Primary antibody deficiency

This is the most common PID, affected patients having either a severe or partial failure to produce antibodies, usually with low levels of one or more of the main immunoglobulin classes. Most patients with severe primary antibody deficiency (PAD) present as adolescents or adults, although a carefully taken history will uncover a susceptibility to infection in about 20% during childhood. The most common of these disorders is a selective complete deficiency of immunoglobulin A (IgAD), this having a prevalence of about 1 in 700 white people. Most affected individuals are asymptomatic, and the defect may be recognized only during population surveys or during routine investigation of an unrelated problem. However, there is a raised incidence of IgAD in patients with various autoimmune disorders, particularly coeliac disease. Family studies show that IgAD is often genetically linked to a more severe antibody deficiency called common variable immunodeficiency (CVID). Furthermore, many patients with subtle defects in immunoglobulin production (i.e. IgG subclass defects, low serum IgA and/or deficiencies in producing IgG-specific antibodies), appear also to have a disorder genetically linked to CVID and IgAD.

A variety of rare single-gene defects cause severe antibody deficiency as a result of failure of development of B lymphocytes within the bone marrow. The best known is X-linked agammaglobulinemia (XLA), caused by a defect in Bruton's tyrosine kinase (btk), an intracellular signalling molecule whose precise role in B-cell development is still unknown. Other rarer defects involve surface ligands or intracellular signalling molecules involved in the differentiation of B cells (Figure 22.2). Recent work has identified a number of molecules critical for immuno-globulin class switching and somatic hypermutation, these processes being necessary for the generation of antibody diversity. The germline configuration of immunoglobulin genes on chromosome 14 consists of 'variable' V-region genes linked to the 'constant' region genes by a D-J segment. During the later stages of B-cell development in the bone marrow, functional immu-noglobulin genes are assembled by recombination to produce a repertoire of IgM antibodies with low affinity. When these B cells encounter antigen, there is rapid proliferation to form the germinal centres in the secondary lymphoid apparatus, during which there is intense hypermutation in and around the rearranged V gene segments. Class-switch recombination occurs at this stage, a critical requirement being a signal within B cells stimulated via CD40-ligand expressed on the surface of activated T cells and CD40 on the B cell. Activation-induced cytidine deaminase (AID) is another molecule involved in class switching, its role being to deaminate doxycytidine to uracil, which then has to be excised and repaired for the immunoglobulin gene segment to be functional. Uracil-DNA glycosylase (UNG) is the most important molecule for this excision/repair step.

Genetic defects in any of these four molecules are very rare and characterized by a raised serum IgM, and usually very low IgG and IgA (hyper-IgM syndromes: HIM 1-4). However, each has some special features, for example defects in CD40 ligand cause susceptibility to opportunistic infection, particularly with cryptosporidia, and to unexplained sclerosing cholangitis and

Typical features Occasional features

Chronic/recurrent bronchitis Autoimmune disease, e.g. haemolytic anaemia,

Sinusitis/otitis media neutropenia, thrombocytopenia, vitiligo

Pneumonia/septicaemia Enteropathy

Arthritis (usually mycoplasmal)

Meningoencephalitis (usually enteroviral)



Stage 1 Serum immunoglobins (+ serum immunoelectrophoresis)

Baseline functional antibodies >• if low, immunize and check response

e.g. to tetanus toxoid

pneumococcal polysaccharides

IgG subclasses if total IgG <11 g/L

Stage 2 Consider secondary causes:

1 Drugs -anti-inflammatory



2 Increased loss -




3 Lymphoma

Stage 3 Lymphocyte subsets - absence of B cells suggests Btk, p-chain defect, etc.

Family history - XLP, X-HIM and XLA need to be excluded in males

Exclude thymoma in those > 40 years (lateral chest radiograph)

Most patients with B cells will be 'labelled' as having

common variable immunodeficiency

Figure 22.3 Clinical features and diagnosis of antibody deficiency.

liver cancer at a young age; the AID and UNG defects cause lymphadenopathy with expanded germinal centres filled with IgM-committed B cells, a feature sometimes confused with follicular lymphoma. Only three patients with UNG defects have so far been described, but they may be prone to B-cell lymphoma as this is a frequent complication in the knockout mouse model.

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