SLE, systemic lupus erythematosus; UNG, uracil-DNA glycosylase.
normal lymphocyte numbers and subsets, but the disorder has an inability to synthesize specific antibody to polysaccharideantigens, such as to the 23-valent pneumococcal vaccine. Thepathogenesis of this disorder is unknown. Lack of specific antibody titers explains the recurrent infections and justifies therapy.
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Disorders that affect T-cell development or function usuallyresult in combined immunodeficiency because T cells providenecessary signals for B-cell differentiation. X-linked hyper-IgM syndrome, the most common form of hyper-IgM syndrome, is a combined immunodeficiency with deficient T-cellfunction due to defects in CD40 ligand. Defects in CD40 causeautosomal recessive hyper-IgM syndrome and present similarly to X-linked hyper-IgM syndrome (Fig. 73-2 and Table 73-2). Hyper-IgM syndrome is characterized by a failure ofimmunoglobulin isotype switching from IgM and IgD to IgG,IgA, or IgE, and a lack of memory responses. Affected patientshave normal or elevated serum levels of IgM with low or absentlevels of IgG, IgA, and IgE. Immunoglobulin isotype switching allows a B cell to maintain antigen specificity while alteringimmunoglobulin function, and is directed by cytokines and interaction between CD40 ligand on CD4 T cells and CD40 onB cells (see Fig. 73-2). Signal transduction via CD40 activatesseveral signaling molecules and transcription factors, including nuclear factor κB (NF-κB) and two enzymes, activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase(UNG), which are required for class switching. Deficiency ofAID or UNG presents with a failure of immunoglobulin isotype switching without any abnormality in T-cell function.These forms of hyper-IgM are antibody deficiency diseases andnot combined immunodeficiencies (see Table 73-1).
All patients with hyper-IgM syndrome have increased susceptibility to sinopulmonary infections, whereas patients with defects in CD40 ligand or CD40 are susceptible to opportunistic infections, such as P. jiroveci (carinii) and Cryptosporidium parvum. Signaling via CD40 on B cells and other antigen-presenting cells leads to upregulation of co-stimulatory molecules important for promoting T-cell differentiation and for activating cell-mediated immune responses. The hyper-IgM phenotype is also found in an X-linked disorder associated with ectodermal dysplasia, resulting from defects in the gene encoding the NF-κB essential modulator (NEMO). Patients with defects in NEMO are susceptible to a wider spectrum of infectious organisms, especially meningitis and infection with atypical mycobacteria, because NF-κB signaling is important for the function of both innate and adaptive immune systems.
Severe combined immunodeficiency (SCID) is characterized by a profound lack of T-cell numbers or function, andB-cell dysfunction resulting from the absence of B cells fromthe gene defect itself, or secondary to lack of T-cell function(see Table 73-2). T cells develop from bone marrow−derived