Immunity is intrinsic to life and an important tool in the fight for survival against pathogenic microorganisms. The human immune system can be divided into two major components: the innate immune system and the adaptive immune system (Chap. 342). The innate immune system provides the rapid triggering of inflammatory responses based on the recognition (at the cell surface or within cells) of either molecules expressed by microorganisms or molecules that serve as “danger signals” released by cells under attack. These receptor/ligand interactions trigger signaling events that ultimately lead to inflammation. Virtually all cell lineages (not just immune cells) are involved in innate immune responses; however, myeloid cells (i.e., neutrophils and macrophages) play a major role because of their phagocytic capacity. The adaptive immune system operates by clonal recognition of antigens followed by a dramatic expansion of antigen-reactive cells and execution of an immune effector program. Most of the effector cells die off rapidly, whereas memory cells persist. Although both T and B lymphocytes recognize distinct chemical moieties and execute distinct adaptive immune responses, the latter is largely dependent on the former in generating long-lived humoral immunity. Adaptive responses utilize components of the innate immune system; for example, the antigen-presentation capabilities of dendritic cells help to determine the type of effector response. Not surprisingly, immune responses are controlled by a series of regulatory mechanisms.
Hundreds of gene products have been characterized as effectors or mediators of the immune system (Chap. 342). Whenever the expression or function of one of these products is genetically impaired (provided the function is nonredundant), a primary immunodeficiency (PID) occurs.
PIDs are genetic diseases with primarily Mendelian inheritance. More than 350 conditions have now been described, and deleterious mutations in ~346 genes have been identified. The overall prevalence of PIDs has been estimated in various countries at 5–10 per 100,000 individuals; however, given the difficulty in diagnosing these rare and complex diseases, this figure is probably an underestimate. PIDs can involve all possible aspects of immune responses, from innate through adaptive, cell differentiation, and effector function and regulation. For the sake of clarity, PIDs should be classified according to (1) the arm of the immune system that is defective and (2) the mechanism of the defect (when known). Table 344-1 classifies the most prevalent PIDs according to this manner of classification; however, one should bear in mind that the classification of PIDs sometimes involves arbitrary decisions because of overlap and, in some cases, lack of data.
TABLE 344-1Classification of Primary Immune Deficiency Diseases