GENERAL%20FETURES%20OF%20IMMUNODEFICIENCY.

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

• A diverse spectrum of illnesses due to
• various abnormalities of the immune
• system .
• Prevalence (primary) 1 in 10,000 t I in
  2000 .
• ( live births. )

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Overview of Immunodeficiency Disorders.
4
Clinical manifestations.
Increased susceptibility to infections.
I.D. Is considered when infections are
Frequent severe.
Caused by opportunistic Infections.
Resistant to therapy.
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It is critical to maintain an index of
suspicion to diagnose I.D.

Early diagnosis reduce morbidity.
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Classification
Primary (congenital).
Secondary (acquired).
malnutrition.
Genetic mutations. Genetic polymorphism.
viral bacterial infections.
Monogenic or polygenic.
Immunosuppressive drugs. (corticosteroids).
excessive protein loss, burns, nephrotic
syndrome.
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Primary or acquired. can affect.
Natural immunity
Acquired immunity.
Phagocytic cells.
Complement proteins.
T-cells.
B-cells.
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T-cell.
B-cell.
Phagocytes.
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JAK.
STAT.
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IL- 2,4,7,9, 15 All have same unit.
Gamma unit.
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B-cell defects.
Gammaglobulinaemias
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B-cell defects.

• 1. Diverse spectrum of diseases ranging
  from
• Complete absence of B-cells ,
  Plasma cells
• and Immunoglobulins to selective
  absence
• of certain immunoglobulin
  classes.
• 2. X- linked disease
• Female carriers normal .
• Males manifest the disease .
• 3. Severity of the disorder parallels
  the degree
• of the deficiency
  .

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Early B-cell differentiation .
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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.

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1. X-linked Bruton
tyrosine no mature agammaglobulinaemia.
Kinase (Btk) B-cells.

• The first I.D. recognized (1952).
• The most common 80 to 90 percent.
• Defect in Bruton tyrosine kinase
  (BTK).
• The Defect involve a block in
  maturation
• of pre- B- cells to mature B-
  cells in B.M.
• - 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 susceptible to certain viruses
  (polio.)
• and intestinal parasites
  (giardia ).

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

• Newborn infants are often normal,
• infectious complications are delayed
• until 6 -12 months of age.
• ( maternal IgG).
• Most intracellular microbes fungi are
• handled normally (T- cells normal
  ).
• 20 percent may develop autoimmune
• diseases.
  

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2.X-linked hyper-IgM defective CD40
markedly Syndrome.
Ligand. elevated IgM.
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X- linked hyper-IgM Syndrome.
(cont.) .
Characterized by - Low IgG, IgA
IgE. - Markedly elevated
IgM. - High levels of
autoantibodies to neutrophils ,
platelets , red cells. -
Recurrent infections especially
Pneumocystis carinii .
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X-linked hyper-IgM Syndrome.
(cont.) .
Defect in the CD 40L in T- cells .
No co-stimulatory signal for B-cells.
No response to TD
antigens . No class switching.
No memory
cells. Marked lymphadenopathy .

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3. Common variable Immunodeficiency .(CVI).
Heterogynous group that cause late -
onset hypogammaglobulinaemia
. Recurrent infections between 15 - 35
yrs. Characterized by -
Mature B- cells reduced. - B
cells normal but do not differentiate
into Plasma cells.
- Defective T- helper cells.
- Excess T suppressor cells.
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Common variable Immunodeficiency .(CVI) .cont.

• Features
• 1. Low IgG IgA .
• 2. Impaired antibody responses.
• 3. Associated autoimmune diseases.
• (seronegative arthritis,vasculitis.)

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

• Most are asymptomatic. ( but have
• increased rate of (R.T.I.)
• Some have recurrent R.T.I. an
• G.I.T. symptoms
• Increased incidence of allergic
• manifestations.
• anti- convlusant drugs (phenytoin) may
  cause deficiency .

2.IgG subclass deficiency .
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5. Transient hypogammaglobulinaemia of infancy

• Characterized by
• Abnormally low IgG with recurrent
• Bacterial viral infections mainly
  
• R.T.I.
• Resolve spontaneously by age 4.

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6. Specific antibody deficiency with normal
immunoglobulin (SANDI).

• Recurrent respiratory bacterial
  infections.
• Impaired specific antibody
  responses, particularly against
  polysaccharide microbial
  antigens .

