The Immune System – in Health and Diseases

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The Immune System in Health and Diseases

• Dr. Ilan Dalal
• Pediatric Allergy/Immunology/Infectious Unit
  Department of Pediatrics
• E. Wolfson Medical Center, Holon, Israel

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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
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The Neutrophil
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Function of Neutrophils
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Neutrophil Migration
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Neutrophil Migration
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Respiratory Burst
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Complement System
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Function of the Complement System
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Lymphocyte Development
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B Cell Activation
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Immune Globulin Structure
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Different Isotypes of Igs
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The process of V(D)J gene rearrangements in BCR
and TCR
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CD4 T Cell Differentiation
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The Two Signal Theory
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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.
  WBC3200, PMN 75, Lymphocytes15, Hb9.2,
  Plt132,000
• Family history the parents are first cousins
  and the mothers sister had a baby died at 6
  month of age because of infection 3 years ago.

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Case report - II

• 15 months old boy. Normal history until 3 months
  ago when he started to experience recurrent
  URIs, 2 episodes of otitis media and 1 episode
  of wheezing. Physical examination was normal

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Epidemiology of PID

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

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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,

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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

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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

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Classification - ESID

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

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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

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Incidence

• 110,000
• Selective IgA deficiency - 1300-500
• CF - 12,500
• Congenital hypothyroidism - 15,000
• Classical cases are only the Tip of the Iceberg

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Age and Sex

• 40 - first year of age
• 80 - by 5 years of age
• X-linked - 70-80 males

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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

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The 10 Warning Signs of Immunodeficiency

• FTT - chronic diarrhea, catabolic state
• Persistent thrush (gt 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

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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

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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)

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Laboratory Investigations - First Line (1)

• CBC differential
• Lymphocytes lt 1500/ mm3 (SCID)
• Neutrophils lt 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)

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Laboratory Investigations - First Line (2)

• T cell defects
• Total lymphocyte count (lt 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

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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

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Primary B Cell Diseases

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

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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

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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

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Common Variable immunodeficiency (1)

• Second to third decade of life
• Recurrent pyogenic sinopulmonary infections
• Males to females ratio 11
• Usually IgG levels lt 250 mg/dl, low IgA
• Inability to produce specific antibodies
  hallmark!
• Malabsorbtion is common - giardia lamblia,
  campylobacter jejuni

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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

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Selective IgA Deficiency (1)

• lt 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)

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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