The Immune System – in Health and Diseases Dr. Ilan Dalal Pediatric Allergy/Immunology/Infectious Unit Department of Pediatrics E. Wolfson Medical Center, Holon, Israel

The Three Main Branches of the Immune System Physical Barriers Skin Respiratory and GI epithelial cells Mucous Cilia Acquired-specific B lymphocytes - antibodies T lymphocytes - cellular Innate non-specific PMN Phagocytes NK cells Soluble proteins - CRP, MBP,LPS-BP Complement

The Neutrophil

Function of Neutrophils

Neutrophil Migration

Neutrophil Migration

Respiratory Burst

Complement System

Function of the Complement System

Lymphocyte Development

B Cell Activation

Immune Globulin Structure

Different Isotypes of Ig’s

The process of V(D)J gene rearrangements in BCR and TCR

CD4+ T Cell Differentiation

The Two Signal Theory

Case Report - I 5 months of age was admitted to the hospital due to high fever respiratory distress and skin rash. Physical examination revealed severe FTT, severe oral and diaper thrush and crackles on both lungs. X ray – disseminated pneumonitis. WBC=3200, PMN= 75%, Lymphocytes=15%, Hb=9.2, Plt=132,000 Family history – the parents are first cousins and the mother’s sister had a baby died at 6 month of age because of infection 3 years ago.

Case report - II 15 months old boy. Normal history until 3 months ago when he started to experience recurrent URI’s, 2 episodes of otitis media and 1 episode of wheezing. Physical examination was normal

Epidemiology of PID Heterogenous group of disorders Main presentation - recurrent infections Other features - malignancy, autoimmunity Rare

Disorders with increased susceptibility to infection Circulatory – cardiac defect, diabetes, nephrosis, sickle cell Obstructive – asthma, allergic rhinitis, CF, foreign body, ureteral stenosis Surface defects – eczema, burn, skull fracture, ciliary defects Foreign body – shunt, catheter, artificial heart valve,

Secondary Immunodeficiency (1) Premature and newborn Hereditary and metabolic diseases Down syndrome Malnutrition Vitamin and mineral deficiency (vitamin B12 due to transcobalamin II deficiency, zinc) Protein-losing enteropathy Nephrotic syndrome Immunosuppressive therapy Radiation Chemotherapy Steroids

Secondary Immunodeficiency (2) Infiltrative and hematologic diseases Leukemia Lymphoma Aplastic anemia Sickle cell anemia Infectious diseases – HIV, congenital infections (TORCH), EBV, Varicella Surgery and trauma

Classification - ESID Humoral - B lymphocytes (50%) Cellular - T lymphocytes (10%) Mixed (20%) Phagocytes - PMN (18%) Complement (2%)

Incidence and Classification in Israel 294 cases (5/100,000) Antibody deficiency – 32% T cell or combined Deficiency – 27% Phagocytic Deficiency – 18% Complement Deficiency – 16% Other – 7%

Incidence 1:10,000 Selective IgA deficiency - 1:300-500 CF - 1:2,500 Congenital hypothyroidism - 1:5,000 Classical cases are only the “Tip of the Iceberg”

Age and Sex 40% - first year of age 80% - by 5 years of age X-linked - 70-80% males

The 10 Warning Signs of Immunodeficiency Two or more systemic bacterial infections (sepsis, osteomyelitis, meningitis) Three or more bacterial infections within one year (cellulitis, pneumonia, severe otitis media, sinusitis, lymphadenitis) Infection in an unusual organ (liver, brain abscess) Unusual or opportunistic infection (aspergillus, serratia, pneumocystis carinii, etc.) Common pathogens (pneumococcus, HI, strep, staph) but unusual severity or inadequate response to appropriate antibiotic therapy

