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Immunodeficiency diseases.
Prof. Mohamed Osman GadElRab.
College of Medicine & KKUH.
Introduction.
• Immunodeficiency diseases are :
A diverse spectrum of illnesses due to various
abnormalities of the immune
• Prevalence :
 Primary (congenital) 1 : 10,000 to 1 : 200,000
present at birth .
 Secondary (acquired) is more common .
Overview of
Immunodeficiency
Disorders.
The defect might be
In the level of
stem cell
or
in any other
level of tree
Clinical manifestations.
( is increased susceptibility to infections )
The patient is considered to have I.D. if the infections are :
Frequent & severe.
Caused by opportunistic
Infections.
Resistant to antimicrobial
therapy.
Since the main presentation is infection,
It is critical to maintain an index of suspicion
to diagnose I.D.
Important :
Early diagnosis & management
reduce morbidity (disease).
Classification :
Primary (congenital).
Secondary (acquired).
Its common
malnutrition.
Genetic mutations.
Genetic polymorphism.
They could be :
Most important cause
viral & bacterial
infections.
e.g. AIDS which is caused
by HIV
either Monogenic
( defect in one gene )
or polygenic
( defect in more than one gene )
Immunosuppressive drugs.
(corticosteroids).
For long-time use,
it’ll depress the immune system
excessive protein loss,
burns, nephrotic syndrome
( loss of cells like RBC and loss of protein liek Ig )
Primary or acquired.
can affect.
Natural immunity
(non-specific body defenses).
Phagocytic
cells.
Complement
proteins.
Acquired immunity.
(specific body defenses).
T-cells.
B-cells.
SCID.
Combined T& B cells
(SCID).
T-cell.
T-cell.
B-cell.
B-cell.
Phagocyte.
Phagocytes.
• The severe combined immunodeficiency is
characterized by effecting both B- and T- cells
B-cell defects.
Gammaglobulinaemias:
Properties of B-cell defects
1. Diverse spectrum of diseases ranging
from:
Complete absence
of B-cells , Plasma cells and
Immunoglobulin's , to selective absence of
certain immunoglobulin classes
2.
•
•
•
X- linked disease :
If heterozygous
Female carriers are normal .
Males manifest the disease .
3. Severity of the disorder parallels
( is Proportional to ) the degree of
deficiency .
the
] FEATURES OF B-CELL DEFECT [
- Reduced B-cell counts to 0.1 percent
( normally 5-15 percent .)
- Absence of Immunoglobulins .
- Small Lymph nodes , no germinal centers ( the
home of B-cells in the lymph node )
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
IMPORTANT
Patients with B-cell defects are subject to:
Recurrent bacterial infections
but
Display normal immunity to most
viral & fungal infections.
because :
T-cells are unaffected.
Because T-cell which stands in the face of viral
and fungal infection
( The disease )
( the level of defect )
1. X-linked
Bruton tyrosine
agammaglobulinaemia.
Kinase (Btk)
( the result )
no mature
B-cells.
Is the first I.D. Recognized in (1952)
The most common ( 80 to 90 percent )
Defect in Bruton tyrosine kinase enzyme (BTK).
The Defect involve a block in maturation
of pre- B- cells to mature B- cells in
marrow.
Pre B-cell + BTK enzyme  Mature B-cell
bone
Features of XLA.:
- Reduced B-cell counts to 0.1 percent
( normally 5-15 percent .)
- Absence of Immunoglobulins .
- Small L.nodes , no germinal centers
.
X-linked
agammaglobulinaemia. (XLA) .cont.
.
Affected children suffer from recurrent
pyogenic bacterial infections of : :
( conjunctiva , throat, skin , ear,
bronchi & lung )
Infecting microbes include :Pneumococci, H.influenzae
Streptococci.
Also the patient is susceptible to certain viruses
( polio)
and intestinal parasites (giardia ).
X-linked
agammaglobulinaemia. (XLA) .cont.
*
.
Most intracellular microbes & fungi are
handled normally by (T- cells ).
2. Selective immunoglobulin deficiency.
1. IgA deficiency (1:700)
Most are asymptomatic , but have
increased rate of ( respiratory tract infection R.T.I )
Some have recurrent R.T.I. and G.I.T. Symptoms
Because of  lack of secretion of IgA on the mucous membrane of
GIT and respiratory tract .
] Increased incidence of allergic manifestations [
anti - convlusant drugs (phenytoin) may cause secondary deficiency (
these drugs are used to treat epilepsy, they destroy IgA )
X- linked hyper-IgM Syndrome.
Characterized by :
- Low IgG, IgA & IgE
- Markedly elevated IgM
- High levels of autoantibodies
(against neutrophils , platelets , red cells )
] So, low levels of RBCs, neutrophils, and platelets [
Recurrent infections especially
Pneumocystis carinii
] Pneumocystis carinii usually found in people who have AIDS [
X-linked hyper-IgM Syndrome. (cont.) ‫هاااااااام جدا جدا‬
Defect in the CD 40L in T- cells lead to :
( CD 40L is the hand that Th cell use it to shake other cells hands )
* No co-stimulatory signal for B-cells.
* No response to T-dependent antigens .
* No class – switching.
( The change of one class of Ig to another one )
* No memory cells.
* Marked lymphadenopathy .
( The disease )
3. X-linked hyper-IgM
Syndrome.
( the level of defect )
defective CD40
Ligand.
( the result )
markedly
elevated IgM.
Management of immunoglobulin deficiencies :
repeated intravenous immunoglobulin
(IV Ig) reduces infectious complications .
--- GIVE Ig ---
T- cell
defects.
