A 3-month-old girl is brought to the emergency department due to fever, irritability, and vomiting for the past 2 days. On examination, she is ill-looking, lethargic, and febrile. Blood cultures grow Mycobacterium tuberculosis. One of her brothers died from disseminated mycobacterial infection during infancy. Impairment of which of the following protective mechanisms is most likely contributing to this patient's infection?

Question

A 3-month-old girl is brought to the emergency department due to fever, irritability, and vomiting for the past 2 days.  On examination, she is ill-looking, lethargic, and febrile.  Blood cultures grow Mycobacterium tuberculosis.  One of her brothers died from disseminated mycobacterial infection during infancy.  Impairment of which of the following protective mechanisms is most likely contributing to this patient's infection?

Quizplus · Accepted Answer

11ec160b_37bb_0f79_9249_cfb41b6990f6_MD0001_00 Host defense against mycobacterial infections depends on the ability of macrophages to sequester mycobacteria in granulomas and directly kill the bacteria in phagosomes. Infected macrophages produce IL-12, which stimulates T cells and natural killer cells to produce interferon-γ (IFN-γ). Binding of IFN-γ to its receptor on a macrophage causes transcription of IFN-γ-regulated genes through activation of the JAK-STAT signaling pathway. The result is upregulation of IL-12 production, enhanced mycobacterial intracellular killing in phagolysosomes, and production of tumor necrosis factor-α (TNF-α) which promotes formation of granulomas. Autosomal recessive deficiencies of the IFN-γ receptor (or other elements of this pathway) result in disseminated mycobacterial disease (or BCG infection if the vaccine is administered) in infancy or early childhood. These patients require lifelong treatment with continuous antimycobacterial antibiotics. (Choice A) X-linked agammaglobulinemia (XLA) is an immunodeficiency disorder characterized by significantly reduced mature B cell production. These patients are deficient in all types of immunoglobulins; predisposing them to recurrent lower respiratory tract infections due to encapsulated bacteria (eg, S. pneumoniae, H. influenzae). (Choice B) Deficiencies of C5-C9, the components of the complement membrane attack complex, can lead to recurrent infections with Neisseria meningitidis or gonorrhoeae. (Choice D) Isotype switching is a process that occurs in naïve B lymphocytes on initial exposure to antigen. It is dependent on the interaction of CD40 with its ligand and cytokines including IL-4 and IL-5, which promote IgE and IgA class switching, respectively. (Choice E) Leukocyte adhesion deficiency is a rare immunodeficiency resulting from a defect in CD18, an integrin component that allows for leukocyte adherence and transmigration through endothelial walls. These patients present with delayed separation of the umbilical cord, poor wound healing, and recurrent cutaneous infections without pus formation. Educational objective: Inherited defects involving the interferon-γ signaling pathway result in disseminated mycobacterial disease in infancy or early childhood. Patients require lifelong treatment with antimycobacterial agents. __________ References: Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood. (http://www.ncbi.nlm.nih.gov/pubmed/11420412)

A 3-Month-Old Girl Is Brought to the Emergency Department Due