Philip Levine

The role of iso-immunization in the pathogenesis of erythroblastosis fetalis☆

STUDIES on the cause of intra-group transfusion accidents associated with pregnancy have established the importance of the concept of iso-immunization of the mother by blood factors in the fetus transmitted from the father.1–5 More recently it was found that the same theory of iso-immunization may serve as the basis for a theory on the pathogenesis of erythroblastosis fetalis, the well-described familial hemolytic disease of the newborn.3, 4, 6

Further Observations on Individual Differences of Human Blood.

In a previous communication 1 we described an agglutinable factor (M), independent of the blood groups and present in many but not in all human bloods. A somewhat higher incidence of M among colored than white individuals, as indicated by our first results, was confirmed by examination on a larger scale; among 902 white individuals 165 (18.3 per cent), and among 338 colored 95 (28.1 per cent) whose blood reacted negatively. A differentiation of bloods (in the same group) lacking or possessing the factor M, was possible also with dried specimens. The heredity of the property M was studied in more than 100 families. The results are in keeping with the assumption that M is inherited as a mendelian dominant. In the following table the families are arranged in 3 classes according to the presence or absence of the factor M in the parents, and its incidence among the offspring is given. It may be mentioned incidentally that the character 2 A 1 present in most bloods of group A, seems to be an inheritable quality. For, in our tests, if the property was not or slightly developed in the blood of both parents, this, as a rule, was also the case for the children. With a method similar to that employed for the detection of M, namely, suitable absorption of certain rabbit immune sera for human blood, two other agglutinable qualities were found which may be denoted as N and P. These reactions, further distinguishing individual human bloods, vary in intensity from very strong to weak or negative.

A New Agglutinable Factor Differentiating Individual Human Bloods.

By absorbing a number of anti-human blood immune sera from rabbits with the blood corpuscles of certain individuals regardless of the group, fluids were obtained from a few sera which give a sharp differentiation of individual human bloods within the common blood groups. Among 116 individuals selected from the four blood groups the distribution of the agglutinable factor (which may be designated as M) was as shown in Table II. This reaction is distinguished by its intensity from some others known to show individual differences within the groups, such as the reactions with cold agglutinins. This is a preliminary report.

Isoimmunization by a New Blood Factor in Tumor Cells

In the course of preparing a 66-year—old female patient, Mrs. D. S. J., for gastric resection of a tumor later diagnosed as adenocarcinoma, difficulties were encountered in selection of compatible donors.∗ The patient was in group O, Type MNS, presumably of the Rh genotype DCe/DCe (R1R1), Duffy and Cellano positive. The factors P, Lewis, and Lutheran could not be demonstrated in her blood. Among 3000 random group O individuals, all bloods were hemolyzed by the unheated serum or agglutinated by the inactivated serum. The hemolysin could also be demonstrated in the patients inactivated serum by adding sensitive red cells suspended in pooled fresh group compatible unheated serum from normal individuals. The unusually high incidence of positive reactions is apparently attributable to a single antibody since all activity is removed after treatment of the serum with each of 10 different bloods. These observations suggested the presence of a new hereditary factor which is present in the red blood cells of almost all individuals tested. For identification purposes, the blood factor and its antibody may be designated as “Jay” and “anti—Jay” respectively. Because of the relationship to the tumor described below, the abbreviated symbols for the gene, blood factor, and antibody are Tia, Tja, and anti—Tja, the letter “T” referring to the tumor. The corresponding symbols for the theoretical allelic gene, factor, and antibody can be designated as Tib, Tjb, and anti—Tjb, respectively. Tests of anti—Tja with the blood of her 3 siblings, all in group O, showed that the blood of one of her sisters did not contain the factor, but it was present in the red cells of the sisters 4 children.† The factor could be demonstrated in the blood of the patients husband and their 4 children, all in group A, since their red cells absorbed anti—Jay.

Ah, an Incomplete Suppression of A Resembling Oh

1 A modified form of the Oh (Bombay) type with incomplete suppression of A is described. 2 The A property in this blood termed, Ah, is readily detected by standard anti‐A sera, but not by anti‐A1. 3 The red cells are H negative and Le(a+). 4 The saliva has no H, A or B substances but does secrete Lea. 5 The serum contains anti‐H, anti‐A1 and anti‐B. 6 A system of terminology is suggested for the phenotypic expression of typical and modified forms of the Bombay type. 7 Theoretical implications are briefly discussed, involving a series of suppressor genes at the X locus of X1, X2 … x. To explain the Ah blood the genotype of the suppressing genes may be represented as either X1X2 or X2x.

