To better understand CARS, it is helpful to understand what responses characterize the proinflammatory state that precedes it. It now is known that inflammation can be triggered in two main ways, either by infections with pathogens like bacteria, or by the products of tissue destruction. The innate immune system describes a network of immune cells and their surface receptors designed to recognize and react to either dead tissue or pathogens. When elements of either of these encounter certain lymphocytes or monocytes, they bind to pre-existing receptors and cause activation (lymphocytes) or are ingested and then presented on cell surface receptors to activate other cells (monocytes). What follows is an expansion and activation of several immune cell lines such as polymorphonucleocytes (PMNs) and B lymphocytes stimulated by the proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF). The presence of these cytokines also leads to other clinical manifestations of infection such as fever, capillary leak, vasodilation, and the expression of heat shock proteins from the liver.8
The CARS response essentially reverses many of these processes and has been characterized over the last several decades to include:
Reduction of lymphocytes by means of apoptosis
Decreased cytokine response of monocytes to stimulation
Decreased numbers of human leukocyte antigen (HLA) antigen-presenting receptors on monocytes
Expression of cytokines such as IL-10 that suppress TNF expression (Box 1)
Much research suggests that the clinical effect of this has a profound impact on patient outcomes. Indeed clinicians long have noted that many people who succumb from sepsis die after the initial proinflammatory insult has ceased, often from a second infection. Additionally, many patients who have sepsis, especially those who have poor pre-existing health, seem never to mount the inflammatory response that should characterize infection, instead presenting with low leukocyte counts and hypothermia (). This article discusses some of the major studies that led to current knowledge of CARS and what may be coming in the future.
Fig.1 Three different immunologic responses to sepsis in three hypothetical patients of varying pre-existing health status. The relative magnitude of the anti-inflammatory (CARS) response in relation to the proinflammatory (SIRS) response is what is important (more ...)
Lymphocytes in Compensatory Anti-inflammatory Response Syndrome
Lymphocytes play a central role in modulating the sepsis response. This is highlighted by altered proinflammatory immune response and increased mortality, after polymicrobial septic challenge in mice lacking both T- and B-cells.9
Their importance relates to their capacity to interact with the innate and adaptive immune responses and their ability to coordinate, amplify, and attenuate the inflammatory response. Lymphocyte anergy (the inability to respond to recall antigens in vivo, [eg, tetanus toxin]) or decreased responsiveness to mitogenic stimulus long has been demonstrated in patients following major surgery, blunt trauma, and thermal injury.10–12
Further studies using both animal and human in vitro models helped better characterize these lymphocyte alterations.
In 1985, Abraham and Chang13
demonstrated reduced ability of T lymphocytes to respond to the mitogens concanavalin A and phytohemagglutinin following traumatic injury. Later, it was discovered that the period of immunoparalysis after trauma was characterized by increased expression of inhibitory coreceptors (PD-1, CD47, CTLA4) on T lymphocytes and decreased expression of coactivator receptors such as CD28 on lymphocytes.14
This altered phenotype of lymphocytes correlated with diminished proliferation response contributing to anergy. Most significantly, a relationship between the loss of cell-mediated immunity in patients following traumatic injury, and the development of sepsis and late death had been established.12,15
As investigators began to look at lymphocyte function in sepsis (as opposed to trauma), it was clear that similar, if not identical patterns of dys-function were occurring. For example, it was shown that patients who have sepsis exhibit defects in their T lymphocytes, because the cells fail to proliferate in response to mitogenic stimuli and also fail to produce IL-2 or -12.16–18
Activated CD4 T-cells can be subdivided into two functionally distinct, highly polarized subsets, termed type 1 helper T-cell (Th1) and type 2 helper T-cell (Th2), depending on their pattern of lymphokine secretion and related functional activities. They secrete either cytokines with inflammatory Th1 properties, including TNF-α, interferon-γ, and IL-2, or cytokines with more anti-inflammatory Th2 properties (eg, IL-4 and -10). Lymphocytes from patients with burns or sepsis have reduced levels of Th1 cytokines but increased levels of the Th2 cytokines IL-4 and -10, and reversal of the Th2 response improves survival among patients who have sepsis.17,18
Some newer studies, however, show a somewhat different picture. For example, global down-regulation of Th1 and Th2 responses in patients after sepsis or severe trauma also has been observed.19,20
This suggests that there may be complete down-regulation of T-cell effector response rather than a shift to an anti-inflammatory response. Similarly, Heidecke and colleagues16
examined T-cell function in patients who had peritonitis and found that they had decreased Th1 function without increased Th2 cytokine production. In this study, effective T-cell proliferation and cytokine secretion correlated with mortality.
More recent findings have been identified a role for other regulatory T-cell populations suppressing T-cell immunity, including natural killer T-cells (NKT) and Gamma delta T-cells (γδ). Blocking the activation of NKT cells by means of an anti-CD1d antibody prevented this immune suppression.21
Using a model of burn injury on γδ T-cell deficient mice, Schwacha and colleagues22
demonstrated a reduced production of proinflammatory cytokines, suggesting that γδ T-cells played an important role in postburn survival. The exact mechanisms by which these regulatory lymphocyte subsets affect the immune response remain subjects of controversy but may represent future therapeutic targets in the management of sepsis.