Primary immunodeficiencies can be classified on the basis of the components of the immune system involved. However, because of the integration of many aspects of immune defense, defects in one component of the immune system can impact the function of others. Therefore, primary defects in innate immunity can lead to defects in adaptive immunity, and vice versa. Nevertheless, it is instructive to consider immune defects in the context of the major types of immunity affected, as these can lead to distinct patterns of infection and clinical disease. By examining which infectious diseases accompany a particular immunodeficiency, we gain insights into components of the immune system that are important in the response to particular agents. The inherited immunodeficiencies also reveal how interactions between different immune cell types contribute to the immune response and to the development of T and B lymphocytes. Finally, these inherited diseases can lead us to the defective gene, often revealing new information about the molecular basis of immune processes and providing the necessary information for diagnosis, genetic counseling, and eventually the possibility of gene therapy for cure.
13-1 A history of repeated infections suggests a diagnosis of immunodeficiency.
Patients with immune deficiency are usually detected clinically by a history of recurrent infection, often by the same or similar pathogens. The type of infection is a guide to which part of the immune system is deficient. Recurrent infection by pyogenic, or pusforming, bacteria suggests a defect in antibody, complement, or phagocyte function, reflecting the role of these parts of the immune system in defense against such infections. Alternatively, a history of persistent fungal skin infection, such as cutaneous candidiasis, or recurrent viral infections suggests a defect in host defense mediated by T lymphocytes.
13-2 Primary immunodeficiency diseases are caused by inherited gene defects.
Before the advent of antibiotics, most individuals with inherited immune defects died in infancy or early childhood because of their susceptibility to particular classes of pathogens. Such cases were not easily identified, because many normal infants also died of infection. Most of the gene defects that cause inherited immunodeficiencies are recessive, and many are caused by mutations in genes on the X chromosome. As males have only one X chromosome, all males who inherit an X chromosome carrying a defective gene will be affected by the disease. In contrast, female carriers with one defective X chromosome are usually healthy.
Gene knockout techniques in mice (see Appendix I, Section A35) have created many immunodeficient states that are adding rapidly to our knowledge of the contribution of individual proteins to normal immune function. Nevertheless, immunodeficiency diseases.
human immunodeficiency diseases remain the best source of insight into the normal pathways of defense against infectious diseases. For example, deficiencies of antibody, of complement, or of phagocytic function each increase the risk of infection by certain types of bacteria. This reflects the fact that the normal pathway of host defense against such bacteria is the binding of antibody followed by the fixation of complement, which allows the opsonized bacteria to be taken up by phagocytic cells and killed. Breaking any of the links in this chain of events causes a similar immunodeficient state.
Immunodeficiencies also teach us about the redundancy of defense mechanisms against infectious disease. By chance, the first person to be reported with a hereditary deficiency of complement (C2 deficiency) was a healthy immunologist. This teaches us that there are multiple protective immune mechanisms against infection, such that a defect in one component of immunity might be compensated for by other components. Thus, although there is abundant evidence that complement deficiency increases susceptibility to pyogenic infection, not every human with complement deficiency suffers from recurrent infections.
Examples of immunodeficiency diseases are listed in Fig. 13.1. None is very common (a selective deficiency in IgA being the most frequently reported), and some are extremely rare. These diseases are described in subsequent sections, and we have grouped the diseases according to where the specific causal defect lies in the adaptive or innate immune systems.