A hole you can drive a MAC through

The complexity of host defense mechanisms is awe inspiring. A wide range of cell types can interact and produce an enormous spectrum of products that work together to protect the organism against the hostile environment in which it lives. The network of host defense is sufficiently fine-meshed and redundant that a very small fraction of all the possible hostile invaders sneak through it under normal circumstances. Two kinds of observations assist us in understanding the role of individual components of host defense in the complex interworkings: (1) experimental work (for example, we create knockout mice in which a single component of the system is removed or damaged and the resulting phenotype carefully characterized) and (2) careful observation of human illnesses. If one can understand the pathophysiologic basis for the existence of a particular hole in the network, insights about the entire system emerge.

Sakai and colleagues (page 2688) define the error in host defense that made a young man susceptible to disseminated Mycobacterium avium complex (MAC). They found that the patient was unable to produce interferon gamma (IFN-γ) as a consequence of an inability to respond to interleukin-12 (IL-12). The IL-12 unresponsiveness was due to a mutation in the IL-12β1 gene (tryptophan substituting for arginine at position 213, or R213W in the vernacular) that resulted in the rapid proteolysis of the mutant gene product and defective IL-12 receptor expression and function. A prior report had suggested that Q214R mutation of the same gene produced an immune deficiency state, but Sakai and colleagues find this mutation existing in otherwise normal people as a polymorphism in a normally functioning receptor. Thus the redundancy in host defenses does not extend to IL-12–induced IFN-γ production. Defective IL-12 receptors create a specific vulnerability to MAC. How widespread this disease may be is yet to be determined.