Immunodeficiency

Question 1

Which is more common: primary or secondary immunodeficiency?

Answer 1

Secondary

Question 2

What is the presentation of patients with immunodeficiency?

Answer 2

• Increased susceptibility to infection
• Increased susceptibility to certain cancers (e.g. those caused by EBV and HPV)
• Certain immunodeficiencies are associated with increased incidence of autoimmunity
• Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Question 3

What are the types of congenital defects in innate immunity?

Answer 3

• Chronic granulomatous disease
• Leukocyte adhesion deficiencies
• Complement deficiencies
• Chédiak-Higashi syndrome

Question 4

What is the cause of chronic granulomatous disease?

Answer 4

Mutation in components of the phagocyte oxidase (phox) enzyme complex, resulting in impaired production of the superoxide anion, a ROS important in the microbicidal activity of neutrophils

Question 5

What are the features of chronic granulomatous disease?

Answer 5

• Recurrent infections with intracellular fungi and bacteria, e.g. Staphylococcus, Aspergillus
• Because infections are not controlled by phagocytes, T cell–mediate macrophage activation occurs, with formulation of granulomas

Question 6

How is X-linked chronic granulomatous disease treated?

Answer 6

IFN-γ

Question 7

What are the leukocyte adhesion deficiencies?

Answer 7

A group of autosomal recessive disorders caused by defects in leukocyte and endothelial adhesion molecules:

• LAD1: deficient expression of integrin β₂
• LAD2: absence of sialyl Lewis X, the ligan of E-/P-selectins

Question 8

What are the features of leukocyte adhesion deficiencies?

Answer 8

• A failure of leukocyte (particularly neutrophil) recuritment to sites of infection
• Severe periodontitis and other recurrent infections starting early in life
• Inability to make pus

Question 9

What are the types of complement deficiency?

Answer 9

• Genetic deficiencies in classical pathway components, including C1q, C1r, C4, C2 (most common deficiency), and C3
• Deficiencies in components of the alternative pathway, including Factor D, C3, and properdin
• Deficiencies in the terminal complement (MAC) components, including C5, C6, C7, C8, and C9. These patients have a propensity for disseminated infections by Neisseria, including N. gonorrhoeae and N. meningitidis, and other meningococcal infections

Question 10

What is Chédiak-Higashi syndrome?

Answer 10

A rare autosomal recessive disorder characterized by recurrent infections by pyogenic bacteria

Question 11

What is the pathogenesis of Chédiak-Higashi syndrome?

Answer 11

Mutations in the gene encoding the protein LYST, which regulates intracellular trafficking of lysosomes. This results in defective phagosome–lysosome fusion in neutrophils and macrophages (leading to reduced resistance to infection), defective melanosome formation in melanocytes (causing albinism), and lysosomal abnormalities in cells of the nervous system (causing nerve defects) and platelets (leading to bleeding disorders)

Question 12

What are severe combined immunodeficiencies (SCIDs)?

Answer 12

Immunodeficiencies that affect both humoral and cell-mediated immunity, arising from impaired T lymphocyte development, with or without defects in B cell maturation

Question 13

What is the inheritance pattern of SCIDs?

Answer 13

Half are autosomal recessive, the rest are X-linked

Question 14

What are the types of SCIDs?

Answer 14

• Defects in cytokine signaling, e.g. in receptors or second messengers
• Defects in nucleotide salvage pathways
• Defects in V(D)J recombination
• Defective thymic development

Question 15

What is the cause of DiGeorge syndrome?

Answer 15

Deletions in chromosome 22

Question 16

What are the symptoms of DiGeorge syndrome?

Answer 16

• Cleft palate
• Abnormal facies
• Thymic absence or underdevelopment
• Cardiac abnormalities
• Hypocalcemia

Question 17

What is the pathogenesis of DiGeorge syndrome?

Answer 17

A congenital malformation results in defective development of the thymus and the parathyroid glands as well as other structures that develop from the third and fourth pharyngeal pouches during fetal life

Question 18

How is DiGeorge syndrome treated?

Answer 18

Fetal thymic transplantation or bone marrow transplantation, although this treatment is usually not necessary since T cell function tends to improve with age in most patients

Question 19

What is the most common defect in B cell activation and development?

Answer 19

Selective IgA deficiency—the most common primary immunodeficiency

Question 20

Which primary immunodeficiency is the most common?

Answer 20

Selective IgA deficiency, notably in Caucasians

Question 21

What are the features of IgA deficiency

Answer 21

• Many patients are entirely normal
• Others have occasional respiratory infections and diarrhea
• Rarely, patients have severe, recurrent infections leading to permanent intestinal and airway damage

Question 22

What are the types of antibody deficiencies?

Answer 22

• Agammaglobulinemia—reduction in all serum Ig isotypes, e.g. X-linked agammaglobulinemia
• Selective hypogammaglobulinemias, e.g. selective IgA deficiency, common variable immunodeficiency
• Hyper-IgM syndromes

Question 23

What are the features of X-linked agammaglobulinemia?

Answer 23

• Low or undetectable serum Ig
• Reduced or absent B cells in peripheral blood and lymphoid tissues
• No germinal centers in lymph nodes
• No plasma cells in tissues
• Normal T cell count and function

Question 24

How is X-linked agammaglobulinemia treated?

Answer 24

Periodic injection of pooled gamma-globulin preparations

Question 25

What is common variable immunodeficiency?

Answer 25

A group of heterogeneous disorders defined by reduced levels of serum Ig, impaired antibody responses to infection or vaccines, and increased incidence of infections

Question 26

What is the cause of hyper-IgM syndromes?

Answer 26

Mutation in CD40L on T cells, leading to the absence of germinal centers and no isotype switching

Question 27

What is Wiskott-Aldrich syndrome?

Answer 27

An X-linked disease characterized by eczema, thrombocytopenia, and susceptibility to bacterial infection.

Question 28

When should immunodeficiency be suspected?

Answer 28

• Increased frequency of infection, above what would be expected
• Increased severity of infection, e.g. severe gastroenteritis from a herpes virus
• Infection by unusual or opportunistic viruses, e.g. JC virus, Mycobacterium avium complex
• Infection not responsive to treatment

Question 29

What are the causes of secondary immunodeficiency?

Answer 29

• Malnutrition
• Infections
• Drugs
• Metabolic and chronic conditions
• Extremes of age

Question 30

What is the most common cause of immunodeficiency?

Answer 30

Protein malnutrition (secondary)

Question 31

Deficiency in which nutrients may cause immunodeficiency?

Answer 31

• Proteins
• Zinc
• Vitamins, especially A, C, D, and E

Question 32

What types of infections may cause immunodeficiency?

Answer 32

• HIV
• Measles, causing transient immunodeficiency
• Certain bacteria and parasites

Question 33

What types of drugs may cause immunodeficiency?

Answer 33

• Anti-inflammatory agents (e.g. steroids)
• Immunosuppressive medications
• Chemotherapeutic agents

Question 34

What types of metabolic and chronic conditions may cause immunodeficiency?

Answer 34

• Chronic renal disease
• Diabetes

Question 35

Which age groups are particularly susceptible to secondary immunodeficiency?

Answer 35

• Neonates
• The elderly

Question 36

How is immunodeficiency investigated?

Answer 36

• Clinical history and physical examination
• Laboratory tests:
  
  • CBC
  • Differential white blood cell percentages
  • Percentages of lymphocyte subsets
  • Serum antibody levels