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Gene mutation responsible for fatal EBV complication discovered
SCIENCE AND MEDICINE
Gene mutation responsible for fatal EBV complication discovered cientists working in the USA and the UK report this week that they have identified the gene involved in X-linked lymphoproliferative (XLP; Duncan’s) disease, a rare and almost always fatal complication of EpsteinBarr virus (EBV) infection. The gene codes for a protein that seems to have a crucial role in modulating the interaction between T and B cells mediated by cell-surface proteins called signalling-lymphocyte activation molecules (SLAMs). SLAMs stud the surfaces of T and B cells, and when SLAMs come into contact and couple, both cell types are activated in a reciprocal fashion. Signalling from SLAMs also modulates the cytokine profile of activated T cells. The newly discovered protein, called SLAM-associated protein (SAP) by a group led by Cox Terhost of Harvard Medical School (Boston, MA, USA; Nature 1998; 395: 462–69) and SH2D1A by a group led by David Bentley of the Sanger Centre (Cambridge, UK; Nat Genet 1998; 20: 129–35), is expressed in
S
T cells and binds to the cytoplasmic domain of SLAMs. Mutations in SAP/SH2D1A may, therefore, affect normal immune-system signalling and could result in an inappropriate immune response. The primary target of EBV is the B cell. When the virus infects these cells it causes them to proliferate, and at the height of infection as many as 10% of peripheral B lymphocytes will be infected. In normal children the infection triggers a vigorous, but regulated T-cell response, which rapidly destroys large numbers of the infected B cells and controls the infection. In patients with XLP, however, EBV infection triggers a polyclonal expansion of B and T cells. The Tcell response seems to be unregulated and causes severe damage to the liver, bone marrow, and other tissues, but is unable to control the B-cell proliferation. Elliot Kieff (Boston, MA, USA) who, with Michel Sadelain (New York, NY, USA), wrote a commentary on the paper by Bentley et al,
Gene mutation linked to smoke exposure in utero the mutational spectra in samples pidemiological data have indifrom exposed and non-exposed newcated that passive exposure of born babies. This mainly involved an pregnant mothers to tobacco smoke increase in illegitimate genomic raises cancer risk in their children but HPRT deletions mediated by V(D)J hard evidence of a biological link has recombinase, the kind of event that been lacking. Now, US researchers has been associated with haematologreport that passive maternal ical malignancies in children. smoking changes the type of mutaIn an accompanying editorial, tions seen in the reporter gene Gabriella Sozzi and hypoxanthine-guanine Marco Pierotti (Milan, phosphoribosyltransItaly) comment that ferase (HPRT), an this study is a “first” observation that in showing “smokingstrengthens the link induced genetic dambetween passive smokage in utero” while ing and cancer develhighlighting the greater opment in newborn risk from environmenbabies. tal toxins among the The researchers young due to their compared the muta“physiological immatutional distribution in rity”. However, given HPRT in cord blood the small study size, T-lymphocyte samples Sozzi and Pierotti say from 12 infants whose Exposed to danger early that more studies are mothers were passively needed on the effects of smokeexposed to tobacco smoke and from related mutagens on newborn babies 12 non-exposed infants (Nat Med 4: and children. These should include, 1144–51). for example, an investigation of the What is significant, explains role of active as well as passive smoke lead researcher Barry Finette of the exposure. Department of Pediatrics, University of Vermont (Burlington, VT, USA), is that there were differences between Angela Pirisi Sally and Richard Greenhill
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THE LANCET • Vol 352 • October 3, 1998
says it is not clear exactly why mutations in SAP/SH2D1A cause this immune dysregulation (Nat Genet 1998; 20: 103–04). Children who develop XLP seem normal before they become infected with EBV, generating healthy immune responses to bacterial and viral infections, including infections by herpes viruses, explains Kieff. “EBV is somehow doing something that is really different from anything else”, he adds. EBV infection may be unique, he suggests, because it generates such large numbers of activated antigen-presenting cells, including the EBV-infected B cells. In this situation, SAP/SH2D1A might serve as a “brake” to prevent overactivation of T-cell response, says Kieff. But in patients with defective SAP/SH2D1A genes, this massive antigenic stimulation may be too much, overwhelming the impaired immune regulatory mechanisms and creating the uncontrolled cytotoxic-T-cell response seen in XLP. Michael McCarthy
News in brief Ecstasy side-effects Ecstasy may be bad for the teeth, say researchers from Manchester University Dental Hospital, UK. A combination of changes in jaw muscle activity caused by ecstasy and consumption of soft fizzy drinks to counteract dehydration may have contributed to dental erosion in a 17-year-old man with otherwise good teeth (Br Dent J 1998; 185: 266). Falls in nursing homes A study of US nursing-home residents indicates that new users of antidepressants fall more than non-users, and that the increased fall rate persists during drug therapy. But there was little difference in fall rate between residents taking tricyclic antidepressants and those taking selective serotonin-reuptake inhibitors (N Engl J Med 1998; 339: 875–82). Diabetes vaccine? Non-obese diabetic mice fed transgenic potatoes expressing an insulin–cholera toxin B subunit fusion protein develop type 1 diabetes later than control mice (Nat Biotech 1998; 16: 934–38).
