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 he was not able to they were a of by the resorption of red cell or were to from which people had the for the of anti-A and anti-B in have to be The paper with a in which Landsteiner that his might the clinical of human blood transfusion. The of this paper is in He to a published that the experiments he results not In a to this he about Eisenberg and his He to have been by to his in the it was in the The Landsteiner 1 year later to blood for that he that the was but he did not on this 2000). The blood groups were established by and described in Landsteiner's on and (Landsteiner, In von and studies that A and B have a of two A and with a allele (von & after Landsteiner's description of the two blood groups A and blood group determinants are known 2001). to one of blood group the of the have been and and the at the The for most of the blood group are also In only is known about the function of blood group antigens and the physiological role of which have been to influence the to transfusion. red cell antigens are on and Blood group antigen proteins have a of biological from a role in the of cell disease, to and or et al, et al, 1999). The for ABO blood group not the antigen but produce that the of to an oligosaccharide 2001). to the A and B antigens described by Landsteiner are found in who not the antigens on their red cells. antibodies to other blood groups are by with red cells after or The first communication on blood was to the Royal Society in on the A on blood from the Lower was to the Society which was to the in which blood was from one into be at the Lower also out that did not the or of the the most experiments were of a was but between different was often with The first blood to a human was in when the and of blood from the of a into the of a This was by other similar a fourth patient This patient had had one but after the the out over his he of in the the the was in are with a reaction caused by of the patient to the blood in the first transfusion. a in the The of and in what was the first for from blood transfusion. was but the a such in the future was obtained from the The the Royal Society and the a against years, was from medical practice & 2001). The of blood into were not the In and found that human serum was able to or red cells from other The of serum to react with red cells of was to the of antibodies, or In that both antibodies in after of which the results of of blood to the patient by Landsteiner similar experiments on the of by injecting blood from one into but the when appeared The in the Wiener Klinische Wochenschrift human blood groups was a to a on paper published by Landsteiner 1 year earlier in a (Landsteiner, The which out of with the of the mentioned the of of human blood for the first and that serum from healthy not only red cells from animals but also red cells from other Landsteiner this observation was due to original or was caused by but did that the agglutination reaction was in blood from people who were than in blood from healthy subjects. The with its was on 10 1900 when Landsteiner was working at the University Department of Pathological Anatomy It is into and is a paper other experiments on to from various after In part he described the of serum Landsteiner found that the sera from and differ in their to it is that Landsteiner's were due to the of than antibodies against In Landsteiner's such as and as as blood but after the and blood this was This of the paper was of to in the Landsteiner had to tissue is from He to the that the was with or of tissues The first to Landsteiner's on the agglutination of human red cells by serum of other Landsteiner's original on the agglutination of normal human can be found in a by who later the of the Department of at Vienna In his described agglutination experiments with serum from who had normal healthy He his studies on Landsteiner's observation that human serum red cells not only from other but also from other blood from the and the after and the of the serum from one on the red cells of the He that the agglutination he was due to between and The into clinical practice of the ABO blood for as and after the ABO had been additional be carried out to the of a serum the red cells blood were established in the of were and the of who had blood against present in the red cells but from their In with Landsteiner discovered the an of agglutination & This who had been to the in had a was and a transfusion. had not blood and was blood from who was also group 10 and A that serum cells. a of group O blood against serum only were suggested that had been an in this caused by from the The discovery of the factor by Landsteiner and Wiener in the for and the as been caused by to antigen Wiener did not at the Landsteiner had his laboratory at the but in the serological laboratory at the medical in Wiener was in the of and in and He obtained a of and sera from to the of Although the sera reacted with human red cells, red cells and did of the antisera with human cells the specificity for red cells. with red cells of after the sera with human cells. the from the sera was red cells from of were The blood factor by this was different from discovered and was named Although this was in was to the for of sera to be & it was that and human antibodies a on the of both 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 