It has been noted that chimpanzees are less susceptible to diseases associated with immune activation, including HIV and hepatitis C. Immune deficiency from HIV was not seen in experimentally infected chimpanzees until an animal was infected with three different HIV isolates, and only recently has evidence emerged that the natural infection with SIVcpz can cause CD4 T cell loss, illness and mortality in chimpanzees monitored in the wild. Four years ago, a research group led by Ajit Varki published evidence that chimpanzee T cells react less exuberantly to activation signals compared to human T cells, and showed that this blunted response was associated with expression of an inhibitory molecule called Siglec-5. However, another group of researchers subsequently challenged these findings, arguing that they were explained by the specific type of antibody used to stimulate T cells from the two species (I wrote a little about this paper on the blog, quite credulously). In a recent issue of the Journal of Immunology, Ajit Varki and colleagues respond to this challenge and provide a convincing suite of additional data supporting their original hypothesis.
The new paper addresses the critique by employing a wide range of different stimulatory agents and showing that chimpanzee T cells consistently respond less vigorously compared to humans. The same pattern is also shown for B cells. The researchers present evidence that this lower reactivity is associated with upregulation of Siglec-5 on chimpanzee T cells and B cells after activation, which does not occur in humans. One implication of the findings is that enhancement of Siglec-5 expression on human lymphocytes might be pursued as an approach to treating diseases associated with over-active immune responses. Another point raised by the authors is that chimpanzees (and possibly also other animals) may be poor choices for evaluating the safety of immune-based therapies under consideration for trials in humans; one possible example of the problem is the anti-CD28 antibody called TGN1412, which appeared safe in non-human primate studies but caused massive T cell activation and life-threatening cytokine storms in a phase I trial in the UK.
Published online March 15, 2010
The Journal of Immunology, 2010, 184, 4185 -4195
doi:10.4049/jimmunol.0903420
Paula C. Soto,1 Lance L. Stein,1 Nancy Hurtado-Ziola, Stephen M. Hedrick, and Ajit Varki
Department of Medicine, Department of Cellular and Molecular Medicine, Division of Biological Sciences, and Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093
Although humans and chimpanzees share >99% identity in alignable protein sequences, they differ surprisingly in the incidence and severity of some common diseases. In general, humans infected with various viruses, such as HIV and hepatitis C virus, appear to develop stronger reactions and long-term complications. Humans also appear to suffer more from other diseases associated with over-reactivity of the adaptive immune system, such as asthma, psoriasis, and rheumatoid arthritis. In this study, we show that human T cells are more reactive than chimpanzee T cells to a wide variety of stimuli, including anti-TCR Abs of multiple isotypes, L-phytohemagglutin, Staphylococcus aureus superantigen, a superagonist anti-CD28 Ab, and in MLRs. We also extend this observation to B cells, again showing a human propensity to react more strongly to stimuli. Finally, we show a relative increase in activation markers and cytokine production in human lymphocytes in response to uridine-rich (viral-like) ssRNA. Thus, humans manifest a generalized lymphocyte over-reactivity relative to chimpanzees, a finding that is correlated with decreased levels of inhibitory sialic acid-recognizing Ig-superfamily lectins (Siglecs; particularly Siglec-5) on human T and B cells. Furthermore, Siglec-5 levels are upregulated by activation in chimpanzee but not human lymphocytes, and human T cell reactivity can be downmodulated by forced expression of Siglec-5. Thus, a key difference in the immune reactivity of chimp and human lymphocytes appears to be related to the differential expression of Siglec-5. Taken together, these data may help explain human propensities for diseases associated with excessive activation of the adaptive immune system.
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