DISTURBANCES IN GAMMA GLOBULIN SYNTHESIS AS "EXPERIMENTS OF NATURE"
Authors: Good Robert A. , Zak Solomon J. 
Published: December 2021

The experiment of nature presented by patients with agammaglobulinemia is discussed and related to other syndromes associated with disturbance in gamma globulin metabolism.
Measurement of serum gamma globulin concentration by an immunologic method revealed minute amounts of gamma globulin to be present in the serum of each of the patients with agammaglobulinemia. Measurement of the survival time of intramuscularly injected gamma globulin indicated that in patients with agammaglobulinemia this protein has a half-life of approximately 30 days.
The immunologic handicap in patients with agammaglobulinemia is defined in terms of response to ubiquitous antigen, the presence of "natural antibodies" and the primary, secondary, and tertiary responses to bacterial antigens, heterologous blood group antigens and virus antigens. The clinical paradox posed by the apparently satisfactory resistance of patients with agammaglobulinemia to certain virus infections and the failure of their response to virus antigen is discussed. The capacity of patients with agammaglobulinemia to develop bacterial-type hypersensitivity is documented. This observation dissociates bacterial type hypersensitivity from the classical immune response which results in accumulation of antibody in the circulating blood.
The development of immediate-type sensitivity in patients with agammaglobulinemia after intradermal injection of serum from a patient known to be atopic is described. Serum complement, acute phase reactants and properdin are present in normal concentrations in the serums of patients with agammaglobulinemia. The acute phase responses to infection and intoxication are normal in patients with agammaglobulinemia. The persistence of immunologic paralysis after the administration of gamma globulin to patients with agammaglobulinemia is documented.
Skin reactions, febrile and toxic response of patients with agammaglobulinemia to gram-negative endotoxin do not differ from those of immunologically normal persons. Refractoriness to the toxic and pyrogenic effects of gram-negative endotoxin develops in patients with agammaglobulinemia just as in normal persons.
The normal function of the pituitary-adrenal system in patients with agammaglobulinemia is established.
Multiple hematologic disturbances observed in patients with agammaglobulinemia are described. These include transient neutropenia, cyclic neutropenia, persistent neutropenia, eosinopenia, lymphopenia, aregenerative anemia, benign proliferation of the hematopoietic reticulum and thymoma. Virtual absence of plasma cells from the hematopoietic tissues and inflammatory exudates of patients with agammaglobulinemia is described. Failure of plasma cell formation in response to antigenic stimulation is reported as a constant characteristic of the patient with agammaglobulinemia. That all the hematologic abnormalities in agammaglobulinemia have a common basis in a functional abnormality of the hematopoietic reticulum is proposed.
Successful homotransplantation of skin in the patient with agammaglobulinemia is described. Transplantation of skin from 4 patients with agammaglobulinemia to 4 immunologically normal children resulted in the expected homotransplantation failure.
Immunologic, biochemical and hematologic studies of a woman with agammaglobulinemia during pregnancy are briefly described.
Immunologic, biochemical, and hematologic investigations of a child born of a mother with agammaglobulinemia are mentioned.