuppression: glucocorticoids • cytostatics: • alkylating agents- • cyclophosphamide • purine analogs - azathioprine, • mycophenolate, • antimetabolites - metotrexate • antibiotics - cyclosporin A, • tacrolimus • monoclonal antibodies • Organ specific AI - • non-specific immunosuppression • Endocrinopathies - • Substitution of lacking product of endocrinal gland destroyed by AI process • insulin, thyroid gland • hormones