Avidity

AVIDITY, Aviditat (from Latin avidus--greedy), a term in modern immunology denoting the doctrine of the qualitative aspect of immunity reactions. The concept of A. was introduced into science by Ehrlich (Ehrlich) and his collaborators, who attempted to explain various complex phenomena not subject to Ehrlich's chemical theory of immunity by the peculiarities and differences in the A. of antigens and antibodies. The strength of immune sera is still evaluated only from the standpoint of the antibodies or immune units contained in them. This logically follows from the prevailing doctrine of Ehrlich, which postulated the strict dependence and proportionality between the specific action of sera and the content of immune units in them; therefore, sera with a high titer of antibodies were also considered highly active (hochwertige). This principle formed the basis for the method of evaluating the therapeutic strength of antidiphtheritic sera developed by Ehrlich in 1897, which was introduced into the practice of laboratories in almost all countries. Observations at the bedside of patients and laboratory experiments soon showed that the therapeutic strength of sera and their wealth of antitoxic units are not of the same order. Roux, Tizzoni, Cruveilhier, Kraus, and Schwoner showed that to evaluate the therapeutic strength of antitoxic sera, it is necessary to take into account not only their titer but also A. These conclusions did not go unanswered by representatives of Ehrlich's school (Marx, Berghaus, Brustlein and others), who sought in their therapeutic experiments to confirm the said basic rule of Ehrlich. According to these authors, the violation of this law is explained by various reasons (individuality of the animal, different absorption of toxin and antitoxin, etc.). The individual factor of serum avidity, if not denied in these studies, remains in close dependence on the titer—a high titer corresponds to powerful A. (Brustlein). Antitoxic sera, despite the importance of this question for them, represented a poorly suitable object for studying A., since the authors had only one method at their disposal for this purpose—experiments on the treatment and protection of animals with these sera; however, this methodology cannot be considered reliable for determining A. due to the extremely complex and difficult to account for conditions presented by the animal organism. Further development and precise formulation of the doctrine of A. was received only when experiments in vitro were used to study this phenomenon, where the role of A. appears clearly, indisputably, and can be strictly accounted for. The first observations of Kraus and Dorr and others showed that normal antibodies require a longer contact with the toxin for its neutralization than immune ones. In the experiments of Landsteiner and Heyrovsky with bacterio-hemotoxins, immune sera, differing little in titer from normal ones, surpassed them in the speed of reaction. Further observations of the course of the reaction between antigen and antibody established that immunity reactions differ in intensity, which finds expression in the different speed of reaction and in the different completeness and strength of the formed connection of antigen with antibody. Such are the characteristics that characterize A. and serve as its indicators. The different course of the reaction is thus explained by the difference in A. of sera, i.e., that greed with which the antibody strives to combine with the antigen.--In 1912, Barykin proposed for evaluating the A. of antitoxic sera a method of colloidal medium, allowing in vitro determination of A. of sera. The method consists in that the titration of anatoxin is carried out here not in physiological NaCl solution, as in Ehrlich's method, but in serum medium. It turned out that such a serum medium (pool-serum of animals) shows a retarding effect on the reaction of toxin neutralization by antitoxin and thereby makes it possible to determine the difference between sera in the speed of the reaction, i.e., to determine one of the important characteristics of A. In this property of the colloidal medium lies its value and advantage compared to the crystalloid medium of Ehrlich, where this reaction proceeds so rapidly that individual differences of sera cannot be captured. Barykin's experiments showed that the A. of sera, determined by the method of colloidal medium, is in no way connected with the content of antitoxic units in them and is, thus, an individual, independent property of sera, and therefore, to determine the therapeutic strength of sera, it is necessary, in Barykin's opinion, not only to titrate the serum but also to determine A.—both of which can be done in the colloidal medium proposed by Barykin. In Frieze's experiments, sera showing greater A. by the method of colloidal medium also gave a better therapeutic effect, which experimentally establishes the significant importance of A. of sera for evaluating their therapeutic properties; moreover, the same experiments confirm the position that the antitoxic unit of different sera does not represent a constant and equivalent value in the therapeutic sense. However, the role of A. in the therapeutic action of antitoxic sera is not yet universally recognized. With the appearance of Ramon's flocculation method, proposed for titrating antitoxic sera, an attempt was made to evaluate their A. by the speed of flocculation (see). The research of Zilber and Frieze showed that flocculation and neutralization do not coincide in time and that there is no parallelism between the time of appearance of flocculation and the speed of neutralization in Barykin's colloidal medium (i.e., A.), therefore the speed of flocculation in Ramon's method cannot serve as an indicator of A. The phenomena of A., first established in antitoxic sera, soon received visual proof in other immunity reactions, which from a methodological point of view presented greater advantages—precisely thanks to the same possibility of experimenting in vitro. The reaction of agglutination is especially suitable for this purpose, to the study of whose avidity a number of detailed studies are devoted (Muller, his collaborators—Busson and Rintelen, Zarnitsyn).