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Immunodeficiencies and autoimmune diseases PowerPoint Presentation

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Tags : Autoimmune Diseases, immune system, inflammation, Immunodeficiency

Published on : Mar 16, 2023 | Views : 1432 | Downloads : 0

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Immunodeficiencies andautoimmune diseases Martin Liška
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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
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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
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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
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I. Primary immunodeficiencies – phagocytic cell defects 1/ Quantitative – decreased numbers of granulocytes Congenital chronic agranulocytosis Cyclic agranulocytosis (neutropenia)
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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
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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
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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
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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
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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
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V. Primary immunodeficiencies – complement system disorders Hereditary angioedema (HAE) Absence or functional 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)
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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 administration of certain drugs (e.g. oxacilin, quinidine) Chronic GIT 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 exposure to harmful chemical substances
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Acquired ImmunoDeficiency 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
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A.I.D.S. - Treatment Reverse transcriptase inhibitors (e.g.zidovudine) Protease inhibitors - block the viral protease enzyme Combined drug therapy Antimicrobial agents
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AUTOIMMUNE DISEASES
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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
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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)
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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 with development or function
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SYSTEMIC AUTOIMMUNE DISEASES Systemic lupus erythematosus Rheumathoid arthritis Sjögren‘s syndrome Dermatopolymyositis Systemic sclerosis Mixed connective tissue disease Vasculitis
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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 tissue are involved including the skin, mucosa, kidney, joints, brain and cardiovascular system characteristic features: butterfly rash, renal involvement, CNS manifestation, pulmonary fibrosis
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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
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AUTOANTIBODIES Autoantibodies: ANA, dsDNA (double-stranded), ENA (SS-A/Ro, SS-A/La), Sm, against histones, phospholipids
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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
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SJÖGREN‘S SYNDROME chronic inflammatory disease affecting exocrine glands the primary targets are 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
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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
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Vasculitis p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa) c- ANCA (serin proteinase) positive (Wegener granulomatosis, Churg- Strauss syndrome)
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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
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ORGANOLEPTIC AUTOIMMUNE DISEASES Ulcerative colitis Crohn‘s disease Autoimmune hepatitis Primary biliary cirhosis Pulmonary fibrosis
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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
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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 against Saccharomyces cerevisiae (ASCA), a- pancreas
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AUTOIMMUNE ENDOCRINOPATHY Hashimoto‘s thyroiditis Graves-Basedow disease Diabetes mellitus I. type Addison‘s disease Autoimmune polyglandular syndrome
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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)
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Grave‘s disease thyrotoxicosis from overproduction of thyroid hormone (patient exhibit fatigue, nervousness, increased sweating, palpitations, weight loss, exophtalmus) autoantibodies against thyrotropin receptor, autoantibodies cause thyroid cells proliferation
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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
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AUTOIMMUNE NEUROPATHY Guillain-Barré syndrome (acute idiopathic polyneuritis) Myasthenia gravis Multiple sclerosis
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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
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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
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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