Chapter 184

## Abstract

Abstract

• Antibody deficiencies are a heterogeneous group of disorders characterized by recurrent bacterial infections. Otitis, sinusitis, and pneumonia owing to the encapsulated organisms Streptococcus pneumoniae or Haemophilus influenzae are the most common infections. However, more severe infections, such as sepsis, meningitis, cellulitis, and osteomyelitis, are not unusual. An antibody deficiency may occur as an isolated finding, or it may be part of a multisystemic disease that affects other limbs of the immune system or other organ systems. Treatment consists of antibody replacement and aggressive use of antibiotics.

• Antibodies are a highly diverse family of serum glycoproteins that bind to and help remove invading microorganisms, extraneous proteins, or foreign cells. Collectively, they account for over a third of the protein found in serum. The typical antibody molecule is made up of two immunoglobulin (Ig) heavy chains and two light chains. There are five major classes of immunoglobulins or antibodies: IgM, IgG, IgA, IgE, and IgD. The IgG class can be further divided into four subclasses (IgG1, IgG2, IgG3, and IgG4), and IgA can be divided into two subclasses (IgA1 and IgA2). The class of the immunoglobulin is defined on the basis of the type of heavy chain. There are two families of light chains, κ and λ, each of which can function with any class of heavy chain.

• The immunoglobulin heavy-chain genes are located at the telomere of chromosome 14q32.3. The κ family is at 2p12, and the λ family is encoded at 22q11. At each of these three locations, there are three or four families of gene segments: the variable (V) region, the diversity (D) region, the joining (J) region, and the constant (C) region; these gene segments can be assembled in a myriad of ways to create a highly diverse repertoire of antibodies. Additional variation is introduced by the fact that each heavy chain may be associated with many different light chains.

• Antibodies are produced by plasma cells, the terminally differentiated descendants of the B-cell lineage. The early stages of B-cell development occur in the bone marrow, where pro-B cells, which are derived from hematopoietic stem cells, undergo rearrangement of the immunoglobulin heavy-chain genes. This process occurs throughout the life of the individual. At the next stage of B-cell differentiation, in pre-B cells, there is rearrangement of the light-chain genes. This allows the expression of the intact immunoglobulin molecule on the cell surface of the B cell. Each B cell and its progeny express only one rearranged immunoglobulin heavy chain and one light chain. When antigen binds to the surface of the B cell, if the appropriate environmental signals are received, the B cell proliferates and differentiates into a memory B cell that can respond more rapidly to future exposures to that antigen or to a plasma cell that secretes high concentrations of antibodies.

• Defects in early B-cell development are associated with the onset of infections in the first few years of life, profound hypogammaglobulinemia, and an absence of B cells in the peripheral circulation. Between 80 and 90 percent of patients with this disorder have X-linked or Bruton’s agammaglobulinemia (MIM300300), which is caused by mutations in the BTK gene encoding the cytoplasmic Bruton tyrosine kinase (Btk). Mutations in Btk are highly variable; there is some genotype/phenotype correlation, but not enough to predict clinical outcome. Defects in components of the B-cell antigen receptor, including the μ heavy chain, the surrogate light chain, the transmembrane signal-transduction molecules Igα and Igβ, and the downstream scaffold protein BLNK account for another 5–10 percent of patients.

• Patients with hyper-IgM syndrome have normal numbers of B cells and normal or elevated serum IgM, but markedly decreased IgG, IgA, and IgE. Approximately 50–60 percent of patients with this disorder have the X-linked form of the disease (MIM 308230), which is due to mutations in the T-cell-derived activation marker CD40 ligand (also called CD154 or TNFSF5). Patients with CD40-ligand deficiency have a high incidence of neutropenia and opportunistic infections, as well as infections with encapsulated organisms. Mutations in the autosomal recessive gene CD40 result in a phenotype that is identical to that seen in patients with defects in CD40 ligand. Defects in enzymes required for class-switch recombination and somatic hypermutation, activation-induced cytidine deaminase (AID), and uracil-DNA glycosylase (UNG) also cause autosomal recessive hyper-IgM syndrome.

• Common variable immunodeficiency (CVID; MIM 240500) is a term used to describe a heterogeneous group of disorders characterized by onset after the first decade of life, hypogammgalobulinemia, and normal numbers of B cells; however, there are exceptions to each of these features. Approximately 10 percent of patients have a family history of immunodeficiency, usually IgA deficiency (MIM 137100). Autoimmune disease is common in this group of patients. Although the majority of patients with CVID do not have single-gene defects of the immune system, susceptibility genes, including HLA haplotypes and polymorphic variants in the tumor necrosis factor (TNF) receptor family member TACI have been described. A small number of patients with a phenotype have autosomal recessive defects in CD19, a B-cell coreceptor, or ICOS, a T-cell activation marker.

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