Interferon-γ receptor 1 and 2 mutations

Disseminated BCG infections occur in infants with SCID or with other severe T cell defects. However, in approximately half of the cases no specific host defect has been found. One possible explanation for this predilection was found in a 2.5-month-old Tunisian female infant who had fatal idiopathic disseminated BCG infection.

and in four children from Malta who had disseminated atypical mycobacterial infection in the absence of a recognized immunodeficiency. In the case of all five children, there was consanguinity in their pedigrees. All affected were found to have a functional defect in the upregulation of TNFα production by their blood macrophages in response to stimulation with IFNγ. Furthermore, all lacked expression of IFNγR's on their blood monocytes or lymphocytes, and each was found to have a mutation in the gene on chromosome 6q22-q23 that encodes IFNγR1. Of interest, these children did not appear to be susceptible to infection with agents other than mycobacteria. Th1 responses appeared to be normal in these patients. The susceptibility of these children to mycobacterial infections thus apparently results from an intrinsic impairment of the IFNγ pathway response to these particular intracellular pathogens, showing that IFNγ is obligatory for efficient macrophage antimycobacterial activity. Since the initial discoveries of IFNγR1-deficient humans, many more examples have been found, and IFNγR2-deficient individuals have been found as well