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

2. 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

3. The Neutrophil

4. Function of Neutrophils

5. Neutrophil Migration

6. Neutrophil Migration

8. Respiratory Burst

9. Complement System

10. Function of the Complement System

11. Lymphocyte Development

12. B Cell Activation

13. Immune Globulin Structure

15. Different Isotypes of Ig’s

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

18. CD4+ T Cell Differentiation

19. The Two Signal Theory

21. 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.

22. 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

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

24. 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,

25. 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

26. 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

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

28. 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%

29. 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”

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

31. 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

32. 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

33. 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

34. 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)

35. 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)

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

37. 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

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

39. 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

40. 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

41. 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

42. 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

43. Selective IgA Deficiency (1)
< 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)

44. 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