Figure 73-2 Schematic representation of the interaction between a CD4 T cell and a B cell. T-cell activation follows T-cell receptor (TCR) recognition of peptide antigen presented via MHC class II molecules resulting in CD40 ligand (CD40L) expression and cytokine synthesis. CD40L stimulates the B cell via CD40, resulting in expression of co-stimulatory molecules (B7) that are important in T-cell priming and cytokine synthesis that drives T-cell differentiation. CD40 and cytokine signaling in B cells activate activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) to promote immunoglobulin isotype switching and somatic hypermutation. Defects in CD40L cause X-linked hyper-IgM (X-HIM), and defects in CD40, AID, or UNG cause autosomal recessive hyper-IgM (AR-HIM). Defects in either CD40L or CD40 affect T-cell co-stimulation and priming, leading to T-cell defects, whereas defects in AID and UNG maintain normal T-cell co-stimulation and function.
Table 73-2 Combined Immunodeficiency Diseases DISORDER GENETICS ONSET MANIFESTATIONS PATHOGENESIS ASSOCIATED FEATURES Hyper-IgM syndrome (see Table 73-1) X-linked, AR First year Sinopulmonary infections, opportunistic infections, Pneumocystis jiroveci Defect in CD40 ligand (X-linked) or CD40 (AR) Neutropenia, liver disease, cancer
AD, Autosomal dominant; ADA, adenosine deaminase; AR, autosomal recessive; dATP, deoxyadenosine triphosphate; dGTP, deoxyguanosine triphosphate; GVHD, graft-versus-host disease; IL, interleukin; IL-2Rγ, interleukin-2 receptor gamma chain; MHC, major histocompatibility complex; PNP, purine nucleoside phosphorylase; SCID, severe combined immunodeficiency; T− B−, T− cells absent and B cells present; T− B−, T cells absent and B cells absent.
precursors in the thymus (see Fig. 73-2), where they undergoseveral stages of development characterized by DNA recombination of the variable region of T-cell antigen receptor genes togenerate a diverse T-cell receptor repertoire. A process of positive selection occurs in the thymus to select thymocytes withantigen receptors that can interact with major histocompatibility complex (MHC) molecules to ensure their survival (see Fig. 73-2). Thymocytes differentiate into CD4 or CD8 T cells if theyinteract with MHC class II or class I molecules, respectively.Some of the positively selected thymocytes, however, haveantigen receptors that recognize self-antigens presented byMHC molecules in the thymus. These cells are deleted in the thymus by a process of negative selection. Positive selectionand negative selection in the thymus ensure that the mature Tcells that leave the thymus can function with the individual’sMHC molecules and recognize a multitude of foreign antigenswithout mounting autoimmune responses. SCID can resultfrom any specific genetic mutation that interferes with T-celldevelopment in the thymus or T-cell function in the periphery.
Clinical manifestations of SCID include failure to thrive, severe bacterial infections, chronic candidiasis and other fungal infections, chronic viral infections, infection with