GENERAL FETURES OF IMMUNODEFICIENCY.

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Immunodeficiency diseases.
Prof. Mohamed Osman GadElRab.
College of Medicine KKUH.
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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 .

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Overview of Immunodeficiency Disorders.
The defect might be In the level of stem cell
or in any other level of tree
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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.
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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).
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Classification
Primary (congenital).
Secondary (acquired). Its common
malnutrition. Most important cause
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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, itll depress the immune system
excessive protein loss, burns, nephrotic
syndrome ( loss of cells like RBC and loss of
protein liek Ig )
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Primary or acquired. can affect.
Natural immunity (non-specific body
defenses).
Acquired immunity. (specific body
defenses).
Phagocytic cells.
Complement proteins.
T-cells.
B-cells.
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SCID.
Combined T B cells (SCID).
T-cell.
T-cell.
B-cell.
B-cell.
Phagocytes.
Phagocyte.
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• The severe combined immunodeficiency is
  characterized by effecting both B- and T- cells

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B-cell defects.
Gammaglobulinaemias
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Properties of B-cell defects

• Diverse spectrum of diseases ranging
  from
• Complete absence of B-cells , Plasma
  cells and Immunoglobulin's , to selective
  absence of certain immunoglobulin classes
  

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• 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 .

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• 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 )

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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
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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

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( 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

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Features of XLA.

• - Reduced B-cell counts to 0.1 percent
• ( normally 5-15 percent .)
• - Absence of Immunoglobulins .
• - Small L.nodes , no germinal centers .

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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 ).

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X-linked
agammaglobulinaemia. (XLA) .cont. .

• Most intracellular microbes
  fungi are
• handled normally by (T- cells ).

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2. Selective immunoglobulin deficiency.
1. IgA deficiency (1700)

• 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 )

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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
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X-linked hyper-IgM Syndrome. (cont.)
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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 .
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( The disease ) ( the level
of defect ) ( the result
) 3. X-linked hyper-IgM defective
CD40 markedly
Syndrome.
Ligand.
elevated IgM.
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Management of immunoglobulin deficiencies
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• repeated intravenous immunoglobulin
  (IV Ig) reduces infectious complications
  .
• --- GIVE Ig ---

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T- cell defects.
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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

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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.

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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 ).
• Theres 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 ).

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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 bodys cells and
  attack it

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Severe combined immunodeficiency.
(SCID ).
Both T and B cells are defected
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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 .

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Severe combined immunodeficiency (SCID ) in
Autosomal recessive SCID
- ADA deficiency
. toxic metabolites
in
T B-cells.
- PNP deficiency. ( ADA and PNP are missing
enzymes)

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Lead to
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Management of recessive (SCID.)
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• 1. Infusion of purified
  enzymes.
• 2. Gene therapy .

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Leukocyte defects. Its either
Quantitative. ( amount )
Qualitative. ( function )
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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 )

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Phagocyte defects.
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Qualitative.

• 1.Defect in response to
  chemotactic agents.
• 2.Defect in intracellular
  killing.
• A . Defect in chemotaxis
• Leukocyte adhesion deficiency
  (LAD.)

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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.)

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Complement deficiency.
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• 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

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Pathways of complement activation.
LECTIN PATHWAY
CLASSICAL PATHWAY
ALTERNATIVE PATHWAY
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• The main component that needs to be activated is
  C3 , All pathways activate 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

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4. Deficiency of membrane - attack
complex. (MAC).( C5 - C9 )

• Lead to infection with
  N.meningitides
• and
  N.gonorrhea .

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• Deficiency of C3 ( the central point of
  complement )
• no complement proteins
• Lead to infections with
  pyogenic bacteria.
• impaired clearance of
  immune-complexes. .

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C1 - inhibitor deficiencyhereditary
angioedema
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C1 - inhibitor deficiency( hereditary
angioedema )

• Is a deficiency of an enzyme which is responsible
  for prevention of C1 self-activation
• because itll attack the bodys 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.

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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 .)

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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 )

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• 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 its the classic pathway
• If C3 levels are the only reduced ? means lactin
  or alternative pathway.

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HIV virus.
T-cell.
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• )Regarding(GM-CSF)choose the correct answer
• used in bone marrow transplant