Immunodeficiency diseases

Question 1

Primary immunodeficiency

Answer 1

• Congential–many manifest in infancy (between 6 mths and 2 yrs)
• Can affect T or B lymphocyte functions in adaptive immunity.
• Detected through multiple recurrent infections.
• B cell and combined B and T cell disorders more common types

Question 2

Secondary immunodeficiency

Answer 2

• Due to complications of cancer, infection, malnutrition, immunosupression, irradiation, chemo
• Far more common than primary form

Question 3

X-linked agammaglobulinemia (Bruton’s agammaglobulinemia)

Answer 3

• FAILURE OF B CELL PRECURSORS TO DEVELOP INTO MATURE B Cells
• mutation in x-linked gene that encodes cytoplamic tyrosine kinase
• Decreased/absent B cells in peripheral blood
• Decreased/absent Ig
• No plasma cells
• Underdeveloped germinal centers in lymph nodes and Peyer’s patches
• Clinical symptoms appear around 6 mths
• -Recurrent sinopulmonary bacterial infections
• -certain viral infections that require neutralizing Ab
• -often persistent girardia infection
• risk of autoimmune diseases
• Treatment: prophylactic Ig therapy

Question 4

Common variable immunodeficiency

Answer 4

• FAILURE OF B CELLS TO DIFFERENTIATE INTO PLASMA CELLS
• Decreased Ig production
• Normal # of B cells in blood, but no plasma cells
• B cell lymphoid areas (germinal centers) are hyperplastic
• Sporadic and inherited forms exist
• Diagnosis based on exclusion
• Symptoms similar to X-linked agammaglobulinemia
• Both sexes affected equally
• Onset in childhood or adolescence
• Treatment: prophylactic Ig therapy.
• Increased risk of autoimmne diseases lymphoid malignancies, increased gastric cancer risk

Question 5

Isolated IgA deficiency

Answer 5

• FAILURE OF B CELLS TO DIFFERENTIATE INTO IgA PRODUCING PLASMA CELLS
• IgA levels decreased
• May be familial or acquired from infection
• Most asymtomatric (1 in 600 ind. of european descent)
• Mucosal defenses weakened in those with symptoms.
• -Sinopulmonary and diarrhea (giaradia)
• -High risk of respiratory tract allergies, increased autoimmune disease risk
• -May develop severe, even fatal ractions to transfused blood products (normal IgA in blood product acts like foreign antigen)

Question 6

DiGeorge Syndrome (Thymic hypoplasia)

Answer 6

• T CELL DEFICIENCY DUE TO FAILURE OF 3rd AND 4th PHARYNGEAL POUTCHES TO DEVELOP
• Variable loss of T cell mediated immunity (thymic hypoplasia or lack of thymus, tetany or lack of parathyroid glands, congenital heart or great vessel defects, facial abnormalities)
• Usually sproadic deletion of chromosome 22q11.
• Low T lymphocyte levels in peripheral blood, and T cell areas in spleen and lymph nodes depleted.
• Susceptible to fungal, viral and pneumcysitis jiroveci infections.
• Serum Ig levels may be normal or reduced depending on the severity

Question 7

Hyper IgM syndrome

Answer 7

• CAN MAKE IgM, BUT DEFICIENT IN ABILITY TO MAKE IgG, IgA, IgE (DEFECT IN CLASS SWITCHING)
• Elevated IgM levels, no IgA, no IgE, and very low levels of IgG.
• Normal T and B lymphocytes in peripheral blood
• Defects in ability of CD4+ T helper cells to deliver activating signals to B cell s and macrophages (needed for class switching)
• Over 1/2 have X-linked recessive mutation in gene encoding CD40 ligand
• Recurrent pyogenic infections, risk for IgM induced cytopenias, suscceptible to pneumocystis jiroveci

Question 8

Severe combined immunodeficiency (SCID)

