The Inclusive Behavioral Immune System.

Although living in social groups offers many advantages, it comes at a cost of increased transmissible disease. The behavioral immune system (BIS) is thought to have evolved as a first line of defense against such infections. It acts by minimizing the contact of yet uninfected hosts with potential pathogens. The BIS has been observed in a wide range of animals including insects, amphibians and mammals, but most research has focused on humans where the BIS is guided by complex cognitive and emotional processing. When researchers discuss the evolutionary origin of the BIS, they assess how it raises individual fitness. What would happen though if we shift our attention to the evolutionary unit of selection - the gene? Success would be measured as the change in the gene's prevalence in the entire population, and additional behaviors would come to our attention - those that benefit relatives, i.e., behaviors that raise inclusive fitness. One widely-recognized example of the inclusive BIS is social immunity, which is prevalent among eusocial organisms such as bees and ants. Their colonies engage in a collaborative protective behavior such as grooming and the removal of infected members from the nest. Another example may be sickness behavior, which includes the behavioral, cognitive and emotional symptoms that accompany infection, such as fatigue, and loss of appetite and social interest. My colleague and I recently suggested that sickness behavior has evolved because it reduces the direct and indirect contact between an infected host and its healthy kin - improving inclusive fitness. These additional behaviors are not carried out by the healthy individuals, but rather by whole communities in the first case, and by already infected individuals in the second. Since they step beyond the classical definition of BIS, it may be useful to broaden the term to the inclusive behavioral immune system.

Why Do We Feel Sick When Infected--Can Altruism Play a Role?

When we contract an infection, we typically feel sick and behave accordingly. Symptoms of sickness behavior (SB) include anorexia, hypersomnia, depression, and reduced social interactions. SB affects species spanning from arthropods to vertebrates, is triggered nonspecifically by viruses, bacteria, and parasites, and is orchestrated by a complex network of cytokines and neuroendocrine pathways; clearly, it has been naturally selected. Nonetheless, SB seems evolutionarily costly: it promotes starvation and predation and reduces reproductive opportunities. How could SB persist? Former explanations focused on individual fitness, invoking improved resistance to pathogens. Could prevention of disease transmission, propagating in populations through kin selection, also contribute to SB?

Heightened risk of breast cancer following pregnancy: could lasting systemic immune alterations contribute?

The protective effect of having a first full-term pregnancy (FFTP) at a younger age on women's lifetime risk of breast cancer is well known. Less appreciated is the increased risk seen in the years immediately following pregnancy. This adverse effect is more pronounced and more prolonged in women with later age at FFTP. The mechanisms responsible for this increased risk are still poorly understood. In the present paper, we put forward the hypothesis that the marked peripheral immune changes induced by pregnancy may account for these effects. We highlight immune changes that characterize the unique immune state of pregnancy (a combination of cellular immunosuppression and enhanced inflammatory response), note the resemblance of these changes to cancer escape mechanisms, and discuss why such immune changes may be critical for the development of breast cancer following pregnancy. We further support this idea by initial findings from our own laboratory that the age at FFTP is negatively related to natural killer cell cytotoxicity many years later and propose possible models for the kinetics of the immune changes during and following pregnancy. The effect of age at FFTP on the immune function is currently understudied. Its potential relevance to the development of breast cancer stresses the need for further research.

Sleep, fatigue, and NK cell activity in healthy volunteers: significant relationships revealed by within subject analyses.

Poor sleep is thought to compromise health partially through its effect on immune function. Although experimental studies have shown that sleep deprivation reduces natural killer cell activity (NKCA) within individuals, cross-sectional studies of individuals in ordinary life have often failed to find such a relationship. The current study compared cross-sectional and longitudinal approaches to explore the association between sleep and NKCA. The relationship between NKCA and fatigue was also studied since individuals who are highly fatigued due to various clinical conditions often exhibit reduced NKCA. In the present study, fatigue and amount of sleep were assessed by self-report, and NKCA was assessed in peripheral blood samples collected from each of 45 healthy women at two time points approximately one month apart. Using cross-sectional analysis for each of the two sessions, sleep was related to NKCA only in the second session. Fatigue was not related to NKCA at either session. A within-subject design, however, revealed that an increase in the amount of sleep and decrease in levels of fatigue were related to an increase in NKCA. The current findings suggest that NKCA varies with amount of sleep or fatigue within an individual, and that this relationship may often be masked by large interpersonal differences in cross-sectional studies.

