In contrast, cell-mediated immunity is associated with T lymphocytes (such as CD3+, CD4+, and CD8+) that develop from pluripotent stem cells in bone marrow and migrate to the thymus to mature and differentiate. As these precursor cells proliferate and differentiate into mature T lymphocytes, they increase their expression of surface CD (cluster of differentiation) markers that confer cell-type specificity. Immature T cells termed double CD negative cells (CD4-CD8-) lack expression of CD4 and CD8. On activation, one class of mature T cells differentiates into cytotoxic T lymphocytes (CTLs), distinguished by a cell-surface CD8+ marker, that can release cytokines (small molecules that act on cells and stimulate or inhibit their function) and kill tumor- and virus-bearing cells. T cells bearing CD4+ markers recognize antigen on their surface and release signature cytokines. CD4+ cells, critical for immune protection, can be subdivided into T-helper (TH) cells (TH1, TH2, TH3, and TH17) that help other immune cells by activating or directing their activities. For example, TH cells are essential in B-cell antibody class switching, activation and growth of CTLs, and maximizing bactericidal activity of phagocytes (such as macrophages). CD4+ cell populations, classified as either naïve (not exposed to antigen) T lymphocytes (CD45RA+) or activated memory T cells (CD45RO+), also include regulatory cell types, such as natural killer (NK) T cells and T-regulatory cells. TH cells are subdivided (on the basis of the types of cytokines that they release) into TH1 and TH2 phenotypes. Under normal circumstances, the TH1: TH2 ratio is balanced. Skewing toward TH1 or TH2 responses can result in a hyperinflammatory state or autoimmunity, respectively.

The innate (also known as nonspecific) immune system comprises the cells and mechanisms that defend a host from infection in a nonspecific manner. The cells recognize and respond to pathogens and tumor cells, but, unlike the adaptive immune system, they do not confer long-lasting or protective immunity. A number of critical cell types and soluble mediators are essential for nonspecific immunity. Macrophages and neutrophils play an essential role in the uptake (phagocytosis) and killing of ingested bacterial pathogens, whereas NK cells, also essential for innate immunity, kill virus-infected cells and neoplasms without prior sensitization. Each of those cell types is also an important source of immunoregulatory cytokines that mediate a variety of immune responses and inflammation.

Many immune end points, such as serum cytokine and Ig concentrations, are often used as indicators to predict early biologic effects of chemical-induced immunotoxicity. However, such immune measurements can lack sensitivity, are poorly standardized, or are poorly linked quantitatively to a disease process, so their relevance in assessing immunotoxic effects in humans is poorly established. In addition, translation of such early effects to a pathologic response or a disease phenotype on the basis of the toxicologic paradigm exposure image internal dose image biologically effective dose image early biologic effects image altered structure



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