Immunodeficiency Flashcards
Which is more common: primary or secondary immunodeficiency?
Secondary
What is the presentation of patients with immunodeficiency?
- 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
What are the types of congenital defects in innate immunity?
- Chronic granulomatous disease
- Leukocyte adhesion deficiencies
- Complement deficiencies
- Chédiak-Higashi syndrome
What is the cause of chronic granulomatous disease?
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
What are the features of chronic granulomatous disease?
- 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
How is X-linked chronic granulomatous disease treated?
IFN-γ
What are the leukocyte adhesion deficiencies?
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
What are the features of leukocyte adhesion deficiencies?
- 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
What are the types of complement deficiency?
- 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
What is Chédiak-Higashi syndrome?
A rare autosomal recessive disorder characterized by recurrent infections by pyogenic bacteria
What is the pathogenesis of Chédiak-Higashi syndrome?
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)
What are severe combined immunodeficiencies (SCIDs)?
Immunodeficiencies that affect both humoral and cell-mediated immunity, arising from impaired T lymphocyte development, with or without defects in B cell maturation
What is the inheritance pattern of SCIDs?
Half are autosomal recessive, the rest are X-linked
What are the types of SCIDs?
- 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
What is the cause of DiGeorge syndrome?
Deletions in chromosome 22
What are the symptoms of DiGeorge syndrome?
- Cleft palate
- Abnormal facies
- Thymic absence or underdevelopment
- Cardiac abnormalities
- Hypocalcemia
What is the pathogenesis of DiGeorge syndrome?
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
How is DiGeorge syndrome treated?
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
What is the most common defect in B cell activation and development?
Selective IgA deficiency—the most common primary immunodeficiency
Which primary immunodeficiency is the most common?
Selective IgA deficiency, notably in Caucasians
What are the features of IgA deficiency
- 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
What are the types of antibody deficiencies?
- 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
What are the features of X-linked agammaglobulinemia?
- 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
How is X-linked agammaglobulinemia treated?
Periodic injection of pooled gamma-globulin preparations
What is common variable immunodeficiency?
A group of heterogeneous disorders defined by reduced levels of serum Ig, impaired antibody responses to infection or vaccines, and increased incidence of infections
What is the cause of hyper-IgM syndromes?
Mutation in CD40L on T cells, leading to the absence of germinal centers and no isotype switching
What is Wiskott-Aldrich syndrome?
An X-linked disease characterized by eczema, thrombocytopenia, and susceptibility to bacterial infection.
When should immunodeficiency be suspected?
- 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
What are the causes of secondary immunodeficiency?
- Malnutrition
- Infections
- Drugs
- Metabolic and chronic conditions
- Extremes of age
What is the most common cause of immunodeficiency?
Protein malnutrition (secondary)
Deficiency in which nutrients may cause immunodeficiency?
- Proteins
- Zinc
- Vitamins, especially A, C, D, and E
What types of infections may cause immunodeficiency?
- HIV
- Measles, causing transient immunodeficiency
- Certain bacteria and parasites
What types of drugs may cause immunodeficiency?
- Anti-inflammatory agents (e.g. steroids)
- Immunosuppressive medications
- Chemotherapeutic agents
What types of metabolic and chronic conditions may cause immunodeficiency?
- Chronic renal disease
- Diabetes
Which age groups are particularly susceptible to secondary immunodeficiency?
- Neonates
- The elderly
How is immunodeficiency investigated?
- Clinical history and physical examination
- Laboratory tests:
- CBC
- Differential white blood cell percentages
- Percentages of lymphocyte subsets
- Serum antibody levels
