Immunodeficieny with Normal or Increased Immunoglobulin M

Abstract

Immunodeficiency with normal or increased immunoglobulin (Ig)M (HIGMX-1) was discovered by Rosen et al. (1961), when one of the original five patients with what was thought to be X-linked agammaglobulinemia (XLA) appeared at the Boston Children’s Hospital at age 16 years with a diagnosis of acute poststreptococcal glomerulonephritis. When an attempt was made to measure the CH₅₀ in his fresh serum, an unexpected finding supervened. Instead of the CH₅₀ being markedly decreased, as would be anticipated in acute potstreptococcal glomerulonephritis, it was found to be so elevated that an endpoint could not be reached in the hemolytic titration. It was reasoned that this might be due to the presence of Forssman antibodies to sheep red blood cells used to measure the CH₅₀, and this indeed turned out to be the case. It was known then that Forssman antibody, like other antibodies to lipopolysaccharides, were macroglobulins and the serum of this patient was found to have other macroglobulin antibodies in high titer. His serum was analyzed in a Model E ultracentrifuge and found to have an increased 19S peak and no 7S peak. Immunoelectrophoretic patterns revealed the presence of a prominently increased IgM band, very little IgG, and no IgA. Soon thereafter, another male child with chronic purulent sinusitis and bronchiectasis was admitted to the Boston Children’s Hospital. His total serum immunoglobulins were found to be about 230 mg/dl. When his serum was subjected to analytical ultracentrifugation, an increased 19S peak was found and the 7S peak was barely discernible. These two similar cases were reported together (Rosen et al. 1961). Shortly thereafter, another male with an identical immunological abnormality was reported in the French literature (Burtin 1961). Over 100 cases have been reported in the world literature, and these reports have recently been reviewed by Notarangelo et al. (1992). The disease is most commonly inherited as an X-linked phenomenon, but similar cases that appear to have autosomal recessive inheritance have been described, as well as sporadic cases, particularly following the rubella pandemic 3 decades ago. This discussion is confined to the X-linked form of the disease, because the genetic defect in HIGMX-1 has recently been established to be a defect in the T cell ligand for CD40.