Chapter 23 : Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders

Diagram of leukopoiesis, indicating the locations of developmental or functional defects associated with immunodeficiency. The names of some immunodeficiency syndromes are given in pink boxes (for developmental defects) or orange boxes (for functional defects). Note that some defects (for example, LAD) affect the function of more than one cell lineage. Also note that some classes of immunodeficiency (for example, SCID) can result from either developmental defects or functional defects.

Flow chart of lymphocyte development and function, indicating the locations of developmental or functional defects that result in SCID. Some of the defects that are shown (yellow boxes) only affect T cells directly, but result in a SCID phenotype due to an inability of helper T cells to help B cells.

Bare lymphocyte syndrome (BLS). (A) Diagram of trafficking and peptide loading by MHC class I (MHC I) and class II (MHC II) in a normal antigen-presenting cell. (B) The more common type of BLS, BLS (MHC II), usually results from a failure to synthesize MHC class II due to a defect in the transcription factor CIITA. MHC class I is still produced and loaded with peptide normally. (C) A less common form of BLS, BLS (MHC I), is characterized by normal synthesis of MHC class I but greatly reduced membrane expression of MHC class I due to a defect in TAP. TAP deficiency results in an inability to load antigenic peptides onto MHC class I, causing the class I proteins to be retained in the endoplasmic reticulum (ER). Ii, invariant chain.

Defects in phagocytic killing. (A) In a normal phagocyte, phagocytosis of a bacterium is followed by a fusion of the phagosome with a lysosome (large black circles) to form a phagolysosome. In the phagolysosome, hydrolytic enzymes (small black circles) damage ingested bacteria. Simultaneously, a family of NADPH oxidases (p22, p67, and p91) and myeloperoxidase (MPO) enzymes become activated to produce the oxidative burst, resulting in the production of toxic oxygen intermediates such as superoxide (O2 ·−), peroxynitrite (ONOO−), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl), which also participate in microbial killing. (B) Some phagocytic defects, such as CGD and myeloperoxidase deficiency, result from defects in the enzymes needed for the oxidative burst. Without the oxidative burst, hydrolytic enzymes in the phagolysosome are insufficient for microbial killing. (C) Chediak-Higashi syndrome results from a defect in the regulation of lysosome trafficking and fusion. As a result, most lysosomes in a Chediak-Higashi syndrome phagocyte prematurely fuse with each other, resulting in giant, nonfunctional lysosomes. In these phagocytes, the oxidative burst occurs normally, though it alone is insufficient for microbial killing in the absence of phagosome-lysosome fusion.

LAD. (A) In a normal individual, leukocytes are able to leave the circulation and enter solid tissues by a multistep process of extravasation. This involves the following steps: (1) low-affinity rolling adhesion mediates by mucin-selectin interactions; (2) signaling via chemokines such as IL-8; (3) conversion of leukocyte integrin proteins to their high-affinity form via a G protein-dependent signal upon binding to IL-8; (4) high-affinity binding of leukocyte to vascular endothelium, leading to leukocyte arrest; and (5) diapedesis. (B) In an individual with LAD, rolling (I) and signaling via IL-8 (II) still occur normally, but a defect in leukocyte integrin proteins (III) prevents high-affinity leukocyte-endothelium interactions. Therefore, leukocytes never arrest on the endothelium and detach from the latter (IV).

DiGeorge syndrome. A thymic shadow is absent in the anterior-posterior chest radiograph.

Bronchiectasis. (Left) A computed tomographic scan confirms chronic pneumonia/bronchiectasis in the right lower lobe. (Right) A chest radiograph of 12-year-old boy showing chronic right lower lobe infiltrate (arrowheads) consistent with bronchiectasis.

PCP. Diffuse interstitial disease with nodularity suggests PCP.

Lung abscess. A chest radiograph shows early abscess cavities (arrowheads).

Mucocutaneous candidiasis. Fungal plaques are seen on the inner lining of the cheek and coating the tongue.