Immunodeficiencies

Question 1

A crucial part of innate immunity is the involvement of neutrophils. What are their functions?

Answer 1

Chemotaxis (C3a/C5a –> chemokines)
Phagocytosis (Opsonization: IgG + C3b enhance this)
Killing (Lysosomal granules contain many bactericidal agents)

Question 2

Defects of Neutrophil function (Inability to mount a normal inflammatory response)

Answer 2

1. Neutropenia- low neutrophil count e.g. patients receiving chemotherapy
2. Defective opsonization (IgG deficiency, C3b deficiency *rare)
3. Non-killing neutrophils
   - Chronic granulomatous disease (CGD)

Question 3

Chronic granulomatous disease (CGD)

Answer 3

Non-killing neutrophils

• X-linked (*males)
• defect in cytochrome b and NADPH oxidase –> no superoxide anion prod, cant kill staph
• recurrent infection with abscess of skin, lymph nodes, CHRONIC GRANULOMAS

Question 4

Neutropenia

Answer 4

• Defective opsonization (mediated by IgG + C3b).
• Defective inflammatory response (chemotaxis by C3a + C5a).
• Defective phagocytosis.

Question 5

Under normal circumstances, ______________ in the neutrophil cytoplasm collide with the phagosome and release their granules containing numerous bactericidal enzymes and ____________.

Answer 5

lysosomal granules

superoxide anion.

Question 6

Leukocyte Adhesion Deficiency (LFA-1 deficiency)

Answer 6

• Neutrophils fail to emigrate out of vessels towards the ag (no sticking to endothelial cells)
• Failure of CD8+ cells to bind to target cells
• Recurrent bacterial infection
• Failure to heal wounds (Umbilicus)

Question 7

Chediak Higashi Syndrome

Answer 7

• Giant Lysosomal Granules
• Defective phagosome-lysosomal fusion in neutrophils
• Recurrent infection

Question 8

Neutrophil defect immune deficiencies

Answer 8

1. Neutropenia
2. CGD
3. Leukocyte Adhesion Deficiency (LFA-1)
4. Chediak-Higashi Syndrome

Question 9

X-Linked Agammaglobulinemia

Answer 9

• “Brunton’s agammaglobulinemia”
• Absent IgG, IgA and IgM
• Pre-B cells in marrow, but no mature B-cells
• Absent or very small tonsils and lymph nodes
• Btk mutation (TYR KINASE imp for light chain rearrang.)
• Absent germinal centers in lymph nodes, absent B-cells in blood
• recurrent infections

*boys

Question 10

Serum electrophoresis from 1) a normal person and 2) a patient with X-linked agammaglobulinemia

Answer 10

(absent gamma-globulin band)

Normal VDJ recombination of µ light chains in pre-B-cells, but no class switching.

Question 11

Management of X-Linked Agammaglobulinemia

Answer 11

Avoid infections where possible
Abx
Intravenous immunoglobulin (IVIG) every 3 weeks
3 weeks for IVIG to drop, then give another shot

Question 12

IgA Deficiency

Answer 12

• Common 1:700
• many pt asymptomatic
• Pt w/ associated IgG2 or IgG4 deficiency –> severe respiratory and GI infections
• IVIG is not usually helpful

Question 13

Hyper IgM syndrome

Answer 13

• mut CD40L gene (on TCell)
• Failure of isotype switching
• Only IgM and IgD. NO switch to IgG, IgA or IgE
• NO germinal centers. Most cells are T cells.
• Recurrent infections

Question 14

Transient Hypogammaglobulinemia of Childhood

Answer 14

• Delay in the production of normal Abs
• B-cells are present
• Transient ability to prod IgG
• Cause is unknown, may be due to deficiency in #/function of helper T cells
• Resolves with time

Question 15

Common Variable Immunodeficiency

Answer 15

• not common. Appears in teens/adults
• Low serum levels of all immunoglobulins
• B-cells are present, but defective differentiation into plasma cells
• Increased susceptibility to infections
• Defect unknown (poss defect B-cells –> plasma cells)
• tx:IVIG

Humoral deficiency

Question 16

Di George Syndrome

Answer 16

(chromosome 22q11.2 deletion syndrome (22qDS)

-No T-cells, no B-cell class switching

1) Cardiac anomalies
2) Hypoplastic thymus or complete ABSENCE of the thymus.
3) Hypocalcemia (resulting from parathyroid hypoplasia).
4) Facial abnormalities e.g. cleft palate
Majority of patients with DGS have deletions in chromosome 22q11.2.

• recurrent infections with intracellular bacteria,
  fungi, large viruses (also pyogenic organisms bc lack of T-cell help for B-cells)

Question 17

Di George Syndrome CATCH 22

Answer 17

Cardiac abnormality 
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia.

