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Hyper-IgE syndrome, also known as Job's syndrome, is an immunodeficiency disease resulting from the lack of function of a single gene (gene 'X').
Hyper-IgE syndrome, also known as Job’s syndrome, is an immunodeficiency disease resulting from the lack of function of a single gene (gene ‘X’). Patients with this disease are highly susceptible to infections with extracellular bacteria and fungi, most frequently including Staphylococcus aureus infections and Candida albicans infections in the skin. Analysis of the various immune cell compartments indicates that these patients have normal numbers of each
cell lineage (i.e., CD4 and CD8 T cells, B cells, monocytes, dendritic cells, NK cells, granulocytes, etc.), and normal levels of IgG, IgA, and IgM antibodies, but higher than normal levels of IgE.
a) Given this information, name a likely component of the immune response that could be impaired in these patients.
To investigate the immune mechanism impaired in these patients, a mouse model of this gene deficiency was generated. Conditional knockout mouse lines were generated in which gene X was knocked out in either the T cells, the B cells, or the myeloid cells of the mouse. For each conditional knockout line, mice were challenged with Candida albicans, and the ability to clear the infection was assessed. In mice, infection of the oral cavity with Candida albicans has been shown to be a valid model for mucosal Candida albicans infections in humans. After infection, the response was assessed by measuring fungal burden (CFU/g tissue) on the tongue. The resulting data are shown in Figure Q6.A.
b) Based on these data, what is the most likely immune function impaired in the Gene Xdeficient patients?
Histological examination of tongue sections from Candida albicans infected mice were examined, and the numbers of infiltrating leukocytes (white blood cells) were quantified in each microscopic field of each section, and the results are shown in Figure Q6.B.
c) Do these data support or refute your hypothesis stated in response to question (b)? Why or why not?
To examine the details of T cell responses when Gene X is absent from the T cells, a series of in vitro experiments were performed. CD4 T cells were isolated from wild type mice and from T cell-deleted Gene X knockout mice, and were stimulated in vitro with a combination of anti-CD3 and anti-CD28 antibodies to activate the T cells. In addition, each culture was supplemented with one of the following cytokine conditions: (1) IFN- plus IL-12; (2) IL-4; or (3) IL-6, TGF-, IL-1 plus IL-23. After four days, the cells were examined for the expression of transcription factors by RT-PCR, as shown in Figure Q6.C. Note that Gene X does not encode T-bet, GATA3, or RORt. Instead, these data indicated impaired responses of Gene X-deficient T cells to the cytokines used in these in vitro culture experiments.
d) Based on these data, name three candidate genes that could be Gene X.
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