| The CD33-Related Siglecs (CD33rSiglecs), a recently discovered Ig Superfamily protein that binds sialic acids, are expressed primarily on cells of the human innate immune system and seem to be rapidly evolving due to host-pathogen driven selective pressures described as the Red Queen Effect. The function of the CD33rSiglecs is poorly understood, though indirect evidence indicates that when bound to their sialic acid ligands they may be capable of down-regulating certain activation signals. Comparative studies with other hominids (here referred to as the great apes) will provide evidence as to the ancestral state of expression, sialic acid binding patterns, and should illuminate the function of CD33rSiglecs.; This dissertation explores the expression pattern of CD33rSiglecs in the great apes using flow cytometry and antibodies against the CD33rSiglecs (chapter 2). The results are compared to known human CD33rSiglec expression in humans. Next, the sialic acid binding preferences are identified for human, chimpanzee, and orangutan CD33rSiglecs (Chapter 3). ELISAs using synthetic and naturally derived sialic acid probes identify ligand recognition, binding strength and preference that is different for each species examined, i.e. rapid evolution is occurring. A modified form of the classic hemagglutination assay provides further evidence for species-specific sialome preference of the CD33rSiglecs.; Finally, differential expression of Siglec-5 and Siglec-6 was examined in humans and chimpanzees. Chimpanzee T cells express high levels of Siglec-5 while human T cells do not. The T cell response to various forms of stimulation in the presence or absence of Siglec-5 was investigated in humans and chimpanzees (chapter 4). Another human-specific expression pattern is up-regulation of Siglec-6 expression on human placenta, whereas it is not expressed in that of the great apes (Chapter 5). Siglec-6 expression correlates well with the progress of labor, which in humans is uniquely prolonged among the hominids. While the human-specific loss of Siglec-5 on T cells seems to contribute to their hyper-reactivity, the up-regulation of placental Siglec-6 may control the tempo of human parturition. Thus, CD33rSigles are rapidly evolving in hominids and human-specific features can explain aspects of the human condition. |
