Blood, 1 May 2001, Vol. 97, No. 9, pp. 2533-2533
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-
) 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-12
1 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- production. Defective IL-12 receptors create a specific
vulnerability to MAC. How widespread this disease may be is yet to be determined.
Dan L. Longo
National Institutes of Health