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Gene mutation responsible for fatal EBV complication discovered cientists working in the USA and the UK report this week that they have identified the gene involved in X-linked lymphoproliferative (XLP; Duncan’s) disease, a rare and almost always fatal complication of EpsteinBarr virus (EBV) infection. The gene codes for a protein that seems to have a crucial role in modulating the interaction between T and B cells mediated by cell-surface proteins called signalling-lymphocyte activation molecules (SLAMs). SLAMs stud the surfaces of T and B cells, and when SLAMs come into contact and couple, both cell types are activated in a reciprocal fashion. Signalling from SLAMs also modulates the cytokine profile of activated T cells. The newly discovered protein, called SLAM-associated protein (SAP) by a group led by Cox Terhost of Harvard Medical School (Boston, MA, USA; Nature 1998; 395: 462–69) and SH2D1A by a group led by David Bentley of the Sanger Centre (Cambridge, UK; Nat Genet 1998; 20: 129–35), is expressed in
S
T cells and binds to the cytoplasmic domain of SLAMs. Mutations in SAP/SH2D1A may, therefore, affect normal immune-system signalling and could result in an inappropriate immune response. The primary target of EBV is the B cell. When the virus infects these cells it causes them to proliferate, and at the height of infection as many as 10% of peripheral B lymphocytes will be infected. In normal children the infection triggers a vigorous, but regulated T-cell response, which rapidly destroys large numbers of the infected B cells and controls the infection. In patients with XLP, however, EBV infection triggers a polyclonal expansion of B and T cells. The Tcell response seems to be unregulated and causes severe damage to the liver, bone marrow, and other tissues, but is unable to control the B-cell proliferation. Elliot Kieff (Boston, MA, USA) who, with Michel Sadelain (New York, NY, USA), wrote a commentary on the paper by Bentley et al,
Gene mutation linked to smoke exposure in utero the mutational spectra in samples pidemiological data have indifrom exposed and non-exposed newcated that passive exposure of born babies. This mainly involved an pregnant mothers to tobacco smoke increase in illegitimate genomic raises cancer risk in their children but HPRT deletions mediated by V(D)J hard evidence of a biological link has recombinase, the kind of event that been lacking. Now, US researchers has been associated with haematologreport that passive maternal ical malignancies in children. smoking changes the type of mutaIn an accompanying editorial, tions seen in the reporter gene Gabriella Sozzi and hypoxanthine-guanine Marco Pierotti (Milan, phosphoribosyltransItaly) comment that ferase (HPRT), an this study is a “first” observation that in showing “smokingstrengthens the link induced genetic dambetween passive smokage in utero” while ing and cancer develhighlighting the greater opment in newborn risk from environmenbabies. tal toxins among the The researchers young due to their compared the muta“physiological immatutional distribution in rity”. However, given HPRT in cord blood the small study size, T-lymphocyte samples Sozzi and Pierotti say from 12 infants whose Exposed to danger early that more studies are mothers were passively needed on the effects of smokeexposed to tobacco smoke and from related mutagens on newborn babies 12 non-exposed infants (Nat Med 4: and children. These should include, 1144–51). for example, an investigation of the What is significant, explains role of active as well as passive smoke lead researcher Barry Finette of the exposure. Department of Pediatrics, University of Vermont (Burlington, VT, USA), is that there were differences between Angela Pirisi Sally and Richard Greenhill
E
THE LANCET • Vol 352 • October 3, 1998
says it is not clear exactly why mutations in SAP/SH2D1A cause this immune dysregulation (Nat Genet 1998; 20: 103–04). Children who develop XLP seem normal before they become infected with EBV, generating healthy immune responses to bacterial and viral infections, including infections by herpes viruses, explains Kieff. “EBV is somehow doing something that is really different from anything else”, he adds. EBV infection may be unique, he suggests, because it generates such large numbers of activated antigen-presenting cells, including the EBV-infected B cells. In this situation, SAP/SH2D1A might serve as a “brake” to prevent overactivation of T-cell response, says Kieff. But in patients with defective SAP/SH2D1A genes, this massive antigenic stimulation may be too much, overwhelming the impaired immune regulatory mechanisms and creating the uncontrolled cytotoxic-T-cell response seen in XLP. Michael McCarthy
News in brief Ecstasy side-effects Ecstasy may be bad for the teeth, say researchers from Manchester University Dental Hospital, UK. A combination of changes in jaw muscle activity caused by ecstasy and consumption of soft fizzy drinks to counteract dehydration may have contributed to dental erosion in a 17-year-old man with otherwise good teeth (Br Dent J 1998; 185: 266). Falls in nursing homes A study of US nursing-home residents indicates that new users of antidepressants fall more than non-users, and that the increased fall rate persists during drug therapy. But there was little difference in fall rate between residents taking tricyclic antidepressants and those taking selective serotonin-reuptake inhibitors (N Engl J Med 1998; 339: 875–82). Diabetes vaccine? Non-obese diabetic mice fed transgenic potatoes expressing an insulin–cholera toxin B subunit fusion protein develop type 1 diabetes later than control mice (Nat Biotech 1998; 16: 934–38).
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