Karl landsteiner and his major contributions to haematology

Abstract

Karl Landsteiner was born in Vienna in 1868. He graduated from the Vienna Medical School in 1891, which dominated one of his most productive and formative periods in the following years. Although he devoted himself to research in bacteriology, haematology and immunology, he tried to maintain a close relationship with clinical medicine. Landsteiner's intellectual curiosity was centred on fundamental questions about the specificity of antisera directed against various antigens. His research with chemically modified proteins also led to the concept of the specificity of serological reactions, defined in his classical book on this subject. The attachment of small organic molecules to proteins, which in 1921 he called ‘haptens’, was the foundation for future immunological research into the nature of antibody-combining sites, antigenic determinants and antibody–antigen binding forces. In 1930, Landsteiner was awarded the Nobel Prize for his description of the human ABO blood group system, which he himself considered an accidental discovery. Karl Landsteiner discovered human blood groups in 1900 and laid the foundation for the modern medical practice of blood transfusion. The ABO blood groups have a role in physiology beyond their importance for blood transfusion. In the past few years, red cell antigens (A and B carbohydrate structures) have been found on a variety of cells, tissues and proteins, indicating that these antigens might be involved in different physiological processes. The blood group O has an edge in Darwin's concept of the survival of the fittest because it confers protection from vascular diseases. Many studies have established a relationship between the ABO blood groups and the risk of coronary heart disease, atherosclerosis and venous thrombosis (Souto et al, 2000). Hypercoagulation is a risk factor for vascular diseases. It can be caused by excessive concentrations of proteins whose function is to maintain haemostasis. Such proteins include factor VIII (FVIII) and von Willebrand factor (VWF). Lower concentrations of VWF and FVIII are found in the circulation of people who have blood group O than in those with blood group A, B or AB (Souto et al, 2000). The mean VWF antigen concentration is 25% lower in blood group O than in other blood groups (Moeller et al, 2001; O'Donell & Laffan, 2001). This often leads to diagnostic difficulties in distinguishing mild forms of the inherited bleeding disorder, type I von Willebrand's Disease (VWD), from a healthy blood group O (Nitu-Whalley et al, 2000). Plasma phenotypes differ between OO and non-OO genotypes. Recently a link was found between the ABO gene locus and the VWF antigen concentration, and one was suggested between the ABO gene locus and FVIII coagulation activity (Souto et al, 2000). Blood groups influence the VWF antigen level not only in normal subjects but also in heterozygous VWF-deficient subjects who have a null allele with certain missense mutations in the VWF gene. The heterogeneity of plasma phenotypes in heterozygous carriers for type 3 VWD might be due to blood groups (Castaman & Elkenboom, 2002). Von Willebrand factor is a large multimeric glycoprotein that is synthesized in endothelial cells and megakaryocytes. It has a dual role in haemostasis. In primary haemostasis, VWF is essential for the adhesion of platelets to sites of vascular injury. In its second role, VWF is crucial to intrinsic coagulation because it binds to the amino-terminal part of FVIII and preserves it in the circulation (Schwarz et al, 2002). Mature VWF is heavily glycosylated, containing 12 ASN-linked 10 Ser/Thr-linked oligosaccharide chains. The N-linked oligosaccharide chains contain the ABO blood group antigens (Matsui et al, 1993; Sarode et al, 2000). Studies on ABO-mismatched bone marrow transplantations indicate that platelet-derived VWF synthesized in megakaryocytes does not contain these blood group antigens in contrast to the endothelial-cell-synthesized VWF found in plasma (Matsui et al, 1999). The only other known plasma proteins that contain ASN-linked ABO blood group antigens are alpha 2 macroglobulin and FVIII (Matsui et al, 1993). The biological function of blood group antigens on VWF and FVIII is still not clear but blood group sugar chains might influence the functional properties of VWF such as ristocetin-induced platelet agglutination or the metabolic clearance of VWF and its susceptibility to proteolysis (Sarode et al, 2000). The first description of the congenital dysfunctional state of VWF in causing bleeding was published by Erik von Willebrand (von Willebrand, 1931), 1 year after Karl Landsteiner was awarded the Nobel Prize in Physiology or Medicine for the discovery of human blood groups. In his 17th publication, a 1·5 page communication in the Wiener Klinische Wochenschrift (the organ of the Royal and Imperial Society of Physicians in Vienna), which appeared on 14 November 1901, Karl Landsteiner