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. 314). 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. 314). Whenever the expression or function of one of these products is genetically impaired (provided the function is nonredundant), a primary immunodeficiency (PID) occurs.
Primary immunodeficiencies are genetic diseases with primarily Mendelian inheritance. More than 200 conditions have now been described and deleterious mutations in approximately 150 genes have been identified. The overall prevalence of PIDs has been estimated in various countries at 5 per 100,000 individuals; however, given the difficulty in diagnosing these rare and complex diseases, this figure is probably an underestimate. Primary immunodeficiencies 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 316-1 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 316–1. Classification of Primary Immune Deficiency Diseases
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Table 316–1. Classification of Primary Immune Deficiency Diseases
|Deficiencies of the Innate Immune System|
- • Phagocytic cells:
- - Impaired production: severe congenital neutropenia (SCN)
- - Asplenia
- - Impaired adhesion: leukocyte adhesion deficiency (LAD)
- - Impaired killing: chronic granulomatous disease (CGD)
- • Innate immunity receptors and signal transduction:
- - Defects in Toll-like receptor signaling
- - Mendelian susceptibility to mycobacterial disease
- • Complement deficiencies:
- - Classical, alternative, and lectin pathways
- - Lytic phase
|Deficiencies of the Adaptive Immune System|
|• T lymphocytes:|
|- Impaired development||Severe combined immune deficiencies (SCIDs) DiGeorge syndrome|
|- Impaired survival, migration, function|
Severe combined immunodeficiencies
Hyper-IgE syndrome (autosomal dominant)
CD40 ligand deficiency
Ataxia-telangiectasia and other DNA repair deficiencies
|• B lymphocytes:|
|- Impaired development ||XL and AR agammaglobulinemia |
|- Impaired function|
Common variable immunodeficiency (CVID)
|• Innate immunity|
Autoinflammatory syndromes (outside the
scope of this chapter)
|• Adaptive immunity|
Hemophagocytic lymphohistiocytosis (HLH)
Autoimmune lymphoproliferation syndrome
Autoimmunity and inflammatory diseases
The consequences of PIDs vary widely as a function of the molecules that are defective. This concept translates into multiple levels of vulnerability to infection by pathogenic and opportunistic microorganisms, ranging from extremely broad [as in severe combined immunodeficiency (SCID)] to narrowly restricted to a single microorganism [as in Mendelian susceptibility to mycobacterial disease (MSMD)]. The locations of the sites of infection and the causal microorganisms involved will thus help physicians arrive at proper diagnoses. Primary immunodeficiencies can also lead to immunopathologic responses such as allergy (as in Wiskott-Aldrich syndrome), lymphoproliferation, and autoimmunity. A combination of recurrent infections, inflammation, and autoimmunity can be observed in a number of PIDs, thus creating obvious therapeutic challenges. Finally, some PIDs increase the risk of cancer, notably but not exclusively lymphocytic cancers, e.g., lymphoma.
The most frequent symptom prompting the diagnosis of a PID is the presence of recurrent or unusually severe infections. As mentioned above, recurrent allergic or autoimmune manifestations may also alert the physician to a possible diagnosis of PID. In such cases, a detailed account of the subject's personal and family medical history should be obtained. It is of the utmost importance to gather as much medical information as possible on relatives and up to several generations of ancestors. In addition to the obvious focus on primary symptoms, the clinical examination should evaluate the size of lymphoid organs and, when appropriate, look for the characteristic signs of a number of complex syndromes that may be associated with a PID.
The performance of laboratory tests should be guided to some extent by the clinical findings. Infections of the respiratory tract (bronchi, sinuses) mostly suggest a defective antibody response. In general, invasive bacterial infections can result from complement deficiencies, signaling defects of innate immune responses, asplenia, or defective antibody responses. Viral infections, recurrent Candida infections, and opportunistic infections are generally suggestive of impaired T cell immunity. Skin infections and deep-seated abscesses primarily reflect innate immune defects (such as chronic granulomatous disease); however, they may also appear in the autosomal dominant hyper-IgE syndrome. Table 316-2 summarizes the laboratory tests that are most frequently used to diagnose a PID. More specific tests (notably genetic tests) are then used to ...