Transcript Mechanisms of Disordered Immune Regulation

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
Innate non-specific
Acquired-specific
PMN
B lymphocytes - antibodies
Phagocytes
T lymphocytes - cellular
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
– 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,
 Circulatory
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