Mechanisms of Disordered Immune Regulation
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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