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

I. Primary immunodeficiencies – defects of phagocytosis 1/ Quantitative – decreased numbers of granulocytes Congenital chronic agranulocytosis Cyclic agranulocytosis (neutropenia)

I. Primary immunodeficiencies – defects of phagocytosis 2/ Qualitative – phagocytes functional disorders, various enzyme deficits, inability of phagocytes to degrade the ingested material Chronic Granulomatous Disease (CGD) • Approximately in 60% X-linked, some forms AR • Enzymatic inability to generate toxic oxygen metabolites (H 2 O 2) 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 severe cases BMT

II. Primary immunodeficiencies – complement system disorders Hereditary angioedema (HAE) • Absence or functional defect of C 1 -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, C 1 -inhibitor concentrate rescue - administration of C 1 -inh. concentrate (or recombinantly prepared) - administration of bradykinin receptor antagonist (icatibant)

III. Primary immunodeficiencies – antibody deficiencies X-linked hypogamaglobulinemia (XLA, Bruton’s agammaglobulinemia) • Most common X-linked form • Block of maturation of pre-B cells into B cells (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 Immuno. Deficiency • Heterogenous group of B cell functional defects • Low levels of Ig. G and Ig. A, B cell counts normal • Symptoms: onset mostly between 3 rd and 4 th decade recurrent respiratory tract infections (pneumonia, sinusitis) • Treatment: life-long Ig replacement

III. Primary immunodeficiencies – antibody deficiencies Selective Ig. A deficiency • Disorder of B cell function: absence of Ig. A, levels of the other Ig normal • Recurrent mild/moderate infections or asymptomatic • Risk of reaction to live attenuated vaccines or generation of anti-Ig. A antibodies after blood transfusion Selective Ig. G subclasses deficiency, specific Ig. G 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 Ig. G and Ig. A

IV. Primary immunodeficiencies – combined T and B cell disorders di. George syndrome • Disorder of development of 3 rd and 4 th 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

IV. Primary immunodeficiencies – combined T and B cell disorders 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 until 2 nd 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 •

V. Primary immunodeficiencies immunodeficiency with immune dysregulation X-linked lymphoproliferative syndrome (XLP) • Abnormal immune response to EBV infection which leads to uncontroled lymphoproliferation • Disorder of gene localized on X chromosome - mutation of gene coding protein associated with signal activating molecule of lymphocytes SLAM (SAP) or inhibitor of apoptosis (XIAP) • Development of uncontroled lymphoproliferation and NK cell disorder • EBV infection with fulminant or fatal course leading to liver failure → surviving patients are at risk of B cell lymphoma development, hypogammaglobulinemia similar to CVID or aplastic anemia • Without BMT performed before EBV infection development, XLP is fatal sooner or later

VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Hyper. Ig. E syndrome (HIES, Job’s syndrome) • Eczema + combined immunodeficiency manifesting by recurrent abscesses (cold abscesses) + recurrent sinopulmonary infections • More common AD form caused by mutation of STAT 3 gene (Signal Transducer and Activator of Transcription 3), less common AR form caused by mutation of DOCK 8 gene (Dedicator Of Cyto. Kinesis 8) Symptoms: onset frequently in infancy recurrent staphylococcal abscesses of skin, lungs, joints or internal organs recurrent sinopulmonary infections, pneumatocele severe atopic eczema in AD form: skeletal disorders (facial asymmetry, prominent forehead, broad nasal bridge, spontaneous bone fractures, osteopenia), delayed dental erruption

VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Hyper. Ig. E syndrome (HIES, Job’s syndrome) Symptoms: in AR form, recurrent viral infections (herpetic), increased frequency of autoimmune or allergic diseases, skeletal disorders often absent Dg: clinical features enormously increased level of serum Ig. E (˃ 2000 IU/ml) genetic tests Th: prophylaxis with anti-staphylococcal ATB dermatological therapy of eczema surgical treatment of abscesses

VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Wiskott-Aldrich syndrome (WAS) • X-linked recessive disease • Decreased number of small platelets (microthrombocytopenia), eczema and immunodeficiency • Mutation of WASp gene → decreased production of WASp protein (exprimed on hematopoietic cells, provides dynamic changes of cytoskeleton which are necessary for function of immune cells) Symptoms: combined immunodeficiency: decreased Ig levels (↓Ig. M; ↑Ig. A and Ig. E) + defects of T cell function → recurrent otitis and sinusitis, autoimmune diseases thrombocytopenia → increased bleeding

VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Wiskott-Aldrich syndrome (WAS) Dg: clinical symptoms proof of decreased expression of WASp on leukocytes genetic tests Th: symptomatic treatment in case of matched donor BMT studies of gene therapy

Immunoglobulin replacement therapy • Immunoglobulin concentrates are made from human plasma pooled from thousands of donors • Donors are tested for infectious diseases (HIV, hepatitis), inactivating procedures to minimize the risk of transmitting infection • Ig concentrates contain only Ig. G, content of Ig. A is minimal • Preparates for i. v. (Gammagard, Octagam) or s. c. administration (Subcuvia, Gammanorm)

Indications for Ig replacement therapy • Primary antibody deficiencies (IVIG) – life-long in XLA or CVID, transitory in combined immunodeficiencies (SCID) • Ig. G subclasses or specific Ig deficiency is sometimes also indication • Secondary antibody deficiencies – typically multiple myeloma, chronic lymphocytic leukaemia, biological treatment (rituximab)

Dosage of Ig concentrates • Agammaglobulinemia – i. v. imunoglobulins 400 -600 mg/kg/month • Regular administration in day-care centres every 3 or 4 weeks • Last years, „home therapy“ is frequently used - administration of subcutaneous Ig by infusion pump (cca every 5 to 7 days, more comfortable for patient, less adverse effects)

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

Acquired Immuno. Deficiency Syndrome (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 infects macrophages and CNS cells • Viral genome transcribes into human DNA and infected cell provides viral replication • 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

Acquired Immuno. Deficiency Syndrome (A. I. D. S. ) Diagnosis: - Serology - specific antibodies, 4 to 12 weeks after primoinfection Measurement of antigen p 24 – before seroconversion Viral RNA measurement – before seroconversion, PCR testing Th cells counts Therapy: - HAART (Highly Active Antiretroviral Therapy) – combination of nucleoside (Zidovudine) and non-nucleoside (Nevirapin) reverse transcriptase inhibitors and protease inhibitors (Lopinavir)

Acquired Immuno. Deficiency Syndrome (A. I. D. S. ) Therapy: - Prophylaxis with antibiotics and antimycotics - TBC prevention (isoniazid) - Ig replacement

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

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)

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

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

ORGAN SPECIFIC AUTOIMMUNE DISEASES AUTOIMMUNE ENDOCRINOPATHIES • • • 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 thyroglobulin (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 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

ORGAN SPECIFIC AUTOIMMUNE DISEASES AUTOIMMUNE NEUROPATHIES • 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

ORGAN SPECIFIC AUTOIMMUNE DISEASES 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