Hereditary alterations in the immune response: coexistence of "agammaglobulinemia", acquired hypogammaglobulinemia and selective immunoglobulin deficiency in a sibship.

Extract: A longitudinal immunologic study was conducted in a family in which an entire sibship of three males was unduly susceptible to infection. The oldest boy's history of repeated severe infections beginning in infancy and his marked deficiencies of all three major immunoglobulins were compatible with a clinical diagnosis of congenital ‘agammaglobulinemia' (table I, fig. 1). Recurrent severe infections in the second boy did not begin until late childhood, and his serum abnormality involved deficiencies of only two of the major immunoglobulin fractions, IgG and IgM (table I, fig. 1). This phenotype of selective immunoglobulin deficiency is previously unreported. Serum concentrations of the three immunoglobulins in the youngest boy (who also had a late onset of repeated infection) were normal or elevated when he was first studied, but a marked decline in levels of each of these fractions was observed over a four-year period (table I, fig. 1). We could find no previous reports describing apparent congenital and acquired immunologic deficiencies in a sibship. Repeated infections and demonstrated specific immunologic unresponsiveness preceded gross abnormalities in the total and fractional gamma globulin levels in both of the younger boys (tables II–IV). When the total immunoglobulin level in the second boy was 735 mg/100 ml, he failed to respond with a normal rise in titer after immunization with ‘A' and ‘B' blood group substances, diphtheria, tetanus, or Types I and II poliovaccines. When the total immunoglobulin level in the youngest boy was 1564 mg/100 ml, he had absent ‘B' and low ‘A' isohemagglutinins. Later studies showed that he failed to respond with a normal rise in titer after stimulation with ‘A' and ‘B' blood group substances, diphtheria, tetanus, typhoid, and Types I, II and III poliovaccines. Similar studies in family members demonstrated a marked polyclonal IgA hyperglobulinemia and specific immunologic unresponsiveness to ‘B' substance in the mother (tables I and II). She also gave poor circulating antibody responses to immunization with diphtheria and poliovaccines. Two maternal aunts had high normal levels of IgA and low isohemagglutinin titers (table VII). We are unaware of other reports of specific immunologic unresponsiveness and/or antibody deficiency in the apparent heterozygote for what appears to be an X-linked immunologic deficiency. A male maternal first cousin also had a high normal level of IgA, asthma, shortness of stature and repeated respiratory infections. These findings provide direct evidence for a genetic influence in some forms of acquired immunologic deficiency. Speculation: The heterogeneity of immunologic abnormality observed in this family is inconsistent with many of the current hypotheses of the genetic defects in immunologic deficiency. An afferent phase defect seems to offer the best explanation for a single genetic mechanism of immunologic deficiency in this family. The question of a possible contributory role of repeated bacterial infections in the apparent progression and heterogeneity of immunologic deficiency in the members of this sibship is raised.