classified blood into three groups according to its agglutination properties (Landsteiner, 1901). Landsteiner was working at the Department of Pathological Anatomy at the University of Vienna at this time. Landsteiner crosstested sera and red cells from six healthy scientists: five co-workers and himself. He found that none of the sera reacted with their own red cells but Dr Pletsching's serum reacted with Dr Sturly's cells and Sturly's serum reacted with Pletsching's cells. This suggested at least two classes of antibodies were involved, which Landsteiner named anti-A and anti-B. Accordingly, Dr Sturly carried the A antigen on his red cells but had anti-B antibodies in his plasma and Dr Pletsching had the B antigen on his red cells and anti-A antibodies in his serum. Landsteiner's own cells contained neither A antigen nor B antigen but both antibodies, indicating what is now called blood group O (Fig 1). The fourth and rarest group, AB, in which both antigens are present on red cells, and the serum contains neither anti-A nor anti-B antibodies, was described 1 year later by Sturli (Landsteiner's pupil) and von Decastelo (von Decastelo & Sturli, 1902). Landsteiner noted in his paper that his laboratory colleagues' sera did not react with their own red cells (Landsteiner, 1901), an observation that could be considered as the first description of self-tolerance. Landsteiner also mentioned that he had obtained similar results from a patient with haemophilia and 10 additional healthy volunteers, but he did not include these results in a table in the paper. The results of Karl Landsteiner's original 1901 blood group experiments. The table shows the results obtained when mixing the sera and red blood cell suspensions from five of his colleagues and himself. (Wiener klinische Wochenschrift, 1901, 14: 1132). Reprinted with permission from the Institut für Geschichte der Medizin, Vienna. Landsteiner found that the agglutination reaction could be carried out with dried blood samples. He reproduced his results after 14 d of drying and furthermore realized the importance of this observation for forensic purposes. It struck the scientist as strange that he found so few different agglutinins in his subjects. He puzzled over the reasons for the agglutinins and referred to Philipp Eisenberg of the Second Department of Internal Medicine in Vienna, who thought that they were caused by the resorption of red cell particles. Landsteiner, however, rejected this idea because in earlier experiments with animals he had not been able to produce autoagglutinins after injecting the animals with their own suspended red cells. Landsteiner seemed to favour the theory of agglutinins forming as a result of a physiological decay of organ tissue but ultimately he was not able to resolve whether they were a phenomenon of auto-immunization induced by the resorption of red cell particles or were linked to diseases from which people had recovered. Now, 100 years later, the exact triggers responsible for the production of anti-A and anti-B in humans have yet to be identified. The paper concluded with a sentence in which Landsteiner stated that his observations might explain the variable clinical consequences of human blood transfusion. The style of this paper is defensive in some parts. He states, referring to a footnote published earlier, that the experiments he presents show ‘my (previous) results do not require any correction’. In a footnote to this article, he complained about Eisenberg alternately attacking and confirming his work. He seems to have been angered by Eisenberg's failure to cite his work in the text, although it was included in the reference list. The recommendation Landsteiner made 1 year later to use blood grouping for paternity cases suggests that he believed that the A–B classification was genetic but he did not elaborate on this (Owen, 2000). The four blood groups were well established by 1902 and completely described in Landsteiner's monograph on haemagglutination and haemolysis (Landsteiner, 1907). In 1910, von Dungern and Hirszfeld showed through family studies that agglutinogens A and B have a Mendelian pattern of inheritance, suggesting two genes, A and B, each with a recessive allele (von Dungern & Hirszfeld, 1911). Today, 100 years after Landsteiner's description of the two blood groups (antigens A and B), 270 blood group determinants are known (Daniels, 2001). Of these, 227 belong to one of 26 blood group systems. Almost all the genes of the 26 systems have been cloned and sequenced, and the location at the respective chromosomes identified. The molecular bases for most of the blood group polymorphisms are also known. In contrast, only little is known about the function of blood group antigens and the physiological role of polymorphisms, which have been shown to influence the immune response to allogeneic transfusion. Most red cell antigens are located on integral membrane polypeptides and glycoproteins. Blood group antigen bearing proteins have a