A Second Example of —/— or Rhnull Blood

The second example of a —/— or Rhnull, LW‐negative individual is described, who delivered a mildly affected infant and produced only anti‐e. The proposita is a member of a large family and their probable genotypes are known. The parents, who are not related to each other, are R1R1, father, and R1r mother, so that the proposita could be either [R1R1) or [R1r], but none of the Rh antigens are expressed. Her husband is rr and their first infant is R1r. Thus the proposita transmits R1 to her child. Scoring titrations reveal that 12 out of the 16 members of the family, including the parents of the proposita and her child have diminished reactivity of D, C, c, and e.

A New Blood Factor, s, Allelic to S

Summary A new blood factor, s, is described with the aid of an antibody produced by transplacental isoimmunization. Evidence is presented to show its genetic relationship to the S factor, which is probably linked to the M and N system.

THE IDENTIFICATION AND CHARACTERIZATION OF A CALCIFIED LAYER OF CORONAL CEMENTUM IN ERUPTED BOVINE TEETH.

Chemical analyses of the outer one-third of the enamel from erupted bovine teeth showed a very much higher content of hydroxyproline than samples obtained from the middle third of the enamel. The source of this hydroxyproline was found to be a layer of calcified collagen, external to and covering the enamel, and continuous with the cementum covering the roots. A review of the literature revealed that early histologists had described an external layer of coronal cementum not only in Ungulata, but in human teeth as well. The coronal cementum may account for the high hydroxyproline content of enamel prepared from erupted human teeth.

Anti‐LW Specificity in Autoimmune Acquired Hemolytic Anemia

Anti‐LW has been demonstrated in six unselected cases of acquired hemolytic anemia, either by direct testing or after absorption of the sera and cell eluates with Rh‐positive or Rh‐negative LW‐negative cells. Another antibody which is directed toward the Rh complex is also present as indicated by reactions with all bloods except Rhnull. A third agglutinin, apparently nonspecific, is indicated by the reactions of some sera with all bloods including Rhnullnull.

Isoimmunization in Pregnancy and the Varieties of Isoagglutinins Observed.

The production of immune isoagglutinins following repeated transfusions, although of common occurrence in some animal species, is very rare in man. The first instance of this sort in man was described by Landsteiner, Levine, and Janes. 1 Levine and Stetson 2 described a case in which an intra-group ag-glutinin was responsible for severe post-transfusion symptoms, with anuria after the first transfusion. This occurred in a woman who, after retaining a dead fetus for a period of about 2 months, finally delivered a macerated fetus. In view of the activity of the agglutinin at 37° C and because of its gradual disappearance, it was believed that the antibody developed as a result of immunization, and it was suggested that the products of the retained dead fetus served as the antigenic stimulus. This suggestion seemed plausible because the cells of the husband, of the same blood group, (who was the donor) were sensitive to the action of the agglutinin. Presumably, the fetus inherited from the father a dominant agglutinogen which was absent in the tissues of the mother, who could thus be immunized. Our own recent experience and other cases from the literature 3 indicate that the isoimmunization-hypothesis may hold also in certain cases of pregnancy with complications other than the retention of the dead fetus. In each of the cases cited, atypical agglutinins could be demonstrated in the absence of a history of repeated blood transfusions. In 5 cases 4 there was a history of varying degrees of toxic symptoms during the pregnancy (in 2 of which macerated fetuses were delivered). In one of these cases, the patient had some fever, and rupture of the membranes occurred a few days before delivery, which was normal but followed by a post-partum endometritis. In 3 patients 5 the agglutinins were observed following abortion, one of them of the septic variety. One patient, whose eighth pregnancy resulted in premature separation of the placenta, had stillbirths in the 4 preceding pregnancies. 6 In 2 of the remaining 3 cases there were histories of repeated miscarriages but the present pregnancies, apparently normal, had to be terminated by Caesarian section.† In one case the pregnancy was normal except for morning vomiting during the last six weeks; due to lack of progress in labor the delivery was by Caesarian section. 7