In the Light of Evolution Volume IV: The Human Condition (2010) / Chapter Skim
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6 Uniquely Human Evolution of Sialic Acid Genetics and Biology--Ajit Varki
6 Uniquely Human Evolution of Sialic Acid Genetics and Biology--Ajit Varki
Pages 105-126
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From page 105... ...
; expres sion pattern changes (in siglecs -1, -5, -6, and -11) ; gene conversion (SIGLEC11)
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From page 106... ...
here i focus on one aspect of cellular glycan coating that changed during human evolution, potentially explaining aspects of human uniqueness, in health and in disease. 1The term "great ape" refers to chimpanzees, bonobos, gorillas, and orangutans, and the term "hominoid" also includes lesser apes.
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From page 107... ...
. indeed, humans make antibody responses against neu5Gc during "serum sickness reactions" induced by animal serum infusion, characterized by antibodies agglutinating animal red blood cells bearing neu5Gc (higashi et al., 1977; Merrick et
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From page 108... ...
. A SIA DIFFERENCE BETWEEN HUMANS AND NHHS Besides neu5Gc, the other major sia on most mammalian cell types is N-acetylneuraminic acid (neu5Ac)
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From page 109... ...
. A bigger difference lies in the finding that although avian influenza viruses preferentially recognize sias α2–3-linked to the underlying sugar chain, human viruses prefer the α2–6-linked variety (Daniels et al., 1984)
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From page 110... ...
. This supposition fits with the function of CD33rsiglecs to recognize sias as "self" and send dampening signals to immune cells via cytosolic tail iTiMs (varki and Angata, 2006; Crocker et al., 2007; Carlin et al., 2009b)
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From page 111... ...
. eventually, immune cells would have down-regulated inhibitory siglecs to escape the neu5Ac-expressing pathogens while also up-regulating activatory siglecs to respond to them (step 8)
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From page 112... ...
. MANY HUMAN PATHOGENS EXPRESS Neu5Ac, POTENTIALLY ENGAGING CD33rSIGLECS AND ATTENUATING INNATE IMMUNE RESPONSES The switch of human siglecs toward binding neu5Ac (presumably selected to restore proper "self" recognition)
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From page 113... ...
which filter blood or lymph-borne pathogens. in keeping with the human propensity for invasion by neu5Ac-expressing pathogens, sn is up-regulated in the human spleen compared with the chimpanzee (Brinkman-van der linden et al., 2000)
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From page 114... ...
. however, it also shows human-specific placental expression, not in immune cells but in the trophoblast (Brinkman-van der linden et al., 2007)
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From page 115... ...
. CD33rSIGLECS ARE EXPRESSED AT LOW LEVELS ON HUMAN T CELLS ASSOCIATED WITH OVERREACTIVE RESPONSES TO ACTIVATION Although CD33rsiglecs are found on most human immune cells, essentially no expression was found on CD4+ T cells, and only low expression of siglec-7 and -9 was found on CD8+ T cells (ikehara et al., 2004; varki and Angata, 2006; Crocker et al., 2007)
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From page 116... ...
(Parham, 2005) , the most likely explanation is that activatory siglecs were originally selected to respond against sia-expressing pathogens that were using inhibitory siglecs to suppress immune responses (Fig.
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From page 117... ...
Metabolic incorporation of dietary neu5Gc (Gc) from mammalian foods in the face of circulating anti-neu5Gc antibodies may contribute to chronic inflammation in endothelia lining blood vessels and in epithelia lining hollow organs, perhaps contributing to the increased risks of cardiovascular disease and carcinomas associated with these foods.
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From page 118... ...
indeed, cultured human cells express neu5Gc because of uptake and metabolic incorporation from animal products in the medium (e.g., FCs) (Tangvoranuntakul et al., 2003; Bardor et al., 2005)
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From page 119... ...
. We mimicked the human situation using neu5Gcnull mice bearing a syngeneic mouse tumor line that expresses low lev els of neu5Gc, similar to human tumors.
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From page 120... ...
, which can cause sudden death by altering heart rhythm or slower death by progressive cardiac failure. "heart disease" in humans is different, caused by deposition of cholesterol in atherosclerotic plaques in the walls of large blood vessels, including coronary arteries (Pham et al., 2009; varki et al., 2009)
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From page 121... ...
it should be noted that most diseases associated with red meat and/or milk consumption would not have affected natural selection in times past, because they are manifest primarily after the age of peak reproductive fitness. We now live much longer and have much greater access to red meat and milk, thus transforming these once beneficial foods into likely culprits for exacerbating diseases of older humans (Finch and stanford, 2004)
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From page 122... ...
Siglecs in Bacterial Pathogenesis Details of how neu5Ac-expressing pathogens suppress immune responses via inhibitory siglecs (Carlin et al., 2009b) are as yet unknown.
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From page 123... ...
Mechanisms of Anti-Neu5Gc Antibody Induction We are studying the tempo and mode of appearance of these highly variable antibodies in human samples and the potential mechanisms for their induction, using Cmah-null mice as a model. We also need to address whether neu5Gc-containing glycans are truly T-cell-independent antigens, whether the antibody response involves a germline v-set domain, and if the antibody-binding pockets undergo affinity maturation.
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From page 124... ...
Discussed here are some specific ways in which these changes would have impacted the immune system and human pathogen regimes. Although this discussion focuses on current human diseases, it also suggests a role for infectious diseases during human evolution.
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From page 125... ...
All these approaches must be combined in a transdisciplinary manner if we are eventually to explain human origins and human uniqueness. ACKNOWLEDGMENTS i gratefully acknowledge helpful comments from Miriam Cohen, sandra Diaz, Jeff esko, Pascal Gagneux, Chris Gregg, and nissi varki and Dr.
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