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Ataxia telagiectasia defctive cell-
low IgA, IgE.
cycle kinase.

• A disease syndrome that include
• Deficiency of IgA some times IgE .
• Characterized by Cerebellar ataxia ,
  cutaneous telangectasia,
• and immunodeficiency.
• Due to Defective cell-cycle kinase .

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Management.

• Periodic intravenous immunoglobulin
  (IVIG) reduces infectious
  complications.

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T-cell defects.
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T-cell defects.

• Introduction
• Several genetic lesions selectively
• impede cellular mechanisms involving
• T-cells , NK-cells Monocytes,
• leaving antibody production intact .

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DiGeorge Syndrome.

DiGeorge Thymic aplasia.
Impaired T-cell Syndrome.
development.

• (congenital thymic aplasia )
• First described in 1952.
• Characterized by
• - Absence of the Thymus gland .
• - Hyperparathyroidism.
• - Cardiovascular abnormalities .
• - Characteristic facial features .

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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.
• 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 common bacterial infections.
• (Partial Di George Syndrome.)
• ( thymic hypoplasia,Nezelof syndrome ).
• In some T-cell dependant antibody
• production is absent .

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DiGeorge
Syndrome.

• Management
• Fetal thymus tissue graft (14 week
  old)
• to prevent G.V.H. Reactions .
• ( graft versus host )

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Severe combined immunodeficiency.
(SCID ).
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Severe combined

• 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 Autosomal
recessive SCID . immunodeficiency
(SCID ).

- ADA deficiency . toxic
metabolites in

T B-cells.
- PNP deficiency.

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Severe combined

• A. Inherited enzyme deficiencies
• 1. Adenosine deaminase (ADA).
• 2. Purine nucleoside
  phophorylase(PNP).
• Both result in the accumulation
  of
• dGTP dATP which are toxic
  metabolites
• to dividing cells.
• Result in defective T-cells
  B-cells.

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Severe combined I.D.

• A. Inherited enzyme deficiencies
• 1. Adenosine deaminase (ADA).
• 2. Purine nucleoside
  phophorylase(PNP).
• Both result in the accumulation
  of
• dGTP dATP which are toxic
  metabolites
• to dividing cells.
• Result in defective T-cells
  B-cells.

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Severe combined I.D.

• B. JAK-3 deficiency
• Defective IL-2R (gamma chain ).
• The defect lie in the
  gamma chain
• of the IL-2 receptor .
  Defect in this chain
• impede signaling through
  receptors for
• IL-2, IL-4 , IL-7,
  IL-9 , IL-15.
• Lymphocytes fail to
  develop .
• Markedly depressed T-cells
  B-cells.

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Severe combined I.D.

• C. RAG-1 RAG-2 deficiency
  
• No TCR or Ig gene rearrangement.
• . D. ZAP-70 deficiency .
  
• Defective signal from TCR.
  

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3. Bare lymphocyte syndrome.

• Form a class of SCID
  individuals .
• Severe combined immunodeficiency
• Caused by a defect in the
  expression of the MHC class11 gene
  promoter.
• A defect in the (TAP) transporters genes
• is associated with defect in
  antigen processing by class 1 MHC
  molecules.
• (defective CD 8-mediated immunity.)

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Bare lymphocyte syndrome.
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Bare lymphocyte types

• 1. Type 1 defective MHC. Class1.
• 2. Type2 defective MHC. Class 11.
• 3. Type 3 defective MHC.Class1 11.
• This results in impaired
  antigen
• presentation.
• Children suffer recurrent bacterial
  viral
• infections.
• The condition is fatal.

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1.Reticular dysgenesis - Rare
fatal congenital disease. -
Lymphoid myeloid stem cells
fail to differentiate.
- Children lack T-cells , B-cells,
Monocytes
granulocytes.
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Management of recessive (SCID.)

• 1. Infusion of purified enzymes.
• 2. Gene therapy .

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Defect in signalling pathways
Wiskott-Aldrich defect in
cytoskeletal defective T-cells
syndrome. protein
(CD43). Platelets.

• X-linked.
• Consist of Eczema, thrombocytopenia,
• immunodeficiency.
• Defect in WAS protein (WASP), which
• connect T-cell signal
  pathway.
• Result in defective T-cell help to B-cell
  in
• response to encapsulated
  bacteria.

