Absolute Lymphocyte Count
The total white blood cell counts of all great apes studied is significantly higher than in humans, and this includes the lymphocyte subset. The mechanism and significance of this difference are unknown. Human lymphocyte counts greater than 4000 lymphocytes/µL of blood are classified as lymphocytosis in humans. Levels this high are often associated with infection or malignancy in humans, but counts in the great apes often exceed this value under normal conditions (Cite). Interspecies differences may have been selected by factors like population density, environmental pathogen persistance, prevalance of injury, and sexual promiscuity (Semple 2002).
Lymphocytes are immune cells that are responsible for adaptive immunity. In contrast to innate immunity, which is encoded by the genome, lymphocytes undergo mutation after differentiation (somatic mutation) in order to maximize the ability of a host organism to recognize different pathogen antigens. Gene recombination, class switching, and somatic hypermutation are molecular tools that allow most vertebrates (jawless fish use a different system) to generate pathogen-specific probes and clonally expand immune cells that are tailored to fight a specific infection. Mammals are especially adept at this process, adapting lymphocyte populations faster than fish or other vertebrates. Current hypotheses speculate that lymphocytes acquired their impressive recombinant abilities from a bacterial transposon or retrovirus which infected a vertebrate ancestor. AID and APOBEC, which mutate nucleic acids, are thought to have originated as antiviral proteins. Lymphocytes are divided into B-cells, which are responsible for antibody production (humoral immunity) and T-cells, which are responsible for cell-mediated immunity. Lymphocytes are also responsible for immunologic memory, persisting in the host organism in a state that is ready for reactivation and expansion should a familiar pathogen infect the host again. Vaccines use pathogen antigens to trigger an immunologic response and memory in advance of exposure, protecting the host from pathogen infection (Danilova 2012).
Lymphocyte images can be accessed through the UCSD Medpics Portal: http://medpics.ucsd.edu/index.cfm?curpage=main&course=heme
Pathogen recognition by adaptive immunity requires antigen presentation by infected cells, which carry out this task using a protein called major histocompatibility complex. MHC complexes show significant sequence and structural overlap between humans, chimpanzees, and old world monkeys. In contrast, new world monkeys show significantly different genomic organization of their MHC loci and less polymorphism. Regardless, the MHC antigen system that our lymphocytes recognize appears to have existed during early primate evolution, before the branching of modern taxa (Kennedy 1997, Bontrop 2006). Lymphocyte cell surface markers are also largely conserved, with human T and B cell markers present in nonhuman primates. Antibodies raised against these markers cross-react with lymphocytes in chimpanzees, orangutans, baboons, macaques, capuchins, marmosets, and others. These animals represent species from the hominoids, old world monkeys, and new world monkeys. In addition, human colony stimulating factors are able to induce lymphocytosis (increased blood lymphocytes) in other primates. Taken together, these data indicate that the adaptive immune system existed in the common primate ancestor, and genetic differences are a product of species divergence (Clark 1983, Mayer 1987).
Within mammals, there is significant variation in the degree of immune defense. These differences can be quantified in terms of spleen size, number of circulating leukocytes, and ease of lymphocyte activation. The overall hypothesis contends that increased immune defense should correlate with increased disease risk due to the high cost of maintaining immune defenses. Studies have identified a number of factors that contribute to pathogen exposure and active immunity. These include increased body size, longer life span, group size and density, diet, and habitat diversity. The major confounding factor in these studies is that better studied species have more known pathogens, and thus appear to suffer from an increased pathogen load. Primates show significant differences, with prosimians exhibiting the lowest overall parasite species diversity, and old world monkeys showing the highest viral species diversity. A striking correlation involves promiscuity. Species with multiple mating partners appear to have higher leukocyte counts. These are thought to combat the increased risk of STD infection (Nunn 2002, Nunn 2003).
Surprisingly, humans demonstrate somewhat more active lymphocytes than chimpanzees, with stronger cytokine and activation marker responses to a variety of stimuli. In 2006, for example, attempts to develop a therapeutic using CD28 T-cell activation triggered an extreme inflammatory reaction in human test subjects. Tests in rats and monkeys using a dose 500 times greater showed no adverse effects. Differences in lymphocyte activity may explain inter-species differences between disease incidence and severity. Excessive activation of adaptive immunity may explain why HIV, hepatitis C, and autoimmune disorders are more severe in humans than other primates (Nguyen 2006, Soto 2010).
Recent work attributes increased lymphocyte activation in humans to decreased expression of inhibitory sialic acid recognizing lectins (Siglecs). Specifically, the expression of siglec 5 appears to moderate T and B cell immune responses in chimpanzees. Siglec 5 is not upregulated in humans during lymphocyte activation, leading to increased lymphocyte activity. This difference may be more important than differences in lymphocyte numbers between species.
If the pathogen challenge hypothesis is correct, our increased lymphocyte activation may also have been selected by the use of home bases, extensive population density, and social living including inter-group contacts through trade, which existed with limited sanitation during our evolution as a species. Our social structure and our ecology of scavanging from and hunting large numbers of animal species may have predisposed us to repeated, chronic exposure to group pathogens. Vigilant adaptive immunity may have been selected to address these conditions.
Understanding the difference in lymphocyte number and activity may explain why humans are particularly susceptible to certain diseases, such as those due to T-cell mediated attack. Comparative studies with adaptive immunity in other primates may highlight key mechanistic differences that ultimately lead to therapeutic immunomodulation.
Adaptive immunity appears to be shared by all vertebrates. Lymphocyte specialization, with B and T cells extends to birds, mammals, reptiles, and fish. Although they use a different recombination mechanism, the jawless fishes also feature T and B like cells. There is some speculation as to whether the jawless fish adaptive immunity is the product of a common ancestor or represents convergent evolution.
The evolution of adaptive immunity., , Adv Exp Med Biol, 2012, Volume 738, p.218-35, (2012)
Relative over-reactivity of human versus chimpanzee lymphocytes: implications for the human diseases associated with immune activation, , J Immunol, Apr 15, Volume 184, Number 8, p.4185-95, (2010)
Comparative genetics of MHC polymorphisms in different primate species: duplications and deletions., , Hum Immunol, 2006 Jun, Volume 67, Issue 6, p.388-97, (2006)
Loss of Siglec expression on T lymphocytes during human evolution, , Proc Natl Acad Sci U S A, May 16, Volume 103, Number 20, p.7765-70, (2006)
Comparative tests of parasite species richness in primates., , Am Nat, 2003 Nov, Volume 162, Issue 5, p.597-614, (2003)
A comparative study of leukocyte counts and disease risk in primates., , Evolution, 2002 Jan, Volume 56, Issue 1, p.177-90, (2002)
Immune system evolution among anthropoid primates: parasites, injuries and predators., , Proc Biol Sci, 2002 May 22, Volume 269, Issue 1495, p.1031-7, (2002)
Nonhuman primate models to evaluate vaccine safety and immunogenicity., , Vaccine, 1997 Jun, Volume 15, Issue 8, p.903-8, (1997)
Recombinant human GM-CSF induces leukocytosis and activates peripheral blood polymorphonuclear neutrophils in nonhuman primates., , Blood, 1987 Jul, Volume 70, Issue 1, p.206-13, (1987)
Evolution of epitopes on human and nonhuman primate lymphocyte cell surface antigens., , Immunogenetics, 1983, Volume 18, Issue 6, p.599-615, (1983)