High NK cell activity in recurrent miscarriage: what are we really measuring?

BACKGROUND: Several studies have shown that women with unexplained recurrent miscarriage (RM) have increased numbers and activity of peripheral blood NK cells and that elevated levels of these cells predict subsequent miscarriages in women with RM. Because catecholamines rapidly mobilize NK cells into the circulation, such increases may not reflect a steady state of overactive immunity but may result from a transient increase in the number of NK cells because of the stress associated with blood withdrawal. METHODS: Blood was drawn from 22 controls and 38 RM patients immediately after vein cannulation, and again 20 min later. The percentage of NK cells within lymphocytes, their concentration per microlitre of blood and their activity were assessed. RESULTS: All three indices of NK cells did not change in the controls across the two samples. However, women with RM had elevated levels in all three NK indices in the first blood sample, but these levels declined to values similar to those seen in the controls. This decline was mainly observed in primary aborters whose NK activity was highest in the first blood withdrawal. Accordingly, there was a high correlation between the magnitude of the decline and the initial NK cell indices in women with RM. The change in activity highly correlated with the change in the concentration of NK cells. CONCLUSION: The increased NK number and activity previously observed in RM patients may result from a transient stress response at the time of blood withdrawal. Patients with primary RM may be characterized by exaggerated acute stress responses in other circumstances.

Poly I-C induces early embryo loss in f344 rats: a potential role for NK cells.

PROBLEM: Natural killer (NK) cells were associated with first trimester embryo loss. The current study in the inbred F344 rat assessed the role of NK cells in mediating resorptions caused by poly I-C, a non-specific immunostimulator. METHOD OF STUDY: On fifth day of gestation, rats were injected intraperitoneally with anti-NKR-P1 (1.5 mg/kg, i.p.) to deplete NK cells, and with mouse serum or saline to control for non-specific effects. Poly I-C (4 mg/kg, i.p.) or vehicle were administered 2 days later. Resorptions were assessed on day 13.5. RESULTS: Poly I-C significantly elevated resorption rates, and anti-NKR-P1 abolished this effect. Body weight was reduced in all rats treated with poly I-C, including NK-depleted rats. This indicates the ability of NK-depleted rats to respond to poly I-C, yet to refrain from the resorption-promoting effects of poly I-C. CONCLUSIONS: This study suggests a role for NK cells in mediating poly I-C-induced resorptions.

Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor.

Surgery is imperative for cancer treatment, but was suggested to suppress immunity and facilitate metastasis. Here we study the involvement of catecholamines and prostaglandins (PG) in such outcomes, and the role played by marginating-pulmonary (MP)-NK cells in controlling MADB106 metastasis. Non-operated and laparotomized F344 rats were injected postoperatively with a PG synthesis inhibitor (indomethacin, 4 mg/kg i.p.), a beta-blocker (nadolol, 0.6 mg/kg s.c.), both drugs, or vehicle. Rats were then inoculated intravenously with non-immunogenic syngeneic MADB106 cells, and 24 h later lung tumor retention was assessed, or 3 weeks later lung metastases were counted. Additionally, 12 h after surgery we harvested MP-NK cells and circulating-NK cells and compared their numbers and cytotoxicity against MADB106 cells and standard YAC-1 target cells. Surgery significantly increased MADB106 metastasis. Nadolol and indomethacin reduced this effect by approximately 50% when used alone, and significantly more (75%) when used together. Only MP-leukocytes exhibited NK cytotoxicity against MADB106 cells. Surgery markedly suppressed it, and nadolol and indomethacin additively restored it. Similar effects were observed assessing MP-NK and circulating-NK cytotoxicity against YAC-1 target cells. Alterations in the numbers of NK cells were partly associated with alterations in total MP-NK activity, but not with circulating-NK activity. Last, administrating nai ve rats with physiologically relevant doses of a beta-adrenergic agonist (metaproterenol), and/or with PGE2, additively and independently of each other promoted MADB106 metastasis, simulating the effects of surgery. These findings point at potential prophylactic measures in cancer patients undergoing surgery, and suggest a role for MP-NK cells in resisting metastasis of apparently insensitive tumors.

Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures.