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2. X-linked lymphoprolferative disorders.

• Pleomorphic disease .
• Defect in signal transducing protein .
• Inability to control B-cell growth .
  
• EBV - driven B cell tumor
  fatal
  I
  infectious mononucleosis .
• Pulmonary granulomatosis lymphoma.

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Leukocyte defects.
Quantitative.
Qualitative.
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Quantitative.

• 1. Congenital agranulocytosis
• Kostmann syndrome .
• Defect in the gene inducing G-CSF
  (granulocyte colony stimulating
  factor).
• Features pneumonia ,otitis media,
  gingivostomatitis
• perineal abscesses.
• Management
• Respond to G-CSF therapy.

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Phagocyte defects.
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2. Cyclic neutropenia

• Deficiency of elastase lead to regular
• fluctuations in the level of neutrophils.
• (every 21 days).
• Features
• Fever , stomatitis, periodontitis
• skin infections.

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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.)
• 2 types.
• LAD type 1 defect in gene encoding CD18.
• (B integrin .)

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LAD type 1

• 3.TYPES
• CD18CD11a- leukocyte function
• associated molecule
  (LFA-1).
• CD18CD11b- complement receptor (CR3).
• CD18CD11c- complement receptor (CR4).
• LFA-1 mediate tight adhesion of leukocytes
• to the endothelium .

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WITH DEFECT IN LFA-1

• Leukocytes are trapped in the
  circulation.
• Leukocyte count can reach 100,000 cells per
  mm3.
• Abscesses do not suppurate.

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LAD type 2

• Defect in Sialyl lewis protein
• (ligand for E- selectin).
• Leukocytes cannot attach to
• endothelium.
• Defective chemotaxis .

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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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2. Glucose -6- phosphate dehydrogenasedefic
iency . (G6-P-D). (no resp.burst.)

• 3. myeloperoxidase deficiency .
• (no resp. burst).
• 4. Chediak - Higashi syndrome defect
  in formation of
  phagolysosome .
• Associated with
• abnormal platelet function.
• partial albinism .

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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.

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Pathways of complement activation.
LECTIN PATHWAY
CLASSICAL PATHWAY
ALTERNATIVE PATHWAY
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4. Deficiency of membrane - attack
complex. (MAC).( C5 - C9 )

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

5. Deficiency of C3.
Lead to infections with
pyogenic bacteria.
impaired clearance of immune-complexes. .

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C1 - inhibitor deficiencyhereditary
angioedema
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2. Deficiency of mannose - bindinglectin.
(lectin pathway)

• MBL , C2, C4.
• Lead to bacterial infections mainly
  in
• Early childhood .
• 3. Deficiency of Factor D Factor
  P.
• (alternative pathway ).
• Lead to infection with pyogenic bacteria
  .

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Diseases (other than I.D. ) , causedby
complement defects.

• 1.Loss of control proteins.
• (decay accelerating factor, DAF,
  CD59.)
• Lead to destruction of R.B.C.,
  which result
• in paroxysmal nocturnal
  hemoglobinuria .
• 2.C1 esterase inhibitor deficiency (C1
  inhibitor.)
• result in excess of vasoactive
  mediators
• (kinins).
• Causes Hereditary angioneurotic
  edema.
• Recurrent attacks of subepithelial
  swellings
• involving the larynx intestinal
  mucosa.
• ( may be fatal )

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Clinical approach to suspectedimmunodeficien
cy.

• 1.History.
• Infections of unusual frequency,
  chronicity or
  severity .
• Family history of infectious problems.
• Consanguinity should be investigated
• (inter-family marriages ).

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2.Physical examination.

• Absence of tonsils.
• Partial albinism.
• Telangiectasia .( bleeding capillaries ).

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3.Radiologic evaluation .

• Absence of thymic shadow .
• Pneumatocele (hyper IgE syndrome)

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4. Laboratory evaluation.

• 1. Complete blood count .(total differential).
• 2. Evaluation of antibody responses.
  . A. determination
  of serum immunglobulins.
• 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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Analysis of lymphocytes in umbilical cord
blood during gestation

• Help to diagnose immunodeficiency
  
• In pregnancies at risk .
• Bone marrow or stem cell
  transplantation
• may be applied before birth .

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Therapy of immunodeficiency.

