Editorial: CD73 deficiency and immune dysregulation in HIV infection: cause or effect?

Extract

5′-NT grabbed the attention of immunologists long before it received a CD number in 1989 (CD73). The time was the late 1970s, shortly after mutations in the genes encoding ADA and PNP were discovered to cause severe primary immunodeficiency diseases. Although ADA and PNP are ubiquitously expressed and frequently thought of as housekeeping genes, the consequences of mutations that destroy enzyme activity are largely restricted to the immune system. Before the identification of patients with ADA and PNP deficiency, no one appreciated that normal purine metabolism was needed for immune-system development and function. Rheumatologists who investigated abnormalities in purine metabolism as a cause of gout expanded their focus to include the immune system. In 1977, Johnson et al. (reviewed in ref. [1]) reported a deficiency in 5′-NT enzyme activity in the PBMCs of patients with CVI, a type of hypogammaglobulinemia caused by a defect in the ability of B cells to make antibodies. In the following year, Edwards et al. (reviewed in ref. [1]) made a similar observation in patients with congenital XLA, in which peripheral blood B cells are absent. At the time, I was a postdoctoral fellow in the laboratory of Dr. J. Edwin Seegmiller at the University of California, San Diego, working with a new assistant professor of medicine, Dr. Gerry Boss. As 5′-NT is part of the same metabolic pathway as ADA and PNP (Fig. 1A), we were curious to know whether CVI and/or XLA might be caused by mutations in the gene encoding 5′-NT. As it eventually became clear, 5′-NT expression in lymphocytes is developmentally regulated, and patients who have blocks in early lymphocyte development have reduced 5′-NT expression as a consequence of their disease—not the cause [1]. Nevertheless, we spent several years measuring 5′-NT enzyme activity (this was long before mAb to 5′-NT were available) in the T and B cells of healthy subjects and patients with every type of immune deficiency we could find. When previously healthy gay men with Pneumocystis carinii pneumonia surfaced in Los Angeles in the early 1980s, we started measuring 5′-NT enzyme activity in men with AIDS. Much to our amazement, 5′-NT enzyme activity was low in the PBMCs of many of these subjects, much like what we had observed previously in patients with a variety of primary immunodeficiency diseases. Other groups made similar observations [2]. The finding of 5′-NT deficiency in patients with an acquired immunodeficiency suggested that assessment of 5′-NT expression might have broader clinical significance.