20 pts Case Study Details Jean-Baptiste Emanuel Zorg, otherwise known as Zorg, w
ID: 254512 • Letter: 2
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20 pts Case Study Details Jean-Baptiste Emanuel Zorg, otherwise known as Zorg, was 17 years old when first seen at the Children's Hospital. He had severe bronchiectasis (dilatation of the bronchi from repeated infections) and a persistent cough that produced yellow-green sputum. Zorg had been chronically ill from the age of 4 years old, when he started to get repeated viral infections of the sinuses, middle ears, and lungs. Interestingly, his brother Mangalore, aged 7 years, also suffered from chronic respiratory infections. Like his brother, he had begun to suffer severe repeated viral infections of the upper and lower respiratory infections at an early age and showed signs of severe bronchiectasis As infants in Europe, both Zorg and Mangalore received routine immunizations for poliovirus, diphtheria, pertussis, tetanus, measles, mumps, rubella, and tuberculosis and tolerated all of these immunizations well. They also showed ample antibody titers to the vaccines When Zorg and Mangalore were examined, they both had elevated levels of lgG, at more than 1500 mg/dl (normal levels 600-1400 mg/dl). They had white blood cell counts of 7000 and 6600 cells/ul, respectively. Of these cells, 25% (1750 and 1650 cells/ul, respectively) were lymphocytes and it was determined that only 10% of these cells were cytotoxic T cells (a profound deficiency in CD8 T cells). Blood tests on siblings and parents showed no deficiency of CD8 T cells. It was also determined that both Zorg and Mangalore had normal neutrophil function and complement titers. Evaluation of their CD4 T cell response indicated a normal response and antibody levels were also normal Because a deficiency in CD8 T cell response was suspected as the etiology of the recurrent infections, white blood cells were evaluated for MHC typing. While MHC class II molecules were expressed normally, neither Zorg nor Mangalore expressed any MHC class I molecules on their cells. Subsequent genetic testing of Zorg and Mangalore identified a deleterious mutation in the genes for calnexin and calreticulin production, which resulted in a loss of MHC class I being expressed on their cells Questions What are calnexin and calreticulin? What are their involvement in MHC class 1? Why would their loss result in a deficiency in MHC class I expression on a cell? How would a loss of MHC class I affect an individual immunologically? What aspects ould be affected. Please be specific in your response Why would a loss of MHC class I specifically result in an increased susceptibility to viral infections? 3. Why were Zorg and Mangalore still able to have a robust protective response to the vaccine components that were received regardless of their loss of MHC 1? 4.Explanation / Answer
Calnexin is an endoplasmic reticulum membrane protein which acts as the first molecular chaperon involved in class1 MHC assembly. It promotes class1 alpha chain to fold by binding with it. When beta 2 microglobulin binds with the Calnexin+class1 alpha chain assembly, Calnexin is released and another molecular chaperone binds with class 1 alpha chain & beta 2 microglobulins with the help of Tapasin. The new chaperon is known as Calreticulin. As discuss, these two chaparon along with Tapasin functions for the proper folding and binding to an antigen to MHC-I, if they lost their function the MHC1 will not bind and release protein antigen from the rough endoplasmic reticulum. MHC-I molecules are critically responsible for displaying endogenous antigen on the cell so that immunological response can be generated by the body. For example, viral protein that are synthesized in host cell endogenously is processed by proteasome system and displayed on the cell with MHC-I. If MHC-I will be detected the endogenous antigenic peptide will not be displayed and immunological response against them will not activate in the body. In such instance viral disease will rise in the body. Due to the inability of displaying system of endogenous antigen the immunological response fail and no immunological response will develop against endogenous antigen, so viral infection increase. As vaccines given to them are processed and are displayed in different manner so they will show robust protection. Vaccine are displayed by MHCII, and MHCII is unadulterated in these children so the response would be normal.
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