• 1. IVIG .( IV infusion of
  immunoglobulin.)
• For a.
  agammaglbulinaemia .
• b. CVI. c. WAS.
• 2. Periodic antibiotic treatment.
• 3. Bone marrow transplantation .
• For a. SCID . b. WAS.
• 4. Enzyme replacement .
• For a. ADA
  deficiency.

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5. G-CSF.(colony stimulating factor )
For neutropenia .

• 6. Thymus transplantation .
• For DiGeorge syndrome.
• 7. IFN gamma .
• For CGD.

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HIV virus.
T-cell.
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Practical points

• 1.Immunodiffusion plate.
• ( single radial immunodiffusion , SRID. )
• Antibody mixed in the agar medium.
• Antigen applied in the holes around.
• antigen molecules will diffuse into
  the
• agar precipitate with antibody forming
• a ring .
• The diameter of the ring is
  proportional
• to the concentration of the
  antigen.

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SRID.
Measure Diameter.
3-standards,conc. 10,25,50
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Applications

• 1.For measurement of immunoglobulins
• in serum IgG ,IgA IgM.
• 2.For measurement of complement
• proteins in serum .
• NOTE Immunoglobulins complement
• can also be measured by
• nephlerometry (measures optical
• density )

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2. Immunonephelometry

• A more accurate method for measurement of
  a. immunoglobulins
• b. Complement proteins .
• - proteins form immune complexes with specific
  antibodies. A beam of light is passed through
  the sample. The intensity
• of the scattered light is proportional to the
• concentration.

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2.Flow cytometry

• 1.For enumeration of lymphocytes in the
• peripheral blood..
• ( laser operated machine that utilize
• monoclonal antibodies to CD markers).
• 2.measures T-cells ,B-cells , NK-cells.

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3.CH 50 test .

• Complement hemolytic assay.
• measures the functional activity of the
• complement system ( amount of
• complement that causes 50 lyses
• of a fixed amount of cells. )

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Immunology quiz . (1)
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A previously healthy 30 years old man was
admitted following a car accident .He is
unconscious and had signs of brain damage.
The patient has a tube inserted into his
trachea , and a central venous lineand urinary
catheter are inserted .He is given high dose
corticosteroidsin an attempt to reduce
cerebral edema . After a series of
convulsionsthe anti convulsant phenytoin is
given intravenously . Two weeks later he
developed pneumonia. In addition to
physicalstress this patient has poor
nutrition .1. What factors may impair the
defense mechanisms in this patient ?2. What
type of immunodeficiency is affecting this
patient ?
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Immunology quiz .
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Immunology quiz No.1

• A 9-month old boy presented with history
  of recurrent episodes of serious bacterial
  infections.
• These included bacterial pneumonia, otitis
  media ,
• Sinusitis septicemia. Repeated
  bacteriological cultures revealed Streptococcus
  pneumonae, H.
• influenzae Staphylococci.
• 1.List the relevant immunologic investigation
  in this
• case .
• 2.What immunologic processes are likely to
  be
• involved .

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3. What is the probable diagnosis
?

• 4.What are the appropriate lines of
• management ?
• .5.Why was the child normal up to 9-month
• of age and then started to develop
  infections?
• 6.Can this disease affect female children ?

