A clinical and experimental study of agammaglobulinemia.

GAMMAGLOBULINEMlA and extreme hypogam; maglobulinemia occur as concomitants of 'yeral human diseases. Depression of the serum ~roma glob~ concentration may occur be~use of loss of protein from the body, generaled failure of protein fabrication, inordinately . id destruction of serum protein, or because of -isolated deficit in gamma globulin synthesis, n the nephrotic syndrome, for example, hypo.maglobulinemia and hypoalbuminemia oc~reflectingthe loss of these two protein comients in the urine." Patients with nephrosis are lacking in capacity to synthesize protein. In.d>.)Kelley and associatesshowed that in~sed rather than decreased protein fabrica: characterizes patients with -this disease. .e findings are in substantial agreement with conclusions of Kunkel and Ward" and oth.that patients with nephrosis are producing . than normal amounts of serum albumin in ttempt to keep up with the urinary losses. "the same conclusions hold for the gamma .' metabolism in these patients has rey received experimental support. .. ogammaglobulinemia and perhaps even C aglobulinemia occur also as part of a diseatured by failure of protein production ally observed by McQuarrie and associ! Similar patients have since been studied ported by others."?" In the oiiginalpatient d by McQuarrie, the patient's disease was ed by generalized edema, very low total proteins, especially low serum globulins, : ordinate susceptibility to infection. Fried ,,!:mley11studied a similar case and empha;the deficiency of circulating gamma globu. ese patients. In this disorder, the albumin pbulin deficiencywas attributed to failure ncation of serum proteins by the liver. .qnally, as pointed out by Krebs.P nutri~e£ciency may result in hypogammaglobu~'associated with generalized hypopro,·a. Hypogammaglobulinemia along with lized hypoproteinemia-may also be a func-' {.excessivelYrapid destruction or utiliza:'setuinprotein as in a patient intensively studied by Dixon.v Recently Ulstrom and associates= described an infant suffering from hypoproteinemia, edema, anemia, and agammaglobulinemia in whom all the abnormalities were self limited. In each of the above disorders of protein .IQe~ tabolism, depression of gamma globulin concentration occurs in the plasma or serum, butin each instance it is associated with a disturbance in the metabolism of other ,serum protein components. . In 1952, Bruton;" and Bruton and associates= described a disease entity expressed clinically as an inordinate susceptibility to bacterial in-' fection. Electrophoretic studies revealed that. this disease was featured by complete absence of gamma globulin from the serum. Bruton's patient, an Ll-year-old boy, was shown to be lacking in circulating antibodies and to be unable to produce antibodies in response to antigenic stimulation. Unlike the instances of agam-' maglobulinemia previously described, electrophoretic analysis of the plasma or serum from this patient revealed a protein partition essentially normal except for the absence of gamma globulin. Following Bruton's case report, Janeway and Citlin'" gathered together 9 such cases. Each of the latter group exhibited the cardinal features described by Bruton, namely: (1) increased susceptibility to bacterial disease', (2) absence of gamma globulin in the serum, (3). absence of antibody in the blood and tissues, and (4) failure of antibody production in response to antigenic stimulation. . . These studies of the Boston group established that' agammagloblllinemia is due to failure. of synthesis of this particular electrophoretic component of the serum proteins and, is not a function of generalized protein dysmetabolism. Further, it was established that this type ofagammaglobulinemia is not due to inordinately rapid decay of gamma globulin. For example, parenterally administered gamma globulin had, in· these patients, a half life essentially the same or somewhat longer than that described by others18-20 for normal human subjects. During the