DiGeorge`s syndrome

Pathophysiology of
Immunodeficiency Diseases
Host Defense Mechanisms
Skin and mucosal barriers
Humoral immunity (B cells, plasma cells, Ab)
Cell-mediated immunity (T cells)
Overview of
The defect might be
In the level of
stem cell
in any other
level of tree
• Immunodeficiency diseases are :
A diverse spectrum of illnesses due to various
abnormalities of the immune system
• Prevalence :
 Primary (congenital) 1 : 10,000 to 1 : 200,000
present at birth .
 Secondary (acquired) is more common .
Origins of Immunodeficiency
o Primary or Congenital
Inherited genetic defects in immune cell
development or function, or inherited deficiency in
a particular immune component
o Secondary or acquired
A loss of previously functional immunity due
to infection, toxicity, radiation, splenectomy,
aging, malnutrition, etc.
Primary or acquired.
can affect.
Natural immunity
(non-specific body defenses).
Acquired immunity.
(specific body defenses).
Immunodeficiency /
Immunocompromised States
– Intrinsic abnormality of one or more components of the
Immune System
• >150 Conditions Characterised
• Individually, uncommon, but important to recognise
• Range from global, overwhelming immune failure ( SCID) to subtle
defects in individual components of function
• 1/ 10,000 live births
• Look for infections that are:
Unusual organisms: aspergillous, nocardia
Organisms that respond poorly to therapy
Unusual site: liver abcess, brain abcess
Severity of infection
The Ten Warning Signs of Primary Immunodeficiency
8 or more ear infections
within 1 year
Recurrent, deep skin or
organ abscesses
2 or more serious sinus infections
within 1 year
Persistent candidiasis
after the age of 1 year
2 or more months on
antibiotics without resolution
Need for I.V. antibiotic to
clear infections
2 or more pneumonias
within 1 year
2 or more deep-seated
Failure to gain weight or grow
A family history of
Primary Immunodeficiency
Classification of Primary Immunodeficiency
1. Antibody
Cellular deficiencies
3. Phagocytic disorders
4. Complement deficiencies
5. Combined
HUMORAL Immunodeficiencies
(B-cell defects)
Antibody deficiencies include:
 Common
variable immunodeficiency (CVID)
 X-linked agammaglobulinemia (XLA)
 Selective IgA deficiency (SIgAd)
 Selective IgG subclass deficiency (SIgGsd)
 Hyper IgM syndrome (HIgM)
 Transient hypogammaglobulinemia of Infancy (THI)
 Functional antibody deficiency
Early B-cell differentiation .
Lesions can occur at any site in the pathway of B-cell development.
B-cell defect could be in any level in the pathway
B-cell Defect
Onset after maternal antibodies diminish
Usually after 5-7 m/o, later childhood to
Bacteria: pneumococci, staphylococci,
Hemophilus, campylobacter, mycoplasma
Virus: entovirus
Recurrent sinopulmonary infections, chronic
GI symptoms, malabsorptions, arthritis,
entroviral meningoencephalitis
X-linked agammaglobulinaemia(bruton)
In X-LA early maturation of B cells fails
Affect males
Few or no B cells in blood
Very small lymph nodes and tonsils
No Ig
Recurrent pyogenic infection
IgA deficiency
 Serum IgA level < 10 mg/dl
 Prevalence :1:700 , the most common PID
 Most are asymptomatic , but have Increased rate of
respiratory tract infection (R.T.I )
 Some have recurrent
G.I.T. , Urogenital tract
Because of  lack of secretion of IgA on the mucous
membrane of GIT and respiratory tract
 Increased incidence of allergic and autoimmune
 Anti - convlusant drugs (phenytoin) may cause
secondary deficiency
2- IgA and IgG subclass defeciency
About 20% lack IgG2and IgG4
Susceptible to pyogenic infection
Result from failure in terminal
differentiation of B cells
3- Immunodfeiciency with increased IgM (HIgM)
Low or absent levels of IgA, IgG , IgE
Production of large amount of IgM >200mg/dl
of polyclonal IgM
Susceptible to pyogenic infection
Due to inability of B cells to isotype switching
They have B cell
4- Common Variable Immunodeficiency (CVID)
There are defect in T cell signaling to B cells
Acquired agammaglobulinemia in the 2nd or 3rd
decade of life
Pyogenic infection
80% of patients have B cells that are not
B cells are not defective but donot
differentiate into immunoglobulin producing
cell and fail to receive signaling from T
Risk of autoimmune disease and malignancy
5- Hypogamaglobulinaemia of infancy
Due to delay in in IgG synthesis
approximately up to 36 months
In normal infants synthesis begins at 3
Normal B lymphocytes
Probably lack help of T lymphocytes
Immunoglobulin Levels vs. Age
Cellular Immunodeficiencies
Cellular deficiencies include:
Combined immunodeficiency (CID)
 Severe combined immunodeficiency (SCID)
 Ataxia-Telangiectasia syndrome (AT)
 Wiskott-Aldrich syndrome (WAS)
 DiGeorge syndrome
 Chronic mucocutaneous candidiasis (CMCC)
DiGeorge's syndrome
It the most understood T-cell immunodeficienc
Also known as congenital thymic aplasia/hypoplasia
Associated with hypoparathyroidism, congenital
heart disease, fish shaped mouth.