diversity of biological functions, ranging from adhesive properties, playing a role in the context of sickle cell disease, to complement-related functions and enzymatic or transport functions (Rao et al, 1991; Parsons et al, 1999). The genes responsible for ABO blood group polymorphisms do not encode the antigen directly but produce glycosyl transferases that regulate the addition of monosaccharides to an oligosaccharide substrate (Schenkel-Brunner, 2001). Antibodies to the A and B antigens described by Landsteiner are found in all adults who do not carry the corresponding antigens on their red cells. Most antibodies to other blood groups are induced by immunization with antigen-positive red cells after exposure through transfusion or pregnancy. The first scientific communication on blood transfusion was made to the Royal Society in London on the 16 September 1666. A report on dog–dog blood transfusion from the physiologist R. Lower was read to the Society which was sufficiently impressed to request the experiments, in which blood was infused from one dog's cervical artery directly into another's vena jugularis, be repeated at the next monthly meeting. Lower also pointed out that transfusion did not alter the character or behaviour of the dog. Following the demonstration, most experiments were successful. Death of a recipient animal was rare but transfusion between different species was often associated with death (Benedum, 1996). The first successful blood transfusion to a human was in 1667 when the French physicians Denis and Emmerez transferred 9 ounces of blood from the carotid artery of a lamb into the vein of a young man. This was followed by other similar procedures until a fourth patient died. This unlucky patient had already had one successful transfusion but after the second, ‘his arm became hot, the pulse rose, sweat burst out over his forehead, he complained of pain in the kidneys, the next day the urine was dark, in fact black’. These symptoms are consistent with a haemolytic reaction caused by immunization of the patient to the sheep's blood given in the first transfusion. Finally, a third transfusion resulted in the patient's death. The patient's wife accused Denis of having poisoned her husband and sought redress in what was probably the first lawsuit for death from blood transfusion. Denis was exonerated but the court nevertheless made a ruling prohibiting such transfusions in the future unless prior approval was obtained from the Académie de Médicine. The French parliament, the Royal Society and the Catholic Church subsequently issued a general prohibition against transfusions. For 150 years, transfusion was banned from orthodox medical practice (Blakemore & Jennett, 2001). The detrimental effects of transfusing animal blood into humans were not clarified until the 19th century. In 1875, Landois and Ponfick found that human serum was able to haemolyse or clump red cells from other mammals. The ability of animal serum to react with red cells of another species was attributed to the presence of natural antibodies, heterohaemolysins or heteroagglutinins (Landois, 1875). In 1898, Bordet showed that both antibodies increased in titre after immunization of rodents, which explained the harmful results of repeated transfusions of sheep blood to the same patient by Denis (Bordet, 1903). Landsteiner conducted similar experiments on the production of immune heteroagglutinins by injecting blood from one animal into another but withdrew the manuscript when Bordet's publication appeared (Wiener, 1969). The short article in the Wiener Klinische Wochenschrift describing human blood groups was a follow-up to a footnote on another paper published by Landsteiner 1 year earlier in a bacteriological journal (Landsteiner, 1900). The footnote, which seems out of context with the text of the article, mentioned the phenomenon of isoagglutination of human blood for the first time and stated that serum from healthy humans not only agglutinates red cells from animals but also frequently agglutinates red cells from other humans. Landsteiner left open whether this observation was due to original individual differences or was caused by bacterial damage but did mention that the agglutination reaction was more pronounced in blood from people who were seriously ill than in blood from healthy subjects. The paper, with its footnote, was submitted on 10 February 1900 when Landsteiner was working at the University Department of Pathological Anatomy under Weichselbaum. It is divided into four parts and is a rather confusing paper describing, amongst other things, experiments on exsanguinating dogs to obtain fluids from various organs after perfusion. In part one, he described the inhibitory effects of rabbit serum towards rat trypsin. Landsteiner found that the sera from guinea pigs, rabbits and rats differ in their capacity to inhibit trypsin. Nowadays it is obvious that Landsteiner's observations were due to the effect of serine protease inhibitors, especially