DSHP: a "power bar" for sustained immune responses?

Abstract

Primary human immunodeficiencies comprise a broad group of disorders ranging from severely impaired lymphocyte development to more subtle functional abnormalities (reviewed in ref. 1). The recent identification of the genetic basis of several of these diseases has enriched our understanding of the molecular events controlling the development and function of the immune system. These gene products fall into four major categories: enzymes regulating DNA recombination and nucleotide metabolism, cell cycle regulators, proteins involved in antigen presentation, and components of B and T cell signal transduction pathways (1). Nichols et al. (2) describe the most recent addition to the latter group in this issue of the Proceedings. DHSP encodes a single SH2 domain and is mutated in patients with X-linked lymphoproliferative syndrome (XLP). DHSP represents a new paradigm in signal transduction defects associated with immunodeficiencies. All signaling molecules previously shown to be involved in these diseases, including γc, JAK-3, and ZAP70 in severe combined immunodeficiency and Btk in X-linked agammaglobulinemia, are “hard wired” components essential for signal transmission (1). In contrast, DSHP is up-regulated late in the immune response and likely modulates signal duration or amplitude.