Joseph Shuster

Carcinoembryonic antigen (CEA) in clinical medicine. Historical perspectives, pitfalls and projections

Carcinoembryonic antigen (CEA) was first detected by the immunization of rabbits with human colon cancer extract. The techniques of antiserum absorption and immunologic tolerance were employed in an attempt to render the resulting antisera tumor‐specific. Using the procedures of precipitation and precipitin‐inhibition in gel media, hemagglutination, passive cutaneous anaphylaxis and immunofluorescence, CEA was identified exclusively in all cancers of gastrointestinal origin and fetal digestive organs in the first two trimesters of gestation. The subsequent development of radioimmunoassays for CEA has raised the question of the presence of this material, in very low concentrations, in other normal and diseased (cancerous and noncancerous) tissue, but the problem of cross‐reactivity within a family of closely related, but nonidentical, molecules remains to be resolved. CEA was initially purified by a sequence of steps involving extraction in perchloric acid, sieve chromatography, and preparative block electrophoresis. The molecule was characterized as a relatively heterogeneous acid glycoprotein with a molecular weight of approximately 200,000 and its carbohydrate (one‐half to two‐thirds of the molecule) and protein composition were determined. CEA was localized to the glycocalyx of the colon cancer cell and it was found that the CEA could be released from this site into the circulation of the cancer patient, where it could then be detected by means of radioimmunoassay. The clinical implications of this observation, as they have evolved over the past eight years, form the basis of the papers that constitute this supplement.

Pepsin hydrolysis of IgA--delineation of two populations of molecules.

Abstract Kinetics of pepsin hydrolysis of IgA molecules were studied by a chromatographic technique employing radioiodinated proteins. Secretory IgA and IgA paraproteins of the α1 and α2 subclass were compared. Two population of molecules were demonstrated—a pepsin sensitive and a pepsin resistant group. Secretory IgA and the α1-paraproteins belong to the pepsin resistant population while the α2 paraproteins were 3–4 times more susceptible to the enzyme. Secretory IgA was the molecule most resistant to degradation by pepsin.

Ability of anti-brain heteroantisera to distinguish thymus-derived lymphocytes in various species☆

Abstract Anti-brain heteroantisera prepared in rabbits against mouse and dog brain tissues appear to distinguish T from B lymphocytes in homologous species, although some sensitivity of bone marrow cells to these antisera is also observed. Cross-reactivity of these antisera with heterologous thymus cells could not be demonstrated. The brain T lymphocyte antigen (BAθ) could not be detected in fetal mouse brain and was only present in neonatal dog brain in low concentration, increasing in concentration in a sigmoidal fashion with maturation. Rabbit antisera to human brain tissue (frontal lobe) did not have corresponding specificity for human thymus cells. Anti-mouse brain antisera are not immunosuppressive in allografted mice.

Endocrinopathy and IgA deficiency

Abstract Three cases of IgA deficiency occurring in association with endocrine hypofunction—Turners syndrome, hypothyroidism, and diabetes—are described. The significance of IgA deficiency associated with chromosome abnormalities are discussed in view of the present finding of IgA deficiency in a patient with Turners syndrome displaying a karyotype of 44 autosomes, X, isochromosome of the long arm of X.

Leukopenia, leukoagglutinins, and low IgM in a family with severe febrile illnesses.

Abstract A family is described in which the propositus and four of his ten siblings suffered severe virus-like illnesses. Leukopenia, leukoagglutinins and low IgM found in several family members were associated with a history of severe febrile illness. It is possible that the described abnormalities have pathogenic significance and possible mechanisms are discussed.

Isolation of HLA and tumor antigens by means of affinity chromatography employing anti-β2,-microglobulin (β2m) antiserum

A method for the isolation of HLA antigen molecules from normal and cancerous solid human tissue is described. The method employs anti‐β2‐microglobulin (β2m) antiserum coupled to Sepharose beads as an immunosorbent affinity medium. The anti‐β2m affinity chromatography procedure greatly purifies and selectively enriches HLA and any material that copurifies by affinity, with β2m and /or HLA molecules. The HLA isolated by this purification procedure was used to immunize rabbits. The antisera obtained were absorbed on β2m to remove all anti‐β2m antibody activity. The use of such anti‐HLA antisera in radioimmunoassays, immunoprecipitation studies, and F(ab′)2 blocking experiments demonstrated that these antisera are directed against a common HLA determinant present on the heavy (alloantigen‐bearing) chain of all HLA molecules. The use of an identical procedure employing human tumor tissues has resulted in the isolation of HLA‐like or HLA‐associated tumor‐specific antigens as demonstrated by the leukocyte adherence inhibition (LAI) assay.

The isolation of the γ subunit of fetal hemoglobin (HbF) and its use in a radioimmunoassay for HbF

Abstract A method is described for the purification, from fetal hemoglobin (HbF), of the fetal specific globin chain (γ chain) in its native state. In the absence of α chain (the globin chain common to all adult human hemoglobins) γ chain, when used as an immunogen, is able to express its unique antigenicity. Here, a specific, high titer antiserum raised against γ chain has been used to establish a sensitive radioimmunoassay for HbF. This approach may be applicable to the measurement of other normal and abnormal hemoglobins.

Current concepts in clinical immunology--asthma therapy, immune complex disorders and antireceptor antibodies.

THE LAST few years have brought an explosion of knowledge in the field of immunology. We have increased our understanding of the basic functional cell units of immunologic processes such as T-cell subpopulations and their role in the generation and regulation of the normal immune response. Insight has been gained as to the means by which T cells recognize ‘self’, and the role of T cells in disorders of immunoregulation [l-S]. The region on chromosome 6 in man called the major histocompatibility complex has been genetically and functionally dissected. This region codes for the major histocompatibility antigens (HLA-A, HLA-B, HLA-C), the structure of which has been resolved. In addition, regions of the major histocompatibility complex code for the biosynthesis of a variety of complement components. The HLA-D region, and its I-region analogue in the mouse, exercise an important genetic control over immune responses, and appear to be implicated in what are called the HLA-associated diseases [610]. The chemistry and biological functions of the complement components in the classical and alternate pathways have been extensively studied, and the mode of complement activation and regulation within these two pathways has been further elucidated [l l-15]. The role of immunologic parameters in the pathogenesis of various pathological states such as myasthenia gravis [ 16183, transplantation rejection, infertility [ 191 and’ many others, has been clarified. In addition, technological advances have placed new therapeutic modalities at our disposal. This paper will review some of the major therapeutic advances which have greatly facilitated the management of allergic rhinitis and asthma, as well as the revival of the use of plasmapheresis as a viable therapeutic tool for a group of disorders in which circulating antibody plays a pathophysiologic role. Finally, we will discuss circulating immune complexes and their importance in the pathogenesis of disease.