Landsteiner used hapten-conjugated proteins to induce and characterize antibodies that bound to the immunizing epitope and to closely related molecules ( Landsteiner and van der Scheer, 1924 Landsteiner and van der Scheer, 1936). A second series of experiments from Landsteiner’s laboratory provided a more severe challenge to Ehrlich’s theory that preformed antibodies (side-chains) were sufficient to defend against the antigenic universe. They also would have an impact on theories of antibody formation and diversity.Īntibody specificity and diversity. Landsteiner’s development of more precise and quantitative methods to raise and characterize antibody represents a cornerstone in immunochemistry. His studies of paroxysmal nocturnal hemoglobinuria (with Donath) established that this disorder was mediated by antibodies specific for the patient’s hemoglobin ( Donath and Landsteiner, 1904). However, this rule seemed to be violated by a number of observations, including experiments from Landsteiner’s laboratory. According to this model, aberrant production of self-reactive side-chains would give rise to “horror autotoxicus,” a kind of immunological self-poisoning. Ehrlich’s “side-chain theory” held that cells expressed a variety of side-chains (antibodies) at their surface that are released after infection and bind to potential pathogens that neutralize microbial toxins while sparing the organism’s own tissues. Landsteiner performed these studies in an era that was dominated by Paul Ehrlich’s chemical models to explain the interactions of antibody, antigen, and complement ( Ehrlich, 1900). In this case, Landsteiner’s discovery and characterization of an Rh factor provided an explanation for two medical mysteries: the immunological basis of hemolytic reactions in patients that had received blood from A-B-O–compatible donors and a potential genetic basis for an often-fatal hemolytic disease of infants called erythroblastosis fetalis. These studies marked the first systematic attempt to capture and define cell surface antigens by deliberate immunizations of animals-a general approach that was applied to the analysis of lymphocyte differentiation ( Cantor and Boyse, 1977). Further studies established that the Rh factor is expressed at the RBC membrane and is currently termed the erythrocyte D antigen. Genetic studies of Rh factor revealed that it was inherited as a Mendelian dominant autosomal trait that segregated independently from previously defined A, B, M, and N factors (see figure). In their 1941 JEM paper, Landsteiner and Wiener reported that ∼85% of 448 individuals tested were Rh positive and 15% were Rh negative ( Landsteiner and Wiener, 1941). Immunization of guinea pigs with monkey RBCs produced immune sera that agglutinated a novel human blood factor, which was designated Rh to reflect the use of Rhesus RBCs as the source of immunizing erythrocytes ( Landsteiner and Wiener, 1940). These unusual agglutination reactions led Landsteiner to postulate additional blood isoagglutinins that were distinct from the major blood A and B agglutinins and prompted a series of attempts to define them using antisera raised in animals against human RBCs. Although widespread application of these findings (along with anticoagulants to prevent clotting of collected blood specimens) allowed safe and successful blood transfusions during the First World War, the problem of serious hemolytic reactions after recurrent transfusions between A-B-O–matched individuals remained. Individuals that expressed neither A nor B, but whose sera contained antibodies to A and B, were called type O. He explained these reactions by postulating two types of blood cell antigens, called A and B. He found that specific agglutinating antibodies were limited to those individuals who lacked the blood type antigens to which these antibodies were directed ( Landsteiner, 1900 Landsteiner, 1901). Landsteiner’s groundbreaking experiments in blood transfusion began with a simple analysis of the interaction between sera and red blood cells from healthy individuals.
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