Press releases
Please quote Nature Immunology as the source of these items.
The December 2007 issue of Nature Immunology is available online.
December 2007
New AIDS risk factor
More rapid HIV disease progression occurs in individuals who have a specific genetic risk factor, according to a new study published online this week in Nature Immunology.
A team of HIV researchers led by Sunil Ahuja studied a risk factor that significantly predicts HIV disease outcome. Individuals who have certain combinations of the two genes CCR5 and CCL3L1 are much more likely to have reduced immune responses and greater decline in numbers of CD4+ T immune cells, two hallmarks of progressive HIV disease.
The significance of the findings is two-fold. Previous work indicated that the influence of the two genes was much more limited than the new data indicate. These findings suggest a means to more effectively predict the course of HIV disease.
CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms
Matthew J Dolan, Hemant Kulkarni, Jose F Camargo, Weijing He, Alison Smith, Juan-Manuel Anaya, Toshiyuki Miura, Frederick M Hecht, Manju Mamtani, Florencia Pereyra, Vincent Marconi, Andrea Mangano, Luisa Sen, Rosa Bologna, Robert A Clark, Stephanie A Anderson, Judith Delmar, Robert J O'Connell, Andrew Lloyd, Jeffrey Martin, Seema S Ahuja, Brian K Agan, Bruce D Walker, Steven G Deeks & Sunil K Ahuja
Published online: 21 October 2007 | doi 10.1038/ni1521
Responding to sepsis
How quickly key receptors are activated on blood vessel cells can determine whether one survives or succumbs to sepsis, suggests a report online in this week's Nature Immunology.
Sepsis, a potentially life-threatening immune response to blood-borne infections, leads to loss of blood vessel function, resulting in shock and multiorgan failure. Athan Kuliopulos and colleagues looked to see if inhibition or activation of a receptor called PAR1 could limit the severity of sepsis. Mice injected with bacteria directly into the bloodstream developed sepsis and died; however, these mice were protected if given a PAR1 inhibitor within 4 hours.
The surprise came if PAR1 was inhibited at later times, as this failed to protect these mice; rather, activation of PAR1 at these later times 'protected' mice from toxic shock. The authors show this 'late' activation of PAR1 induces another PAR receptor to become activated. This establishes a protective effect by instructing cells lining the blood vessel to maintain tight junctions and averting the widespread edema and intravascular blood clotting that accompanies shock.
These findings might lead to successful therapies for patients with sepsis and other systemic inflammatory responses.
'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage
Nicole C Kaneider, Andrew J Leger, Anika Agarwal, Nga Nguyen, George Perides, Claudia Derian, Lidija Covic & Athan Kuliopulos
Published online: 28 October 2007 | doi 10.1038/ni1525
Genes for transplants
A gene that allows mice to accept human bone marrow cells more efficiently is presented online in Nature Immunology this week. The gene, called Sirpa, limits graft failure of transplanted blood stem cells and was found by studying different strains of immunodeficient mice that varied in their ability to accept human blood stem cell transplants.
Such mice serve as valuable tools to study human blood cell deficiencies or diseases. That closely related inbred mouse strains showed differences in engraftment frequencies quickly narrowed the search for the gene. The mouse Sirpa genes are polymorphic, meaning that stable inherited differences are found in these genes that can alter their function.
The protein encoded by Sirpa, SIRP-alpha, interacts with another protein called CD47 expressed on the surface of the human blood cells. This interaction is thought to prevent a class of immune scavenging cells called phagocytes from attacking and eating cells that lack CD47 or have CD47 molecules that cannot be recognized by SIRP-alpha. This latter possibility is why some mouse strains rejected their human blood transplant while other strains did not.
These differences, however, are not restricted to mice. Humans likewise display polymorphisms in the human SIRPA gene. The authors speculate such differences might explain why some bone marrow transplants are rejected despite being 'tissue matched' by other criteria for donor-recipient compatibility. If correct, SIRPA can be added to this list of markers used to screen for suitable donors to make bone marrow transplant safer and more successful.
Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells
Katsuto Takenaka, Tatiana K Prasolava, Jean C Y Wang, Steven M Mortin-Toth, Sam Khalouei, Olga I Gan, John E Dick & Jayne S Danska
Published online: 4 November 2007 | doi 10.1038/ni1527
Regulating immune suppression
A quartet of papers in the December issue of Nature Immunology show how white blood cells can produce interleukin 10, a chemical mediator that helps keep the immune response in check. This response is vital in fighting autoimmune conditions such as colitis, multiple sclerosis and arthritis.
Four separate groups led by Christopher Hunter, Daniel Cua, Abdolmohamad Rostami and Mohamed Oukka showed a certain type of lymphocyte can be stimulated by specific immune messenger molecules to produce the immune suppressive factor interleukin 10. The messenger molecules included either interleukin 27 or a combination of interleukin 6 and another type of messenger molecule called tumor growth factor beta. These results suggest that modulating these messenger molecules could increase interleukin 10 concentrations and temper overactive immune responses.
Many autoimmune conditions are exacerbated when immune suppressing factors such as interleukin 10 are lacking. The work described in the current four papers may provide directed means to intervene in these and other severe autoimmune diseases.
Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10
Jason S Stumhofer, Jonathan S Silver, Arian Laurence, Paige M Porrett, Tajie H Harris, Laurence A Turka, Matthias Ernst, Christiaan J M Saris, John J O'Shea & Christopher A Hunter
Published online: 11 November 2007 | doi 10.1038/ni1537
TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology
Mandy J McGeachy, Kristian S Bak-Jensen, Yi Chen, Cristina M Tato, Wendy Blumenschein, Terrill McClanahan & Daniel J Cua
Published online: 11 November 2007 | doi 10.1038/ni1539
Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27–stimulated T cells
Denise C Fitzgerald, Guang-Xian Zhang, Mohamed El-Behi, Zoë Fonseca-Kelly, Hongmei Li, Shuo Yu, Christiaan J Saris, Bruno Gran, Bogoljub Ciric & Abdolmohamad Rostami
Published online: 11 November 2007 | doi 10.1038/ni1540
A dominant function for interleukin 27 in generating interleukin 10–producing anti-inflammatory T cells
Amit Awasthi, Yijun Carrier, Jean P S Peron, Estelle Bettelli, Masahito Kamanaka, Richard A Flavell, Vijay K Kuchroo, Mohamed Oukka & Howard L Weiner
Published online: 11 November 2007 | doi 10.1038/ni1541
