Solomon J. Zak

TRANSPLANTATION STUDIES IN PATIENTS WITH AGAMMAGLOBULINEMIA

The discovery of agammaglobulinemia in 1952l provided a new and clear-cut opportunity to gain insight into the nature and significance of the immune response in man. The initial studies2-’ established that patients with agammaglobulinemia have a disease featured by increased susceptibility to infection, absence of gamma globulin from the blood and tissues, and failure of antibody production in response to the most intensive antigenic stimulation. This form of agammaglobulinemia is an isolated defect in protein metabolism. Extreme hypogammaglobulinemia, or even agammaglobulinemia, however, may occur as a part of several diseases featured by more general abnormalities in protein metabolism, such as nephrosis,8 multiple myeloma,g nutritional failure,10 and failure of general protein fabrication.”-14 Since we believe that the isolated forms of agammaglobulinemia offer an unusual opportunity to study the nature of the immune response and its relationship to other biological phenomena in man, we shall limit this discussion to this form of gamma-globulin dysmetabolism. During the past 2 years we have had the opportunity of discovering and studying 12 cases of isolated agammaglobulinemia. Brief summaries of these cases included in TABLE 1 describe the clinical manifestations of the disease observed therein. The purpose of this report is threefold: (1) to summarize briefly general studies carried out on patients with agammaglobulinemia that serve to define the disorder; (2) to report efforts involving various forms of transplantation in patients with agammaglobulinemia; and (3) to record briefly observations made during the course of pregnancy of an agammaglobulinemic patient and throughout the first year in the child born of the agammglobulinemic mother. A detailed study of this “experiment of nature” will be reported elsewhere.16 General considerations of agammaglobulinemia. Although agammaglobulinemia is probably still to be considered an uncommon disease, it is by no means rare. To date, 56 cases have been reported in the literature,l6 and the rate at which reports from. every country are appearing in the medical journals indicates that available accounts describe only a sampling of the existing number of these patients. Isolated agammaglobulinemia occurs in at least 3 distinct forms. Perhaps the most common variety is transient agammaglobulinemia of infancy. This self-limited form of agammaglobulinemia occurs in both sexes and does not appear to have a significant familial distribution. In a sense, this form represents a variety of the normal relationships. Normally, the newborn infant * These studies were aided by rants from the Helen Hay Whitney Foundation New York N . Y . the United States Public Health Service Bedesda Md: the Minnesota Division of the Ame&an C a d So& S t Paul Minn.: the Minnesota Heart kssociatiod, St. kaul, Minn.; and the American Heart Association, New Ybrk; N. Y:

Effect of Meningococcal Endotoxin on the Immune Response.

Summary 1. The enhancement of antibody production against crystalline bovine serum albumin by the simultaneous injection of meningococcal endotoxin is reported. 2. An optimum dosage of endotoxin for production of the adjuvant effect is approximately the same as that required to prepare rabbits for the generalized Shwartzman reaction or to provoke the local Shwartzman phenomenon. 3. Failure of inhibition of antibody production by dosages of endotoxin capable of producing delayed uptake of radio active colloidal gold by the reticuloendothelial system is mentioned. 4. Possible mechanisms responsible for the adjuvant phenomenon are discussed.

A Hypothesis for the Increased Oxygen Affinity in Haemoglobin Malmö

Haemoglobin Malmöβ97HisGln, a high oxygen affinity haemoglobin which causes secondary erythrocytosis, is transmitted in an autosomal dominant manner. A hypothesis accounting for the high oxygen affinity, hyperbolic oxy‐haemoglobin dissociation curve, and the relatively normal Bohr effect is presented. The purified abnormal haemoglobin from the present family provided biochemical and functional data for this hypothesis based on the allosteric model proposed by Perutz. Experimental results support the formation of a chemical bond between the ‐SH proton of the β93 cysteine and the amide of oxygen of the substituted β97 glutamine as an explanation for the high oxygen affinity of haemoglobin Malmö.

Complex α-thalassemia-like syndrome: A cause of neonatal normoblastemia**

A previously unrecognized hypochromic anemia associated with marked normoblastemia during the newborn period is reported. One male and two female siblings and a first cousin had a hypochromic anemia and marked normoblastemia (300 to 900 normoblast index per 100 white blood cells) at birth. Globin chain synthesis studies on peripheral blood of the proband at birth indicated the presence of α-thalassemia trait with possible reduced γ chain synthesis. Studies of globin chain synthesis on the father, two older affected siblings of the proband, and the proband at 1.5 years of age revealed α-thalassemia trait. The data suggest this complex α-thalassemia-like condition as a new syndrome associated with marked neonatal normoblastemia.

Comparison of hemoglobins Wood (alpha 2 beta 2 97 leu) and Malmö (alpha 2 beta 2 97 gln). Diagnostic value of citrate agar electrophoresis.

Diagnostic value of citrate agar electrophoresis. Am J Clin Pathol 71:668-671, 1979. Of approximately three dozen hemoglobin variants that have greater than usual oxygen affinity, nearly half are inseparable from hemoglobin A by electrophoresis at pH 8.6. A comparison of hemoglobins Wood (alpha2beta297leu) and Malmö (alpha2beta297gln) is of interest from several standpoints. They represent similar substitutions at the identical locus in the beta chain. They result in identical clinical and hematologic manifestations. Oxygen affinities of these variants are identical. Both are poorly resolved from hemoglobin A by electrophoresis at pH 8.6. The position of each is identical when studied by isoelectric focusing in polyacrylamide gel. Finally, they are easily distinguished by citrate agar electrophoresis at pH 6.2. The excellent resolution of hemoglobins Malmö and Wood from each other results neither from difference in charge, nor size, nor in quaternary structure. This technic provides a simple but effective means for identifying and differentiating these hemoglobin variants. Comparison with the results of citrate agar electrophoresis of other high oxygen-affinity hemoglobins indicates that the findings for hemoglobins Malmö and Wood are unique and unambiguous.