—Simple observation of the speed of reaction (Scheller) and experiments on the detachment of agglutinins under the influence of thermal action (Landsteiner and Reich) showed that agglutinating sera behave differently, individually, give different speeds of reaction, are adsorbed by the microbe with different strength—possess different avidity. Muller, proceeding from Ehrlich's doctrine of the multiplicity of antibodies, deepened this doctrine with the hypothesis of the existence of antibodies of different avidity, to which his experiments with repeated exhaustion of serum led. According to Muller, serum represents a mixture of agglutinins with different A.s, and the diversity of this mixture in quantity and quality of individual fractions determines its individual A. Observing the A. of sera during immunization, Muller established that A. grows with immunization along with the titer and falls with it; thus, between them a regular connection is observed, expressed in the parallel course of the curves of titer and A., which, however, has an individual character in each particular case (individual parallelism of Busson). The works of Eisler, and above all Zarnitsyn, did not confirm Muller's conclusions. Zarnitsyn's experiments lead him to the conclusion about the fundamental unsuitability of the method of repeated adsorption itself for studying the A. of agglutinins, and therefore the data obtained with this method are little reliable. Muller's hypothesis about the simultaneous presence in serum of many fractions of agglutinins with different A.s, as built on an unreliable method, naturally loses its experimental evidence. The best method for determining A. of sera, according to Zarnitsyn's experiments, is recognized as the speed method. With the help of this method, Zarnitsyn, then Barykin and Frieze, could not establish the regular connection between A. and the titer of agglutinating serum noted by Muller and his collaborators. A. is an individual, independent property of serum, not depending on the titer.—The data obtained in the study of A. of hemolysins confirm the above basic provisions in the doctrine of A. of sera. Here too it was shown that hemolytic sera behave differently under the same experimental conditions and possess different A. to erythrocytes. The number of lytic units bound by erythrocytes (Poggenpohl and Schapiro), the strength of the connection of the sensitizer with erythrocytes (Morgenroth and Rosenthal), the speed of hemolysis in ascitic medium (Frieze), finally, the speed of binding alexin (Amiradzibi and Baecher)—all this is subject to large fluctuations and is an expression of A. of the sera taken in the experiment, and the latter is an independent, individual property of them, not depending on the titer. Observation of A. and titer during immunization showed that the changes of both do not go in parallel and their maxima do not coincide (Frieze). According to Frieze's experiments, in determining both the titer of sera and A., the individuality of alexins, which have different avidity to the sensitized antigen, has a significant influence; therefore, the hemolytic reaction in its course is directed by the influence of two individual factors.

The individuality of hemolytic serum is clearly demonstrated in mixing experiments (Frise). The mixed serum, both in terms of titer and avidity, can differ greatly from the sera forming the mixture and constitutes a completely new individuality. The doctrine of avidity, besides its immense practical significance (the question of the therapeutic strength of sera), has important theoretical significance for the fundamental question of immunology—the relationship between antigen and antibody. Both in its origin and in its subsequent development, the doctrine of avidity was based on the position that this new factor governing the course of the immune reaction is a new property of specific sera. On the basis of this position, the doctrine of avidity was reduced exclusively to the doctrine of antibody avidity. Meanwhile, what is defined as antibody avidity cannot be considered a phenomenon related only to individual antibodies. Serum enters into a reaction not only as a carrier of antibodies but also as a complex colloidal system; the relationship of this system with another (antigen) cannot be limited only to the line of specific binding (titer and avidity) accounted for in the experiment, but is accompanied by other reactions closely related to the physical state and chemical composition of both reaction ingredients. These secondary reactions do not remain without influence on the main one (antigen + antibody), but can modify it, individualize it; hence the fluctuations in titer and avidity that are observed when testing various sera. Many facts in the modern doctrine of avidity lead to this assumption (Barykin and Frise). Although the concept of avidity is theoretically attributed to both reaction ingredients (in the works of Ehrlich and his school, Kraus and Schwoner), in fact the doctrine of avidity has taken a one-sided character and has developed into the form of serum avidity. One must think (some literary data give grounds for this) that avidity is a complex phenomenon, based not only on the individuality of sera but also on the individuality of another colloidal system—the antigen.