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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 :

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Immunodeficiency diseases.

Prof. Mohamed Osman GadElRab.

College of Medicine & KKUH.


Introduction
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 .

MCQ


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

MCQ

malnutrition.

Most important cause

Genetic mutations.

Genetic polymorphism.

They could be :

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).

Acquired immunity.

(specific body defenses).

Phagocytic

cells.

Complement

proteins.

T-cells.

B-cells.


SCID.

Combined T& B cells

(SCID).

T-cell.

T-cell.

B-cell.

B-cell.

Phagocytes.

Phagocyte.



B-cell defects. effecting both B- and T- cells

Gammaglobulinaemias:


Properties effecting both B- and T- cells of B-cell defects

  • Diverse spectrum of diseases ranging from:

    CompleteabsenceofB-cells , Plasma cells and Immunoglobulin's ,to selective absenceof certain immunoglobulin classes


  • X- linked disease : effecting both B- and T- cells

  • If heterozygous

  • Female carriers are normal .

  • Males manifest the disease .

  • Severity of the disorder parallels ( is Proportional to ) the degree of the deficiency .


] effecting both B- and T- cells 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 . effecting both B- and T- cells

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
IMPORTANT effecting both B- and T- cellsPatients 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

MCQ

MCQ


( The disease ) ( the level of defect ) ( the result )

1. X-linked Bruton tyrosine no mature

agammaglobulinaemia. Kinase (Btk) 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 bone marrow.

Pre B-cell + BTK enzyme  Mature B-cell

MCQ

MCQ


Features of XLA.: ( the result )

- Reduced B-cell counts to 0.1 percent

( normally 5-15 percent .)

- Absence of Immunoglobulins .

- Small L.nodes , no germinal centers .

MCQ


X-linked ( the result )

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 ).

MCQ


X-linked ( the result )

agammaglobulinaemia. (XLA) .cont. .

* Most intracellular microbes & fungi are

handled normally by (T- cells ).


2. Selective immunoglobulin deficiency. ( the result )

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 .

] Increasedincidence of allergic manifestations [

anti - convlusant drugs (phenytoin) may cause secondary deficiency( these drugs are used to treat epilepsy, they destroy IgA )

MCQ


X- linked hyper-IgM Syndrome. ( the result )

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[

MCQ

MCQ


X-linked hyper-IgM Syndrome. (cont.) ( the result )هاااااااام جدا جدا

MCQ

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 ) ( the level of defect ) ( the result )

3. X-linked hyper-IgM defective CD40 markedly

Syndrome. Ligand. elevated IgM.


Management of immunoglobulin deficiencies
Management of immunoglobulin deficiencies : ) ( the result )

repeated intravenous immunoglobulin (IV Ig) reduces infectious complications .

--- GIVE Ig ---

MCQ


T- cell defects. ) ( the result )


DiGeorge Syndrome : ) ( the result )

( congenital thymic aplasia )

First described in 1952

  • Characterized by :

    - Absence of the Thymus gland .

    ( So , no T-cells in the body )

    - HypoparathyroidismWhich 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 : ) ( the result )

Failure of the third & fourth pharyngeal

pouches to develop .

*Features :

-Children may present with seizures

( tetany)

-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.

MCQ


DiGeorge syndrome : ) ( the result )

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 ; ) ( the result )

  • 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

MCQ


Severe combined immunodeficiency. ) ( the result )

(SCID ).

Both T and B cells are defected


Severe combined I.D. : ) ( the result )

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 ) : ) ( the result )

inAutosomal recessive SCID

- ADA deficiency . toxic metabolites in

T & B-cells.

- PNP deficiency.

( ADA and PNP are missing enzymes)

MCQ

Lead to


Management of recessive scid
Management of recessive (SCID.) ) ( the result )

1. Infusion of purified enzymes.

2. Gene therapy .

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Leukocyte defects. ) ( the result )

Its either :

Quantitative.

( amount )

Qualitative.

( function )


Quantitative. ) ( the result )

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 )

MCQ


Phagocyte defects
Phagocyte defects. ) ( the result )


Qualitative. ) ( the result )

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
B. Defect in intracellular killing: ) ( the result )

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.)

MCQ


Complement deficiency. ) ( the result )


Deficiency of all complement components ) ( the result )

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 [


antibody ) ( the result )

independent

antibody

dependent

Activation of C3 and

generation of C5 convertase

activation

Of C5

LYTIC ATTACK

PATHWAY

Pathways of complement activation.

LECTIN

PATHWAY

ALTERNATIVE

PATHWAY

CLASSICAL

PATHWAY

MCQ


  • The main component that needs to be activated is ) ( the result )C3 , All pathways activate C3

  • C3 then activates C5 and divide intoC3a and C3b

  • C5 then activate (membrane - attackcomplex) anddivide intoC5a and C5b

  • In classic pathway :

  • C1 activates C2 which activates C4 finally activates  C3

MCQ


4 deficiency of membrane attack complex mac c5 c9
4. Deficiency of membrane - attack ) ( the result ) complex. (MAC).( C5 - C9 )

Lead to infection with N.meningitides

and N.gonorrhea .


  • Deficiency of C3 ) ( the result )( the central point of complement )

    ] no complement proteins [

  • Lead to infections with pyogenic bacteria.

  • impaired clearance of immune-complexes. .

MCQ


C1 - inhibitor deficiency: ) ( the result )hereditary angioedema

MCQ


C1 inhibitor deficiency hereditary angioedema
C1 - inhibitor deficiency: ) ( the result )( 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 onlyagainst pathogens.


4 laboratory evaluation
4. Laboratory evaluation. ) ( the result )

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
3. Determination of T & B cell counts. ) ( the result )( 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 )

MCQ


  • to know which pathway activates the complement : ) ( the result )

  • 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. ) ( the result )

T-cell.


  • ) ) ( the result )Regarding(GM-CSF)choose the correct answer:

    used in bone marrow transplant


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