Answer 8

• PROFOUND DEFECTS IN BOTH HUMORAL AND CELL MEDIATED IMMUNITY
• w/o hematopoietic stem cell transplant, death occurs within 1 yr
• Thrush, extensive diaper rash, FTT. Extremely susceptible to reccurent, severe infections by wide range of pathogens
• Many different genetic mutations. Most common form is X-linked and due to gene encoding common gamma-chain subunit of cytokine receptors. Other types are inherited as autosomal recessive disorders. Most common autosomal recessive form is deficiency in adenosine deaminase (ADA).
• Reduced cytokine signal and impaired T cell development.
• Treatment: hematopoietic stem cel transplantation. Some have also been treated with gene therapy (but some then developed acute T-cell leukemias

Question 9

Immunodeficiency with thrombocytopenia and eczema (Wiscott-Aldrich Syndrome)

Answer 9

• X-LINKED RECESSIVE DISORDER WITH THROMBOCYTOPENIA, ECZEMA, VULNERABILITY TO RECURRENT INFECTION LEADING TO PREMATURE DEATH
• Mutations in gene encoding Wiscott-Aldrich Syndrome Protein (WASP), on short arm of X chromosome. Believed to be responsible for linking membrane receptors to actin filaments. Mutation leads to defects in cell migration and signal transduction
• Depletion of T lymphocytes and variable loss of cell-mediated immunity.
• Ab production to polysaccharide antigens absent
• Low IgM levels (increased risk of infection with encapsulated organisms)
• IgG levels normal, IgE, IgA levels often elevated.
• Risk for Hodgkin lymphoma
• Treatment: hematopoietic cell transplantation

Question 10

X-linked lymphoproliferative syndrome

Answer 10

• INABILITY TO ELIMINATE EBV, LEADING TO SEVERE AND SOMETIMES FATAL INFECTIOUS MONO AND B CELL LYMPHOMAS
• Most cases due to mutation in SLAM-associated protein (invovled in activation of NK cells and T and B lymphocytes

Question 11

Chediak-Higashi syndrome

Answer 11

• Rare autosomal recessive disorder
• Recurrent pyogenic infections, partial oculocutaneous albinism, progressive neuro abnormalities, mild coagulation defects
• CHS1/LYST (BEACH family)–> DEFECTIVE FUNCTION OF PHAGOSOMES AND LYSOSOMES IN PHAGOCYTE FUNCTION
• Diagnoisis: pahogenomic cytoplamsic granules in leukocytes

Question 12

Complement system deficiencies

Answer 12

C5-C9 increased risk of recurrent neisserial infections!

Impaired membrane attack complex that is involved in lyisis of organisms

Question 13

Causes of secondary immunodefieciency

Answer 13

1. Immunosuppressive therapy (meds)
2. Microbial infections
3. Malignancy
4. Disorders of biochemical homeostasis
5. Autoimmune disease
6. Severe burn injury
7. Exposure to radiation/toxic chemicals
8. Asplenia/hyposplenism
9. Aging

Question 14

What type of infection are patients without a spleen at risk for? Why?

Answer 14

• Increased risk of bacterial infection with encapsulated organisms (especially strep pneumoniae).
• Recieve vaccinations for S. pneumoniae, H. influenzae, N. meningitidis
• Loss of splenic macrophages post-splenectomy

Question 15

3 ways one could suspect immunodeficiency

Answer 15

1. Clinical history
2. Presents with opportunistic infection from signature organisms (Nocardia, oral canidiasis, invasive aspergillus, pneumocystis jiroveci pneumonia)
3. Presents with repeated infections

Question 16

CBC with Differential

Answer 16

Assess for decrease in lymphocytes and/or decrease in neutrophils

Question 17

CMP (blood chemistry)

Answer 17

Assess for diabetes, kidney, liver disease

Question 18

Urinalysis

Answer 18

Assess for renal disease

Question 19

Sedimentation rate (CRP)

Answer 19

Assess for inflammatory state (infection, autoimmune disease)

Question 20

Test for antibody deficiencies (B cell function)

Answer 20

Ig levels

Question 21

Tests for cellular immunity (T cell function)

Answer 21

Flow cytometry, skin testing w/candida antigen (Assess delayed-type hypersensitivity)

Question 22

Tests for phagocytic disorders

Answer 22

Peripheral smear (looking for granulocytes), genetic tests

Question 23

Test for complement activity

Answer 23

Total serum complement (CH50)