The 10 Warning Signs of Immunodeficiency FTT - chronic diarrhea, catabolic state Persistent thrush (> 1 year age) Rash (SCID, WAS, Hyper IgE) Family history Association with known syndromes Chromosomal instability or defects - Down, Fanconi, AT, Bloom Metabolic - Glycogen storage type 1b Acrodermatitis Enteropathica

Pathogens - Immunodeficiency Complex Humoral deficiency Pyogenic gram positive bacteria (pneumo, strep, HI) Cellular deficiency Gram negative and positive bacteria Viral - CMV, varicella, herpes, parainfluenza Fungus - candida, aspergillus Protozoa - pneumocystis carinii, Toxoplasma Mycobacterium

Pathogens - Immunodeficiency Complex Phagocytic\PMN deficiency Staph Gram negative catalase positive (Klebsiella, Serratia) Mycobacteria as the sole pathogen (INFg, IL12) Complement Nisseria (distal components) SLE-like syndrome (proximal components)

Laboratory Investigations - First Line (1) CBC + differential Lymphocytes < 1500/ mm3 (SCID) Neutrophils < 200/ mm3 (Kostman) Thrombocytopenia with low MPV (WAS) Howell Jolly bodies - asplenia ESR - elevated in chronic infection B cell defects Immunoglobulin levels - IgG, A, M, E Isohemagglutinins Specific antibodies (vaccines)

Laboratory Investigations - First Line (2) T cell defects Total lymphocyte count (< 1500/mm3) CXR - thymus shadow DTH - Candida, PPD, Tetanus (induration in 48-72 hours) Phagocytic cell defects PMN - number and structure Respiratory burst assay - NBT or Flow Cytometer (CGD) Complement deficiency CH50

Laboratory Investigations - Second Line (1) Lymphocyte subpopulations - flow cytometer In vitro lymphocyte stimulation - mitogens, specific antigens Cytokine production Leukocyte function - mobility, adhesion, phagocytosis, killing Enzyme assay - ADA, PNP Biopsy - thymus, lymph node

Primary B Cell Diseases X-linked (Bruton) Agammaglobulinemia (XLA) Common Variable Immunodeficiency (CVID) Selective IgA and/or IgG subclasses deficiency Transient hypogammaglobulinemia of infancy

X-Linked Agammaglobulinemia (Bruton) (1) First year of life Recurrent bacterial pyogenic infections Meningoencephalitis (enteroviruses), dermatomyositis, malabsorbtion - rare complications Tonsils and lymph nodes - absent All immunoglobulin isotypes markedly decreased

X-Linked Agammaglobulinemia (Bruton) (2) Circulating B cells - profoundly decreased Pre-B cells are present in bone marrow Intact cellular immunity Replacement therapy with IG (IM, IV, SC) Mutations in BTK (cytoplasmic protein tyrosine kinase) Good prognosis

Common Variable immunodeficiency (1) Second to third decade of life Recurrent pyogenic sinopulmonary infections Males to females ratio 1:1 Usually IgG levels < 250 mg/dl, low IgA Inability to produce specific antibodies – hallmark! Malabsorbtion is common - giardia lamblia, campylobacter jejuni

Common Variable immunodeficiency (2) Lymphadenopathy, hepatosplenomegaly, skin , joint Normal circulating B cells Cellular immunity is affected in variable degrees in 60% Autoimmunity, Hematologic or lymphoproliferative disorders (lymphadenopathy, splenomegaly, nodular hyperplasia) High incidence of malignancy - lymphoreticular and gastrointestinal Prognosis is not good as XLA

Selective IgA Deficiency (1) < 7 - 10 mg/dl The most common disorder (frequency of 1/333 in some blood donors) The basic defect is unknown Most cases are a-symptomatic Infections in Respiratory, GI, Genitourinary tracts (mucosal barrier)

Selective IgA Deficiency (2) High incidence of auto-antibodies and auto-immune diseases Allergy ?, Malignancy ? Treatment – aggressive and early antibiotic therapy, immunizations (pneumococcal, influenza) IVIG is not indicated in most cases