 Defects results from abnormal development of
fetus during 6th-10th week of gestation when
parathyroid, thymus, lips, ears and aortic arch are
being formed
Combined T & B
 In about 50% of SCID patients the immunodeficiency is xlinked whereas in the other half the deficiency is
 Early onset( 2-6 m/o)
 Lymphopenia((< 2500 in infants)
 They are both characterized by an absence of T cell and
B cell immunity and absence (or very low numbers) of
circulating T .
 Very small thymus, no lymph node , no tonsil
 Patients with SCID are susceptible to a variety of
bacterial, viral, mycotic and protozoan infections.
The x-linked SCID is due to a defect in gammachain of IL-2 also shared by IL-4, -7, -11 and
15, all involved in lymphocyte proliferation
and/or differentiation.
The autosomal SCIDs arise primarily from
defects in adenosine deaminase (ADA) or
purine nucleoside phosphorylase (PNP) genes
which results is accumulation of dATP or dGTP,
respectively, and cause toxicity to lymphoid
stem cells
 A complex of immunologic, neurologic, endocrinologic,
hepatic and cutaneous abnormalities
 ataxia(10-12y/o) ,telangiectasis (3-6 y/o)
 Mutation in ATM gene
 T-cells and their functions are reduced to various
 B cell numbers are normal to low.
 Low levels of IgA, IgE, high level of IgM
 There is a high incidence of malignancy, particularly
lymphoreicular & adenocarcinoma
Wiskott-Aldrich syndrome
(immunodeficiency with thrombocytopenia and eczema)
 X-linked xp11.22-11.23
 WASP ; assemby of actin filaments required for
microvesicle formation downstream of protein
kinase C and tyrosine kinase signaling
 Low plaletlet, small size platelet
 Associated with normal T cell numbers with reduced
functions, which get progressively worse.
IgM concentrations are reduced but IgG levels
are normal
Both IgA and IgE levels are elevated.
Boys with this syndrome develop severe
eczema,bleeding tendency
They respond poorly to polysaccharide
antigens and are prone to pyogenic infection.
Defects of the phagocytic
• Defects of phagocytic cells (numbers and/or
functions) can lead to increased susceptibility to a
variety of infections.
• Bacteria,fungal infection
• Skin and mucus membrane
Cyclic neutropenia
Autosomal dominant
Mutation in ELA2(neutrophil elastase gene2)
It is marked by low numbers of circulating
neutrophil approximately every three weeks.
The neutropenia lasts about a week during
which the patients are susceptible to
infection. The defect appears to be due to
poor regulation of neutrophil production.
Tx: r-GCSF ( granulocyte stimulating factor)
Severe congenital Neutropenia
Arrest in promyelocyte stage
Neutrophil count< 200
Mutation ELA2 or HAX1, autosomal recessive
or dominant
Severe infections
20% prone to AML
Tx: r-GCSF
Shwachman Diamond Syndrome
Mutation in SBDS gene
Diarrhea, FTT, malabsorption till 4 m/o
Eczema, recurrent infections
Neutrophil count< 1000, pancytopenia
Risk of AML
Chronic granulomatous disease (CGD)
Defect in intra cellular killing
Normal chemotaxis, ingestion
Normal neutrophil count
x-linked (65%)& autosomal recessive
CGD is characterized lymphadenopathy, hepatosplenomegaly and chronic draining lymph nodes.
• In majority of patients with CGD, the deficiency is
due to a defect in NADPH oxidase that participate in
phagocytic respiratory burst.
• Infection with catalase positive organism: e coli,
staph areus , fungal , nocardia, serratia
Leukocyte Adhesion Deficiency
 Autosomal recessive
 Defect in chemotaxis
 These molecules are involved in diapedesis and
hence defective neutrophils cannot respond
effectively to chemotactic signals.
 Neutrophilia >12,000 , with infection >100,000
 Delayed umblical cord separation > 2 wk
 They don't have sign of inflammation such as
swelling, warmth or pus formation
Chediak-Higashi syndrome
(granule sorting disorder)
Mutation in lyst gene
Giant granule in cytoplasm of neutrophils
Respiratory burst is normal.
Associated with NK cell defect, platelet and
neurological disorders
Repeated infections
Mild bleeding tendency
Peripheral neuropathy
Prone to hemophagocytic syndrome
Disorders of complement
 Complement abnormalities also lead to increased
susceptibility to infections.
 There are genetic deficiencies of various
components of complement system, which lead to
increased infections.
 The most serious among these is the C3
deficiency which may arise from low C3 synthesis
or deficiency in factor I or factor H.
 Defect in classic pathway; AUTOIMMUNE
 Congenital deficiency of C5, 6, 7, 8: > 50%
INFECTION( neisseria)
Hyper IgE (Job) syndrome
Autosomal dominant
Coarse facial features/skeletal abnormalities
Recurrent staph infections
Impetigo (resistant)
Pneumonia with pneumatocele formation
 Elevated IgE, Eosinophilia, Eczema
PID - treatments
Immunoglobulin replacement
Bone Marrow Transplantation
Gene-based therapies
Antimicrobial management and prophylaxis
Nutritional Support
Patient Support Groups

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