Question

Case Study 3: The Case of Jean-Baptiste Emanuel Zorg: The Consequences of a Small Flaw in the MHC

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 IgG, at more than 1500 mg/dl (normal levels 600-1400 mg/dl). They had white blood cell counts of 7000 and 6600 cells/μl, respectively. Of these cells, 25% (1750 and 1650 cells/μl, 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 I? 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? Please be specific in your response.

Why would a loss of MHC class I result in an increased susceptibility to viral infections?

Why did Zorg and Mangalore still have a robust protective response to the vaccine components that were received?

Answer 1

Calnexin and Calreticulin both are molecular chaperones, require for folding and assembly of the (MHC) class I molecule. Assembly of MHC class I heavy chain (HC) with β2-microglobulin (β2m) and subsequent acquisition of optimal peptides is necessary for class 1 antigen presentation to cytotoxic T cells (CTLs). Calnexin is important in early stages of class I assembly where it recruits diffrent proteins to facilitate disulphide bond formation in class I HC and protects class I HC from degradation prior to their assembly with β2m. Calreticulin, on the other hand, is involved in the later stages of class I assembly.

in loss of both, no MHC class I assembly, intracellular transport, or antigen presentation function.

Because MHC class 1 are essential and facilitate recognition of virus-infected cells and presenting the internal viral particles processed antigens to cytotoxic T cells. Cyto T cells recognize them and release granzymes and granulysin to kill the virus infected cells, so if there are no MHC class 1 molecule viral/ bacterial infections are not recognized and increased susceptibility to viral/ bacterial infections.