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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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slide1

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

slide3

Overview of

Immunodeficiency

Disorders.

The defect might be

In the level of

stem cell

or

in any other

level of tree

slide4

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.

slide5

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).

slide6

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 )

slide7

Primary or acquired.

can affect.

Natural immunity

(non-specific body defenses).

Acquired immunity.

(specific body defenses).

Phagocytic

cells.

Complement

proteins.

T-cells.

B-cells.

slide8

SCID.

Combined T& B cells

(SCID).

T-cell.

T-cell.

B-cell.

B-cell.

Phagocytes.

Phagocyte.

slide10

B-cell defects.

Gammaglobulinaemias:

slide11

Properties of B-cell defects

  • Diverse spectrum of diseases ranging from:

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

slide12

X- linked disease :

  • If heterozygous
  • Female carriers are normal .
  • Males manifest the disease .
  • Severity of the disorder parallels ( is Proportional to ) the degree of the deficiency .
slide13

] 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 )
slide14

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
IMPORTANTPatients 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

slide16

( 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

slide17

Features of XLA.:

- Reduced B-cell counts to 0.1 percent

( normally 5-15 percent .)

- Absence of Immunoglobulins .

- Small L.nodes , no germinal centers .

MCQ

slide18

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 ).

MCQ

slide19

X-linked

agammaglobulinaemia. (XLA) .cont. .

* Most intracellular microbes & fungi are

handled normally by (T- cells ).

slide20

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 .

] Increasedincidence of allergic manifestations [

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

MCQ

slide21

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[

MCQ

MCQ

slide22

X-linked hyper-IgM Syndrome. (cont.) 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 .

slide23

( 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 :

repeated intravenous immunoglobulin (IV Ig) reduces infectious complications .

--- GIVE Ig ---

MCQ

slide26

DiGeorge Syndrome :

( 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[

slide27

DiGeorge syndrome :

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

slide28

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 ).

slide29

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

MCQ

slide30

Severe combined immunodeficiency.

(SCID ).

Both T and B cells are defected

slide31

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 .

slide32

Severe combined immunodeficiency (SCID ) :

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.)

1. Infusion of purified enzymes.

2. Gene therapy .

MCQ

slide35

Leukocyte defects.

Its either :

Quantitative.

( amount )

Qualitative.

( function )

slide36

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 )

MCQ

slide38

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
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.)

MCQ

slide41

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 [

slide42

antibody

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

slide43

The main component that needs to be activated is 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 complex. (MAC).( C5 - C9 )

Lead to infection with N.meningitides

and N.gonorrhea .

slide45

Deficiency of C3 ( the central point of complement )

] no complement proteins [

  • Lead to infections with pyogenic bacteria.
  • impaired clearance of immune-complexes. .

MCQ

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 onlyagainst pathogens.
4 laboratory evaluation
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
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 )

MCQ

slide50

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.
slide51

HIV virus.

T-cell.

slide52
)Regarding(GM-CSF)choose the correct answer:

used in bone marrow transplant

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