UNLABELLED: Postoperative immunosuppression is partly ascribed to anesthesia and has been suggested to compromise patients' resistance to infection and tumor metastasis. We compared the effects of various anesthetics on natural killer (NK) cell activity and on resistance to experimental metastasis, and studied mediating mechanisms and prophylactic measures. Fischer 344 rats served as controls or were anesthetized for 1 h with ketamine, thiopental, halothane, or propofol. Anesthetized rats were either maintained in normothermia or left to spontaneously reach 33 degrees C-35 degrees C. Rats were then injected IV with MADB106 tumor cells, and 24 h later lung tumor retention was assessed, or 3 wk later, lung metastases were counted. Additionally, the number and activity of circulating NK cells were assessed after anesthesia. All anesthetics, except propofol, significantly reduced NK activity and increased MADB106 lung tumor retention or lung metastases. Hypothermia had no significant effects. Ketamine increased metastasis most potently, and this effect was markedly reduced in rats pretreated with a beta-adrenergic antagonist (nadolol) or with chronic small doses of an immunostimulator (polyriboinosinic:polyribocytidylic acid). Overall, the marked variation in the NK-suppressive effects of anesthetics seems to underlie their differential promotion of MADB106 metastasis. Prophylactic measures may include perioperative immunostimulation and the use of beta-blockers. IMPLICATIONS: This study in a rat model of pulmonary metastasis demonstrates that some anesthetics, but not others, increase susceptibility to tumor metastasis, apparently by suppressing natural killer cell activity. Ketamine was most deleterious, and its effects were prevented by peripheral blockade of beta-adrenoceptors combined with low levels of immunostimulation.

Differences in number and activity of peripheral natural killer cells in primary versus secondary recurrent miscarriage.

OBJECTIVE: To compare peripheral natural-killer (NK) cell numbers and activity in women with primary recurrent miscarriage, secondary recurrent miscarriage and controls. DESIGN: Observational study. Academic medical center. PATIENT(S): Thirty-eight women with primary recurrent miscarriage, 29 women with secondary recurrent miscarriage, and 25 control women. INTERVENTION(S): None.[1] The proportion of NK cells in the total lymphocyte population, [2] the concentration of NK cells per microliter of blood, and [3] NK activity (NKA), using both standard and whole-blood assays. RESULT(S): Primary aborters had the highest proportion and concentration of NK cells and had the highest activity using the standard assay. Secondary aborters had an intermediate level of these NK cell indices, whereas the control patients had the lowest levels. Using the whole-blood NKA assay, the differences between primary and secondary aborters were most apparent: primary aborters had significantly higher NKA than did either secondary aborters or control women (72, 40, and 35 lytic units, respectively). Approximately 50% of the variability in NKA could be attributed to differences in concentrations of NK cell per microliter of blood. CONCLUSION(S): The higher NKA evident in primary recurrent miscarriage and the reported higher efficacy of immunotherapy in primary aborters support the involvement of NK cells in the etiology of primary recurrent miscarriage.

Prostaglandin e(2) suppresses NK activity in vivo and promotes postoperative tumor metastasis in rats.

BACKGROUND: Prostaglandins (PGs) were shown in vitro to suppress several functions of cellular immunity. It is unclear, however, whether physiological levels of PGs can suppress cellular immunity in vivo and whether such suppression would compromise postoperative host resistance to metastasis. METHODS: Fischer 344 rats were administered PGE(2) in doses (18 to 300 micro g/kg subcutaneously) that increased the serum levels approximately 2- to 4-fold. We then assessed the number and activity of circulating natural killer (NK) cells, as well as rats' resistance to experimental metastasis of a syngeneic NK-sensitive tumor (MADB106). To study whether endogenously released PGs after surgery compromise these indices, we tested whether laparotomy adversely affects them and whether a cyclooxygenase-synthesis inhibitor, indomethacin (4 mg/kg), attenuates these effects. RESULTS: PGE(2) dose-dependently suppressed NK activity per NK cell and dose-dependently increased 4- and 24-hour MADB106 lung tumor retention (LTR); 240 micro g/kg of PGE(2) quadrupled the number of lung metastases counted 3 weeks later. Selective depletion of NK cells abrogated the promotion of LTR by PGE(2). Surgery significantly suppressed NK activity and increased MADB106 LTR, and indomethacin halved these effects without affecting nonoperated rats. CONCLUSIONS: PGE(2) is a potent in vivo suppressor of NK activity, and its postoperative release may promote tumor recurrence.