As many behavioral scientists are unfamiliar with the details of the immune system, we provide a brief overview. For a more complete treatment, the reader is directed to the sources for the information presented here (Benjamini, Coico, & Sunshine, 2000
; Janeway & Travers, 1997
; Rabin, 1999
). Critical characteristics of various immune components and assays are also listed in .
Immune Parameters Reported and Critical Characteristics
Components of the Immune System
There are several useful ways of dividing elements of the immune response. For the purposes of understanding the relationship of psychosocial stressors to the immune system, it is useful to distinguish between natural
immunity. Natural immunity is an immune response that is characteristic not only of mammals but also lower order organisms such as sponges. Cells involved in natural immunity do not provide defense against any particular pathogen; rather, they are all-purpose cells that can attack a number of different pathogens1
and do so in a relatively short time frame (minutes to hours) when challenged. The largest group of cells involved in natural immunity is the granulocytes. These cells include the neutrophil
and the macrophage
, phagocytic cells that, as their name implies, eat their targets. The generalized response mounted by these cells is inflammation
, in which neutrophils and macrophages congregate at the site of injury or infection, release toxic substances such as oxygen radicals that damage invaders, and phagocytose both invaders and damaged tissue. Macrophages in particular also release communication molecules, or cytokines
, that have broad effects on the organism, including fever and inflammation, and also promote wound healing. These proinflammatory cytokines include interleukin(IL)-1, IL-6, and tumor necrosis factor alpha (TNFα). Other granulocytes include the mast cell and the eosinophil, which are involved in parasitic defense and allergy.
Another cell involved in natural immunity is the natural killer cell. Natural killer cells recognize the lack of a self-tissue molecule on the surface of cells (characteristic of many kinds of virally infected and some cancerous cells) and lyse those cells by releasing toxic substances on them. Natural killer cells are thought to be important in limiting the early phases of viral infections, before specific immunity becomes effective, and in attacking self-cells that have become malignant.
Finally, complement is a family of proteins involved in natural immunity. Complement protein bound to microorganisms can up-regulate phagocytosis and inflammation. Complement can also aid in antibody-mediated immunity (discussed below as part of the specific immune response).
Specific immunity is characterized by greater specificity and less speed than the natural immune response. Lymphocytes have receptor sites on their cell surfaces. The receptor on each cell fits with one and only one small molecular shape, or antigen, on a given invader and therefore responds to one and only one kind of invader. When activated, these antigen-specific cells divide to create a population of cells with the same antigen specificity in a process called clonal proliferation, or the proliferative response. Although this process is efficient in terms of the number of cells that have to be supported on a day-to-day basis, it creates a delay of up to several days before a full defense is mounted, and the body must rely on natural immunity to contain the infection during this time.
There are three types of lymphocytes that mediate specific immunity: T-helper cells, T-cytotoxic cells, and B cells. The main function of T-helper cells is to produce cytokines that direct and amplify the rest of the immune response. T-cytotoxic cells recognize antigen expressed by cells that are infected with viruses or otherwise compromised (e.g., cancer cells) and lyse those cells. B cells produce soluble proteins called antibody that can perform a number of functions, including neutralizing bacterial toxins, binding to free virus to prevent its entry into cells, and opsonization, in which a coating of antibody increases the effectiveness of natural immunity. There are five kinds of antibody: Immunoglobulin (Ig) A is found in secretions, IgE binds to mast cells and is involved in allergy, IgM is a large molecule that clears antigen from the bloodstream, IgG is a smaller antibody that diffuses into tissue and crosses the placenta, and IgD is of unknown significance but may be produced by immature B cells.
An important immunological development is the recognition that specific immunity in humans is composed of cellular and humoral responses. Cellular immune responses are mounted against intracellular pathogens like viruses and are coordinated by a subset of T-helper lymphocytes called Th1 cells. In the Th1 response, the T-helper cell produces cytokines, including IL-2 and interferon gamma (IFNγ). These cytokines selectively activate T-cytotoxic cells as well as natural killer cells. Humoral immune responses are mounted against extracellular pathogens such as parasites and bacteria; they are coordinated by a subset of T-helper lymphocytes called Th2 cells. In the Th2 response, the T-helper cell produces different cytokines, including IL-4 and IL-10, which selectively activate B cells and mast cells to combat extracellular pathogens.
Immune assays can quantify cells, proteins, or functions. The most basic parameter is a simple count of the number of cells of different subtypes (e.g., neutrophils, macrophages), typically from peripheral blood. It is important to have an adequate number of different types of immune cells in the correct proportions. However, the normal range for these enumerative parameters is quite large, so that “correct” numbers and proportions can cover a wide range, and small changes are unlikely to have any clinical significance in healthy humans.
Protein production—either of antibody or cytokines—can be measured in vitro by stimulating cells and measuring protein in the supernatant or in vivo by measuring protein in peripheral blood. For both antibody and cytokine, higher protein production may represent a more robust immune response that can confer protection against disease. Two exceptions are levels of proinflammatory cytokines (IL-1, IL-6, and TNFα) and antibody against latent virus. Proinflammatory cytokines are increased with systemic inflammation, a risk factor for poorer health resulting from cardiac disease, diabetes mellitus, or osteoporosis (Ershler & Keller, 2000
; Luster, 1998
; Papanicoloaou, Wilder, Manolagas, & Chrousos, 1998
). Antibody production against latent virus occurs when viral replication triggers the immune system to produce antibodies in an effort to contain the infection. Most people become infected with latent viruses such as Epstein-Barr virus during adolescence and remain asymptomatically infected for the rest of their lives. Various processes can activate these latent viruses, however, so that they begin actively replicating. These processes may include a breakdown in cellular immune response (Jenkins & Baum, 1995
). Higher antibody against latent viruses, therefore, may indicate poorer immune control over the virus.
Functional assays, which are performed in vitro, measure the ability of cells to perform specific activities. In each case, higher values may represent more effective immune function. Neutro-phils’ function can be quantified by their ability to migrate in a laboratory assay and their ability to release oxygen radicals. The natural killer cytotoxicity assay measures the ability of natural killer cells to lyse a sensitive target cell line. Lymphocyte proliferation can be stimulated with mitogens that bypass antigen specificity to activate cells or by stimulating the T cell receptor.