Selective immunoglobulin A deficiency

Selective IgA deficiency is the most common of the primary immunodeficiency diseases in the developed world, having an incidence of 1:600 individuals. Clinically it presents as a heterogeneous group of disorders, which include diseases affecting the gastrointestinal tract, allergic reactions, a diverse range of infections, and diseases that are autoimmune or genetic in origin. The clinical presentation of IgA deficiency is dependent upon the degree of abnormal B cell differentiation; the characteristic defect seen in classical IgA deficiency. This arrest in B cell development is thought to be due to abnormal immuno-regulatory signals since in patients with this disease, the genes coding for immunoglobulin molecules appear to be normal, as does their expression.

IgA-producing B cells have undergone somatic rearrangement such that the switch region immediately before the m gene is joined to the one preceding the a gene and the sequences in between are removed. This process is influenced by TGFb1. Patients with IgA deficiency appear to have a decrease in the recombination event (when compared with normal individuals), which may be due to the defective production of TGFbl. However, the levels of mRNA coding for this cytokine in peripheral blood mononuclear cells isolated from patients with IgA deficiency have been shown to be the same as those in control subjects.

Genetic studies have suggested that the disease is related to the presence of a susceptibility gene in the Class II or Class III MHC gene region. The simultaneous change in IgG subclasses, exemplified by an absence of carbohydrate-specific IgG2 or even a lack of serum IgG2, IgG4 and IgE, suggests that these patients have a block in switching to genes downstream of IgGl.

X-LINKED AGAMMAGLOBULINAEMIA (XLA)

Newborn babies normally are unable to produce specific antibodies when exposed to an antigen. At this stage, a baby is protected by maternal antibodies, which have crossed the placenta. Later (7-9 months of age) normal babies begin to produce their own antibodies. Babies with X-linked agammaglobulinaemia (XLA) are unable to do so and present with recurrent bacterial infections. Individuals affected by this disease (the majority of which are male) usually have less than 10% of the normal level of serum IgG and less than 1% of the normal serum levels of IgA and IgM. Additionally, they have low levels of B, and plasma, cells. T cells in affected individuals seem to be normal. Thus, as might be expected, viral infections (which are largely controlled by T cells) are rarely life-threatening in patients with XLA.

As the name of the disease suggests, it is genetically based and the defect is inherited from the mother. In normal women, the active X chromosomes are derived equally from the mother and father. By contrast, in female carriers of a number of X-linked immunodeficiency disorders (including X-linked agamma-globulinaemia, X-linked severe combined immunodeficiency disease, and the Wiskott-Aldrich syndrome) all the active X chromosomes in the affected cell populations are those which carry the abnormal copy of the gene (allele).

Several studies suggest that the genetic defect in XLA affects B cell development at a number of different stages (Table 5.13). In addition, the cytoplasmic protein Bruton's tyrosine kinase (Btk) is mutated in XLA. Since several studies have shown such cytoplasmic kinases are essential for cell growth and differentiation and are involved in lymphocyte signal transduction, this mutated protein is likely to be involved in the developmental abnormalities seen in XLA. Indeed, the gene coding for Btk maps to the position (locus) q22 on the X chromosome, which has been identified as that involved in XLA. In addition, Btk is expressed in B but not T cells, which may explain why, despite the obvious B cell defect in these patients, T cells appear to be functionally, and phenotypically, normal. Interestingly, the abnormal gene is also expressed in the

Table 5.13 B cell abnormalities reported to be associated with XLA

B cell developmental abnormalities

Reduced pre-B cell proliferation, with fewer cells entering the S-phase of the cell cycle

Failure of pre-B cell to thrive

Inversion of bone marrow ratio of pro- and pre-B cells Few, immature circulating B cells myeloid cells of patients with XLA. However, these cells appear functionally normal.

Bruton's tyrosine kinase is intimately involved in signal transduction pathways regulating survival, activation, proliferation and differentiation of B cells. Following ligation of the B cell antigen receptor, Btk is activated by the tyrosine kinases Lyn and Syk resulting in calcium mobilisation mediated by phospholipase C2. Despite this knowledge, it is unclear how mutations in Btk affect downstream events leading to XLA.

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