DiGeorge
Syndrome :
( congenital thymic aplasia )
First described in 1952
• Characterized by :
- Absence of the Thymus gland .
( So , no T-cells in the body )
- Hypoparathyroidism
Which lead to tetany
- Cardiovascular abnormalities and Characteristic
facial features
] Because they appear from the same embryologic
origin of the thymus ( 3-4 pharyngeal pouches) so
they are involved [
DiGeorge syndrome :
Failure of the third & fourth pharyngeal
pouches to develop .
*Features :
-Children
may
present with
( tetany)
seizures
-Extreme susceptibility to viral , protozoal,
and fungal infections.
( Because of no T-cell )
So :
1. profound depression of T-cell numbers.
2. absence of T-cell responses.
DiGeorge syndrome :
In some cases B-cells are normal and produce effective
humoral immunity to bacterial infections .
(Partial Di George Syndrome.)
( thymic hypoplasia, Nezelof syndrome ).
There’s a little number of circulating T-cell but B-cells are normal
In some T-cell – dependant antibody
production is absent .( no helper T- cells ).
DiGeorge syndrome ;
• Management:
Fetal thymus tissue graft (14 week old).
steps should be taken to prevent G.V.H. ( graft versus
host ) Reactions
G.V.H. Reactions :
the transplanted thymus or bone marrow recognize the host
body cells as foreign body’s cells and attack it
Severe
combined immunodeficiency.
(SCID ).
Both T and B cells are defected
Severe combined I.D. :
Features:
1. Increased susceptibility to
viral,
fungal , bacterial & protozoal infection.
( start at 3 month of age )
2. Failure to thrive.
3. Reduced weight gain.
4. Prolonged diarrhea.
5. Moniliasis due to candida .
Severe combined immunodeficiency (SCID ) :
in Autosomal recessive SCID
- ADA deficiency .
Lead to
- PNP deficiency.
( ADA and PNP are missing enzymes)
toxic metabolites in
T & B-cells.
Management of
recessive
(SCID.)
1. Infusion of purified enzymes.
2. Gene therapy .
Leukocyte defects.
Its either :
Quantitative.
( amount )
Qualitative.
( function )
Quantitative.
1. Congenital agranulocytosis :
] Kostmann syndrome [
Defect in the gene inducing G-CSF (granulocyte
colony stimulating factor) it is a stimulatory factor that acts
on bone marrow to produce WBCs, so if its defected, the
amount will decrease
Features: pneumonia ,otitis media, gingivostomatitis
perineal abscesses
Management:
Respond to G-CSF therapy ( gene therapy )
Phagocyte defects.
Qualitative.
1.Defect in response to chemotactic agents.
2.Defect in intracellular killing.
A . Defect in chemotaxis:
Leukocyte adhesion deficiency (LAD.)
B.
Defect
in intracellular
killing:
1.Chronic granulomatous disease:
x-linked. (75%)
autosomal recessive .(25%).
DEFECT:
in the oxidative complex .
( responsible for producing superoxide radicals .)
FEATURES:
Extreme susceptibility to infections.
Granulomatous inflammation.
(chronic T-cell stimulation.)
Complement deficiency.
Deficiency of all complement components
have been described C1-C9.
1. Deficiency of C1, C2 & C4.
( classical pathway )
lead to immune-complex diseases which
can cause significant pathology in
autoimmune diseases.
] N.B : immune-complex = antibody - antigen interaction [
Pathways of complement
activation.
CLASSICAL
PATHWAY
LECTIN
PATHWAY
antibody
dependent
ALTERNATIVE
PATHWAY
antibody
independent
Activation of C3 and
generation of C5 convertase
activation
Of C5
LYTIC ATTACK
PATHWAY
• The main component that needs to be activated is C3 ,
All pathways activate C3
classic
alternative
lactin
C3
• C3 then activates C5 and divide into C3a and C3b
• C5 then activate ( membrane - attack complex) and
divide into C5a and C5b
• In classic pathway :
• C1 activates  C2 which activates C4 finally
activates  C3
4. Deficiency
of membrane - attack complex.
(MAC).
( C5 - C9 )
Lead to infection with N.meningitides
and N.gonorrhea .
5. Deficiency of
•
•
C3 ( the central point of complement )
] no complement proteins [
Lead to infections with pyogenic bacteria.
impaired clearance of immune-complexes. .
C1 - inhibitor deficiency:
hereditary angioedema
C1 - inhibitor deficiency:
( hereditary angioedema )
• Is a deficiency of an enzyme which is responsible for
prevention of ] C1 self-activation [
• because it’ll attack the body’s own cells, and cause
inflammation usually in the ] uvula [ which leads to
choking till death.
• So these patients always have adrenaline in their
pockets to prevent the swallowing
• So the enzyme makes C1 activated only against
pathogens.
4. Laboratory evaluation.
1. Complete blood count (total & differential).
2. Evaluation of antibody responses :A. determination of serum immunoglobulins
B. measure specific antibody responses :
-To polysaccharide antigens.
( measure isohemagglutinins. )
- To protein antigens .
( measure antibodies to tetanus .)
3. Determination of T & B cell counts.
( by flow cytometry )
4. Determination of the complement
components. C3, C4 .
- assess functional activity by CH50
5. Assess phagocyte
function.
- phagocytosis & respiratory burst
6. Carrier detection &
prenatal
diagnosis ( important for genetic counseling )
• to know which pathway activates the
complement :
• we check C2 and C3 levels, if both are decreased,
it means they have been used a lot , so it’s the
classic pathway
• If C3 levels are the only reduced  means lactin
or alternative pathway.
HIV virus.
T-cell.
• )Regarding(GM-CSF)choose the correct
answer:
used in bone marrow transplant