Clinical significance of IgA deficiency.

IgA is one of the five classes of immunoglobulin found in biological fluids. It is the major secretory immunoglobulin and is widely distributed in all mucosal secretions as a dimeric molecule linked by a joining chain and a third molecule, the secretory piece. The dimeric form is resistant to proteolytic digestion and IgA antibodies are important in the protection of mucous membranes against invasion by pathogens. ' The function of serum IgA antibodies, which mainly exist in monomeric form, is unclear. Low serum IgA, however, is a useful marker of secretory IgA deficiency which almost invariably accompanies it. There is only one reported case of absent secretory IgA in the presence of normal serum IgA and this was associated with an absence of the secretory piece.There are two serologically and structurally distinct IgA subclasses, IgAl comprises 90% of circulating IgA, but the IgA found in secretions is equally distributed between IgA, and IgA2.3 IgA deficiency with normal concentrations of other immunoglobulin classes (isolated IgA deficiency) was the first4 and is the most common immunoglobulin deficiency described. The genetic basis of IgA deficiency is not known but there are associations with certain HLA-types, healthy IgA deficient individuals having an excess of HLA-B8 and DR3 and symptomatic ones an increased frequency of HLA-B40. IgA deficiency usually occurs sporadically but is found with variable inheritance patterns within some families. The section of DNA coding for the a heavy chain of IgA within the immunoglobulin gene has always beer found to be present in isolated IgA deficiency. Ho)wever no a chain messenger RNA was generated in polyclonally activated B-lymphocytes from IgA deficient individuals, making a DNA to RNA transcriptional defect possible in such patients. " The incidence of IgA deficiency is approximately one in 500 of the general population. ' Most of these individuals are healthy but a minority have significant symptoms. In these patients frequent upper and lower respiratory tract infections and middle ear infections predominate and in some significant organ damage such as bronchiectasis may result.7 In subjects with allergic disorders and autoimmune diseases the incidence of IgA deficiency is higher, sometimes approaching one in 1)0(. Weak associations with IgA deficiency occur in coeliac disease, systemic lupus erythematosus and other autoimmune disorders, gastrointestinal disease,` and some malignancies.9 The dichotomy between symptomatic and asymptomatic IgA deficient individuals remains, however, often making the significance of the finding in individual patients unclear. A further complication is the transience of IgA deficiency, both in adultsl" and particularly in children,'' where it may represent delayed maturation of the humoral immune system. During ontogeny IgA is the latest of the immunoglobulin classes to develop, and normal serum and mucosal concentrations do not reach adult concentrations until puberty. Reversible IgA deficiency is also induced by some drugs including phenytoin.' There are a number of possible explanations for the presence of symptoms in only a minority of individuals with isolated IgA deficiency. 3 The severity of the deficiency may be important as children with very low concentrations of IgA (<0-05 g/l) had a higher incidence of pneumonia than those who were also IgA deficient but had concentrations >0-05 g/l but < -2 SD below the mean for age. Furthermore, 50% of this latter group had only transient deficiencies but the more severe deficiencies were permanent. "' Most even profoundly IgA deficient individuals are still asymptomatic, however, and in these subjects mechanisms which compensate for the lack of IgA are probably operating. One such mechanism may be the increased local production and passage of IgM into nasal secretions and saliva seen in asymptomatic but not symptomatic individuals. '4 A third reason for the discrepancy of symptoms between individuals with isolated IgA deficiency may lie in variable associations with other covert immunodeficiencies. For example, low concentrations of certain subclasses of IgG, particularly IgG, and IgG4, are found in approximately 15% of patients with IgA deficiency,'5 though in one study of 60 IgA deficient children this combination did not correlate with an increased incidence of infection. '" Furthermore, qualitative'7 or quantitative"X abnormalities in the IgG antibody response to infection or immunisation have been described even in the presence of normal or high total IgG and IgG subclass concentrations. Pulmonary damage is more common in IgA deficient