alpha-1 antitrypsin, rather than specific antibodies against trypsin. In Landsteiner's experiments, freshly homogenized organs such as liver and spleen as well as fresh blood inhibited trypsin activity, but after heating the organs and blood this inhibitory effect was abolished. This section of the paper was entitled, ‘The presence of antifermentative (perhaps equivalent to “anti-enzymatic” today) substances in the organisms’. Landsteiner had wanted to investigate how animal tissue is protected from endogenous proteases. He came to the conclusion that the underlying mechanism was associated with humoral or cellular immunity of tissues towards enzymes. The first reference to Landsteiner's famous footnote, on the agglutination of human red cells by serum of other humans (even before Landsteiner's original article on the agglutination of normal human blood), can be found in a publication by Josef Halban, who later held the chair of the Department of Gynaecology at Vienna University. In his paper, Halban described agglutination experiments with serum from women who had delivered normal healthy infants (Halban, 1900). He built his studies on Landsteiner's observation that human serum usually agglutinates red cells not only from other species but also from other humans. Halban collected blood from the mother and fetus through the vagina immediately after delivery and studied the effect of the serum from one on the red cells of the other. He believed that the agglutination he observed was due to mutual immunization between mother and child through naturally occurring substances. The introduction into clinical practice of the ABO blood grouping test for selecting donors made safe transfusion possible. As early as 1921, Unger reported intragroup transfusion reactions and recommended that, after the appropriate ABO donor had been identified, additional tests should be carried out to exclude the possibility of a recipient serum agglutinating the donor's red cells (Unger, 1921). After blood banks were established in the 1940s, thousands of transfusions were given daily and the incidence of intragroup haemolytic reactions increased (Wiener, 1969). Often, patients who had received previous blood transfusions without reactions became immunized against agglutinogens present in the donor's red cells but absent from their own. In 1939, Levine, with whom Landsteiner discovered the MN types, reported an unusual case of intragroup agglutination (Levine & Stetson, 1939). This woman, who had been admitted to the Bellevue hospital in New York, had a stillbirth. Her fetus was macerated and she needed a transfusion. She had not previously received any blood transfusions and was given whole blood from her husband who was also group O. Within 10 min, she developed severe symptoms and more bleeding. A cross-match revealed that her serum agglutinated her husband's cells. Of a total of 104 group O blood samples tested against her serum only 21 were compatible. Levine suggested that there had been an isosensitization in this woman caused by ‘products’ from the fetus. The discovery of the Rh factor by Landsteiner and Alexander Wiener in 1940 provided the pathophysiological basis for erythroblastosis and possibly explained the Levine case as having been caused by isosensitization to Rh antigen (Wiener, 1969). Alexander Wiener did not work at the Rockefeller Institute, where Landsteiner had his laboratory at the time, but in the serological laboratory at the chief medical examiner's office in New York City. Wiener was interested in studying the evolution of agglutinogens M and N in anthropoid apes and monkeys. He obtained a series of anti-M and anti-N sera from rabbits, allowing him to study the inheritance of MN types (Wiener, 1938). Although all the anti-M sera reacted with human red cells, some strongly agglutinated rhesus monkey red cells and some did not. Absorption of the antisera with human M cells completely removed the antibody specificity for monkey red cells. Rabbits immunized with red cells of rhesus monkeys gave anti-M reactions after the sera with human N cells. the anti-M from the rabbit sera was red cells from of were The blood factor by this was different from all discovered previously and was named Rh Although this was made in publication was until 1940 to the for production of sera to be & it was believed that animal and human antibodies a on the of both rhesus and human red blood cells, but this was not the The original and by Landsteiner and have The was Landsteiner and and the human was & 2000). The Rh blood group is the most of all human blood groups and is of at least antigens. The antigen is and an immune response in of people when with of in most is for blood donors and directed against Rh antigens are usually and of red cells or red blood cells in haemolytic of the This is caused by antibody through the binding the antigen-positive red blood cells and to & 2000). the use of Rh was antibo

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