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Immunosuppresion.
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Immunosuppresion.
Strategies that diminish immune responses.
specific
Non-specific.
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Immunosuppresion is required in
Allogeneic transplantation.
Allergic diseases.
Autoimmune diseases.
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Mitotic inhibitors.
Azathioprine ( Imuran ).
Cyclophosphamide methotrexate.
Effective against rapidly dividing
cells. Sometimes given at time of grafting. May
affect other dividing Cells.
Given just before after Transplantation to
diminish T-cell proliferation. Both T-cells
B-cells are Affected.
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Corticosteroids .( glucocorticoids ) . potent
anti-inflammatory agents.
Prednisone ,prednisolone, dexamethasone etc.
1. Decrease size lymphoid content of the spleen
lymph nodes. 2 .Modify function of certain
T cells. 3. Inhibit inflammatory mediators
including histamine prostaglandins
leukotriens . 4. Inhibit monocyte neutrophil
chemotaxis activity. 5. Change leukocyte
distribution causing lymphopenia. and
neutrophilia. 6. Inhibit IL-1 production
expression of MHC11 by macrophages. decrease
availability of IL-2. 7. Decrease IgG blood level
.
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Nonsteroidal anti-inflammatory agents .(NSAIDs).
The most frequently used medications for
treatment of Pain inflammation. (also
have antipyretic effect.)
They inhibit the cyclooxygenase pathway that
produce Prostaglandins thrmboxanes from
arachidonic acid .
Reduction in prostaglandin production
limits
Increase in vascular Permeability .
Neutrophil chemotaxis.
Reduce edema pain fever.
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Most NSAIDs inhibit both Cox1 Cox2.
Responsible for anti-inflammatory effect.
Damage GIT tract, no significant anti-
Inflammatory effect.
This led to development of Cox2 specific NSAIDs
drugs.
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Inhibition of thromboxanes production
Cause inhibition of platelet aggregation .
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The main adverse effects of NSAIDs
Mild G.I.T. irritation
Decreased G.F.R. Acute renal failure
interstitial Nephritis.
G.I.T. bleeding Caused by ulcers.
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Rheumatoid arthritis therapy .
NSAIDs.
Corticosteroids.
Disease modifying anti-rheumatic drugs
(DMARDS)
Biologic agents. TNF inhibitor IL-1.
The most widely used is methotrexate. Alkylaing
agents cyclophosphamide. Purine analoques
azathioprine .
99
Certain fungal metabolites are immunosuppressants.
- Cyclosporin A. - FK506 (tacrolimus ). -
Rapamycin (sirolimus ).
Inhibit IL-2 gene transcription .
100
The profound immunosuppressive properties of
these three agents have made them a mainstay of
heart ,liver, Kidney, and bone marrow
transplantation
Cyclosporin A has been shown to prolong
graft survival . but ,the
main side effect is acute nephrotoxicity.
FK506 rapamycin are 10-100 times more potent
than CsA as immunosuppressants , therefore have
few side effects can be given at
lower doses.
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Total lymphocyte irradiation eliminates
lymphocytes. The typical protocol is daily
x-irradiation treatments of 200 rads per day for
several weeks until a total dose
of 3400 has been administered.
The bone marrow is not x-irradiated ,lymphoid
stem Cells proliferate and renew the population
of lymphocytes.
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Complement Deficiencies and
Disease.Classical Pathway.
Pathway Component Disease Mechanism
C1INH Hereditary Angioedema Overproduction of C2b (prokinin)
C1, C2, C4 Predisposition to SLE Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation
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Complement Deficiencies and
Disease.Alternative Pathway
Pathway/Component Disease Mechanism
Factors B or D Susceptibility to pyogenic (pus-forming) bacterial infections Lack of sufficient opsonization of bacteria
C3 Susceptibility to bacterial infections Lack of opsonization and inability to utilize the membrane attack pathway
C5, C6, C7 C8, or C9 Susceptibility to Gram-negative infections Inability to attack the outer membrane of Gram-negative bacteria
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Complement Deficiencies and
Disease.Alternative Pathway cont.
Pathway Component Disease Mechanism
Properdin (X-linked) Susceptibility meningococcal meningitis Lack of opsonization of bacteria
Factors H or I C3 deficiency and susceptibility to bacterial infections Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3
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Specific immunosuppressive therapy.

• anti-cytokine drugs
• -TNF-alpha neutralizing
  monoclonal antibodies.
• - soluble recombinant TNF-alpha
  receptor
• - IL-1 receptor blocking
  proteins.
• 2. Immunoadhesin molecules.
• Compete with cell-bound receptors.
  

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Clinical case 1

• A-52 year old woman
• presents with symptoms of joint
  pains
• and stiffness in hands ,feet and knees for
  the past 6 months .In addition, the patient
  also noted a 10- pound weight loss and a low
  grade fever. She has been receiving
• analgesic medications for 4
  month and has not experienced much
  relief of her symptoms .

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What immunological process is likely to
be involved in her problems ? What
additional information would help you to
confirm this ?
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A. This patient most likely has rheumatoid
arthritis.

• In addition to a complete history and
  physical examination, radiographic evidence of
  joint erosions and a positive
• rheumatoid factor ( RF.) can confirm the
  diagnosis.
• Because this patient has tried
  analgesics for 4-months without much
• relief , DMARDs and / or TNF - alpha
  inhibitors should be considered.