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 Acquired-specific B lymphocytes - antibodies T lymphocytes - cellular Physical Barriers Skin Respiratory and GI epithelial cells Mucous Cilia Innate non-specific PMN Phagocytes NK cells Soluble proteins - CRP, MBP,LPS-BP Complement

The Neutrophil

Function of Neutrophils Granules containing proteases such as gelatinase, heparinase, collagenase Elastase

Respiratory Burst in the Phagosome

Leukocyte Migration

Complement System Opsonization Inflammation Cytolysis Immune complex

Lymphocyte Development

Humoral Immune Response

B Cell Activation

Immune Globulin Structure

Different Isotypes of Ig’s

T Cell Differentiation in the Thymus

CD4+ T Cell Differentiation

Case Report - I u 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 u 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 u 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 u Heterogenous group of disorders u Main presentation - recurrent infections u Other features - malignancy, autoimmunity u Rare

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

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

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

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

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

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

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

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

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