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Rare immunodeficiency provides new insight into immune system function

Cell Press

Photo courtesy of the IRCM. From left to right, Dominique Davidson Ph.D., André Veillette M.D., and Xiaochu Shi.

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Scientists now have a better understanding of the complex events that contribute to the pathology of an inherited immunodeficiency called X-linked lymphoproliferative disease (XLP). Two separate research studies investigating this rare disorder provide critical new information about the regulation of T helper cell cytokine secretion, a process that is absolutely critical for appropriate immune responses to infectious agents. The research is published in the November issue of Immunity.

XLP is a rare, inherited immunodeficiency that is characterized by an abnormal and extreme sensitivity to the Epstein-Barr virus (EBV). XLP patients exposed to EBV have a severe and often fatal massive proliferation of abnormal T lymphocytes. Those individuals who survive the EBV infection have a significant risk of developing lymphomas. XLP is caused by mutation of a gene expressed in T cells that encodes a protein called SAP. Although the precise dysregulation of T cells that underlies XLP is unclear, research using genetically engineered mice that lack SAP demonstrated that T helper cells in these animals exhibit reduced cytokine production.

Dr. Pamela L. Schwartzberg from the National Human Genome Research Institute and colleagues used SAP-deficient T cells to investigate specific aspects of the T cell signaling cascade. Some components of the signaling cascade used by activated T cells are unperturbed in the mutant T cells whereas other aspects are impaired. Dr. Schwartzberg's group dissects specific T cell signaling molecules, such as Fyn, that are linked to reduced cytokine production in the SAP mutants. "Our data argue that a SAP/Fyn pathway may be required for the efficient recruitment of PKC-q and Bcl-10, as well as proper patterns of activation of NF-kB, and suggest a potentially novel pathway of T helper cell cytokine activation," offers Dr. Schwartzberg.

A separate study led by Dr. Andre Veillette from the Institut de recherches cliniques de Montreal (IRCM) provides solid genetic evidence that SAP directly associates with and activates FynT. The researchers show that the ability of SAP to promote cytokine secretion is attenuated in mice expressing a mutated version of SAP that lacks the proper FynT binding site. As in the Schwartzberg study, Dr. Veillette's group shows that Fyn-deficient T cells exhibit defects that are nearly identical to SAP-deficient cells. Results from these studies suggest that in normal cells, an interaction between SAP and Fyn modulates specific signaling molecules involved in regulation of T helper cell cytokine production. This pathway is disrupted in XLP patients, leading to pronounced dysregulation of T helper cell function and of the immune response in general.


Jennifer L. Cannons, Li J. Yu, Brenna Hill, Lilia A. Mijares, Derek Dombroski, Kim E. Nichols, Anthony Antonellis, Gary A. Koretzky, Kevin Gardner, and Pamela L. Schwartzberg: "SAP Regulates TH2 Differentiation and PKC-theta-Mediated Activation of NF-kappaB1"

Dominique Davidson, Xiaochu Shi, Shaohua Zhang, Hao Wang, Mona Nemer, Nobuyuki Ono, Shinji Ohno, Yusuke Yanagi, and André Veillette: "Genetic Evidence Linking SAP, the X-Linked Lymphoproliferative Gene Product, to Src-Related Kinase FynT in TH2 Cytokine Regulation"

Publishing in Immunity, Volume 21, Number 5, November 2004.

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