Question 18

Patients with Di George syndrome will have:
A) Decreased numbers of surface IgM and IgD positive B-cells
B) Normal serum IgE levels
C) Normal serum anti-influenza IgG levels after immunization with the influenza vaccine
D) Normal ability to produce acute phase proteins such as CRP
E) Normal IL-2 production

Answer 18

D

Question 19

Severe Combined Immunodeficiency

Answer 19

• Numerous forms of SCID that can result from any one of several genetic defects.
• Both humoral and cell mediated immunity are defective.
• Patients are susceptible to all infectious agents (severe oral esophageal/nail candidiasis)

Tx: reconstitution of immune system with stem cell transplantation *beware of GVH

Question 20

The commonest form of SCID

Answer 20

• mutation of the common-chain of the IL-2 Receptor

- X-linked severe combined immunodeficiency

Question 21

Adenosine deaminase (ADA) deficiency

Answer 21

Form of SCID

Question 22

Bare lymphocyte syndrome

Answer 22

Form of SCID
Cells lack class I or II MHC molecules

Question 23

Abnormal signal transduction leading to SCID

Answer 23

1) Mutations of protein kinases e.g. JAK3 or ZAP 70

2) Mutations of RAG1 and RAG2

Question 24

Mutations of the CD3 molecule
Defective Cytokine production

Can lead to …

Answer 24

SCID

Question 25

Wiskott Aldridge Syndrome

Answer 25

Immunodeficiency Defective WAS (necessary for for cytokine release). Thrombocytopenia (low platelet count) - purpuric spots Eczema (Elevated IgE, type I allergic rxn) Recurrent infections tx: stem cell transplant

Question 26

Ataxia Telangiectasia

Answer 26

Defective DNA repair, causing a type of SCID. Sx: Ataxia Telangiectasia (of eye) (spider-like vascular abnormalities) no curative tx

Question 27

``` Secondary Immunodeficiency (Defective humoral immunity) ```

Answer 27

Lymphoma Myeloma Burns (loss of Ig in serum)

Question 28

``` Secondary Immunodeficiency (Defective Cell mediated Immunity) ```

Answer 28

Patients taking Immunosuppressive drugs Malnutrition Viral infections especially HIV Ageing

Question 29

Acquired Immunodeficiency Syndrome (HIV)

Answer 29

HIV virus infects the CD4 cell Viral gp120 binds to the CD4 molecule Gp41 binds to the chemokine receptor CCR5 T cells drop dramatically

Question 30

Clinical course of HIV disease

Answer 30

4-6 weeks T cells drop to about half of what they should be. Then stabilize at about half their normal level (clinical latency) Virus goes sky high, drops, continues for months/years (clinical latency), then suddenly goes up. Infections, death.

Question 31

Laboratory diagnosis of HIV

Answer 31

1) Can detect HIV antigen or antibody in the blood 2) Reversal of the CD4:CD8 ratio. This ratio is normally approximately 2:1 3) Measure serum levels of HIV RNA to follow progress of the disease.

Question 32

The commonest immunodeficiency ....

Answer 32

Ageing is associated with significant and continuous immune deficiency Decreasing number and function of many cell types including, neutrophils, antigen presenting cells, NK cells, and T-cells

Question 33

Specific immunodeficiency to papilloma virus

Answer 33

causing very severe warts Pt responded normally to PPD and to other delayed hypersensitivity skin tests (normal cell mediated immunity) cause unknown

Question 34

Chronic mucocutaneous Candidiasis

Answer 34

Lack of IL-17 production or Autoantibody to IL-17

Question 35

B-cell defect immune deficiencies

Answer 35

1. Brunton's (X-linked) aggamaglobulinemia 2. IgA deficiency 3. Hyper-IgM syndrome 4. Transient Hypogammaglobulinemia of Infancy 5. Common Variable Immunodeficiency

Question 36

T-cell/SCID defect

Answer 36

1. DiGeorge Syndrome 2. T-cell Activation Defects 3. Severe Combined Immunodeficiency 4. Bare Lymphocyte Syndrome 5. Wiskott-Aldritch Syndrome 6. Ataxia Telangiectasia

Question 37

SCID (other forms)

Answer 37

1. adenosine deaminase (ADA) deficiency 2. bare lymphocyte syndrome 3. abnormal signal transduction - mut JAK3 or ZAP70 (protein kinases) - mut RAG1 and RAG2 4. CD3 mutation 5. defective cytokine prod

Question 38

Susceptibility to opportunistic infections

Answer 38

T-cell deficiencies like DiGeorge, SCID, Bare lymphocyte syndrome, HIV, mutation of CD3 *NOT B-cell deficiency (like X-linked aggamaglobulinemia)