Antibody deficiencies are a heterogeneous group of disorders characterized by recurrentbacterial infections. Otitis, sinusitis, and pneumonia due to 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.

X-linked, or Bruton, agammaglobulinemia MIM 300300 is associated with the early onset of infections, profound hypogammaglobulinemia, and an absence of B cells in the peripheral circulation. It is caused by mutations in the BTK gene encoding the cytoplasmic Bruton tyrosine kinase (Btk). Mutations in Btk are highly variable, but the severity of the disease cannot be predicted by the specific mutation.

Patients with hyper-IgM syndrome have normal numbers of B cells and normal or elevated serum IgM but markedly decreased IgG and IgA. Approximately 70 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). The genes responsible for the autosomal dominant, the autosomal recessive, and other forms of the disease are not currently known.

Common variable immunodeficiency MIM 240500 and IgA deficiency MIM 137100 are multifactorial diseases that are influenced by susceptibility genes. They may occur in the same family and they may be associated with autoimmune disorders.