Immunodeficiencies and autoimmune diseases Martin Lika Immunodeficiencies Humoral

Immunodeficiencies and autoimmune diseases Martin Liška

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

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

Immunodeficiencies – major clinical features • Antibodies - microbial infections (encapsulated bacteria) respiratory - pneumonia, sinusitis, otitis GIT – diarrhea • Complement system – microbial infections (pyogenic), sepsis edema (HAE) – C 1 -INH deficiency • T lymphocytes - bacterial, fungal, viral GIT – diarrhoea respiratory – pneumonia, sinusitis • Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammation

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

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 (H 2 O 2) 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 catalase • Clinical features: granulomas of skin, organs • Treatment: long-term ATB administration

II. Primary immunodeficiencies – B cell disorders • Bruton’s X-linked hypogamaglobulinemia Blockage of the maturation of pre-B lymphocytes into B lymphocytes (tyrosine kinase defect) 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 Immuno. Deficiency B cell functional disorder, mostly low levels of Ig. G and Ig. A Symptoms’ onset between 2 nd and 3 rd decade Recurrent respiratory tract infections (pneumonia) Treatment: IVIG substitution • • •

II. Primary immunodeficiencies – B cell disorders Selective Ig. A 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-Ig. A antibodies after a blood transfusion Selective Ig. G subclasses or specific Ig. G 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

III. Primary immunodeficiencies – T cell disorders di. George syndrome • Disorder of prethymocytes maturation due to absence of thymus (disorder of development of 3 rd and 4 th 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

IV. Primary immunodeficiencies – combined defects of T and B cells SCID – Severe Combined Immuno. Deficiency • 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), onset of symptoms soon after 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 gene therapy

V. Primary immunodeficiencies – complement system disorders Hereditary angioedema (HAE) • Absence or functional deficiency of C 1 -inhibitor • Anaphylactoid reactions with skin and/or mucosal (oral, laryngeal, gut) edemas caused by activation of kinin system • Injuries or surgical/stomatological interventions are mostly triggering factor • Laryngeal edemas could be life-threatening, immediate treatment is necessary ! • Treatment: preventive – androgens, EACA immediate – C 1 -INH concentrate or fresh frozen plasma administration - newly bradykinin receptor antagonist (icatibant)

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

Secondary immunodeficiencies - A. I. D. S. • Caused by retrovirus HIV 1 or HIV 2 • Virus has a tropism for cells bearing CD 4 surface marker (Th CD 4+ lymphocytes); also affects macrophages and 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

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

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

AUTOIMMUNE PATOLOGICAL RESPONSEETIOLOGY • 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)

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

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

SYSTEMIC LUPUS ERYTHEMATOSUS • chronic, inflammatory, multiorgan disorder • 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, leucopenia, hemolytic anemia, decreased levels of complement compounds (C 4, C 3), elevated serum Ig levels, immune complexes in serum

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

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

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

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)

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

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 (overlap syndrome) • Symptoms : 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-U 1 -RNP antibody (ENA)

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

Vasculitis • p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa) • c- ANCA (serin proteinase) positive (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-Schönlein purpura) • Symptoms: fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

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

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

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

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

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

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)

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

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 insulineproducing 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

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

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

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

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