A 5-year-old girl is brought to the office for evaluation of a persistent cough. The patient has had a productive cough daily for the past month. History includes recurrent episodes of otitis media despite bilateral ear tube placement, numerous lower respiratory tract infections, and occasional ulcerative skin lesions. Laboratory evaluation shows normal levels of total B and T cells and serum immunoglobulin. Genetic testing reveals a mutation in the TAP1 gene, which encodes a protein involved in the transport of cytosolic molecules into the endoplasmic reticulum. Which of the following processes is most likely to be impaired by this mutation?

Question

A 5-year-old girl is brought to the office for evaluation of a persistent cough.  The patient has had a productive cough daily for the past month.  History includes recurrent episodes of otitis media despite bilateral ear tube placement, numerous lower respiratory tract infections, and occasional ulcerative skin lesions.  Laboratory evaluation shows normal levels of total B and T cells and serum immunoglobulin.  Genetic testing reveals a mutation in the TAP1 gene, which encodes a protein involved in the transport of cytosolic molecules into the endoplasmic reticulum.  Which of the following processes is most likely to be impaired by this mutation?

Quizplus · Accepted Answer

11ec160b_37b7_8d03_9249_49c7893de550_MD0001_00 Transporter associated with antigen processing (TAP) proteins are transmembrane proteins necessary for the presentation of cytosolic antigens on major histocompatibility complex (MHC) molecules. When cellular proteins (or pathogen-derived proteins) are degraded by proteasomes, some of the resulting peptide fragments are transported into the endoplasmic reticulum by TAP proteins and loaded onto MHC class I molecules. The MHC class I-peptide complexes then translocate to the cell surface where they can activate cytotoxic T cells through interaction with T cell receptors and CD8 coreceptors. The activated T cells clonally expand and kill damaged or infected cells by releasing cytotoxins (eg, perforin, granzyme) that induce apoptosis. Genetic mutations (eg, TAP1) affecting MHC class I-peptide complex expression (eg, bare lymphocyte syndrome type I) are rare but can cause ulcerative, granulomatous skin lesions and frequent respiratory infections despite normal lymphocyte and immunoglobulin levels. (Choice A) B cell differentiation into plasma cells is impaired in common variable immune deficiency, a multifactorial disorder without a clearly defined genetic basis. A decrease in the overall production of immunoglobulin results in recurrent respiratory tract and gastrointestinal infections. (Choice C) Chronic granulomatous disease is characterized by impaired destruction of phagocytized organisms in neutrophils due to a mutation (usually X linked) that causes decreased production of NADPH oxidase. The lack of superoxide production needed for the oxidative burst in neutrophils results in recurrent, severe bacterial and fungal infections in an infant or toddler. (Choice D) MHC class II molecules are expressed on antigen-presenting cells (eg, macrophages, B cells) after phagocytized proteins are degraded within lysosomes and added to MHC class II molecules. T helper (CD4⁺) cells are activated by the MHC class II-peptide complex and coordinate the adaptive immune response. TAP does not play a role in antigen loading of MHC class II molecules. (Choice E) Migration and extravasation of neutrophils is impaired in leukocyte adhesion deficiency due to a mutation in integrins necessary for the adhesion of immune cells to blood vessel walls. Without this adhesion, neutrophils are unable to leave blood vessels to follow chemotactic signals, resulting in delayed separation of the umbilical cord, recurrent bacterial infections, neutrophilia, and absent pus formation. Educational objective: Transporter associated with antigen processing (TAP) proteins are necessary for loading of cytoplasmic (eg, viral) proteins onto major histocompatibility complex (MHC) class I molecules. The MHC class I-peptide complex can then activate CD8⁺ cytotoxic T cells through interaction with the T cell receptor and CD8 coreceptor.

A 5-Year-Old Girl Is Brought to the Office for Evaluation