blood group is the most of human blood groups and is of at least antigens. The antigen is and an in of people when with of in most is for blood and directed against antigens are and of red cells or red blood cells in of the This is caused by the binding the red blood cells and to & 2000). the of was antibodies caused as a result of the of and The the of after of could be due to antigen or a of the are by are also for when they are The primary of for this is to be an immunological of the system, of platelets with a in the platelet & for for a original for antibodies for diagnostic purposes. In his Wiener found the most of sera were people by or transfusion. Wiener serum for the by injecting small red cells into people who were and could a The of serum from with a small of red cells. least two for the of antibodies were the of the Royal and Imperial Society of Physicians in Vienna on Landsteiner the of to of from a who after d of at the in the This fundamental but laid the foundation for the of this Although the of was and to from various the was not by It from this communication for the first by to in and be by in Although the of to and caused neither nor in the the two which were by Landsteiner of and one of Landsteiner his experiments with from who a in & In with the in Landsteiner did and experiments with containing and studies laid the foundation for diagnostic Landsteiner, with and from the was the first to for the of Landsteiner was awarded the Nobel Prize in Physiology or Medicine after his description of human blood groups in the Wiener Klinische this he had and was working at the in Landsteiner did not his discovery of blood groups as his most to medical as he was to the he have to be for his on the specificity of serological In his Nobel in human on 1930, Landsteiner his at the large of that were and the of the might have been (Landsteiner, to to 10 were in and in one the were between and two with results due to blood group In Landsteiner's the most for a blood was or from or from large in or caused by or He out that the of blood which in often the was of as a result of blood factor was that the their functional in the circulation for were due to and he also of blood in the bone Landsteiner referred to following as of and it was that in these the of blood was than the of the the he had often been with after not only to blood but also to as a He such when the patient was in a Landsteiner on to that results had also been obtained with to with and In other in which had been the results however, been The of the blood group had a to because it was as than the of blood It was not that the of an the This was in to the in the when were and the of was Landsteiner his Nobel Prize by his about the of between proteins that could antibodies to a he thought had not been in and proteins after to be a Landsteiner to that studies of with to and the of reactions, and to the which still The in Vienna in the is in a which appeared in November on the of the of Landsteiner's Nobel that those who for have of and into their is for a has this has not been the of red cell antigens and their clinical to still are to be in the of one in to one in in 12 red cell were in the of which an of 12 could have been & 2002). blood and other have the risk of human to 1 in and the risk for B to 1 in et al, The risk of is now in the of one in et al, the most risk of blood and ABO for of the in one in 12 to one in with clinical of to transfusion. have because of antibodies to red cell antigens that are by transfusion. of of red cells has been suggested in the of for over of of risk of or the known risk of by as as 10 over blood in be as by the to the patient from & 2002). to the of at the of the in to the of Landsteiner's discovery of antibodies directed against human red cells in healthy serum on the of at that 2002). The questions after Landsteiner's blood group discovery which caused the of these antibodies and against which an had to himself. the of the and had only one to the against such as other than to the for survival was The of to were described by the experiments by in were into and the in and & results the the which the of and the on which experiments by different groups in were von the first of the Department of at the University of Vienna, original experiments with he had obtained from but he the with an serum the The in in a This was the first of the of an against and was by and his the in a of experiments. In the observation to the Royal Society in and to the Royal and Imperial Society of Physicians in Vienna to the observation a in at the for Internal Medicine in in the year and his by in serum and was to the reaction to from the Medical in of for the clinical of in of however, also to on the of by the agglutination His in a to The after a similar from A over was with the which is still the for the diagnostic agglutination for Landsteiner in He for 2 and was involved in studies on the agglutination of discovery of antibodies against in it that was not only a reaction against caused by but a to to Landsteiner was the first to that and antibodies can be obtained by injecting and that the was not as a to against an but a reaction (Landsteiner, Landsteiner's of the and role of human agglutinins was one of three the of the Royal for considered his own to result from the against autoagglutinins to be with blood and to result from the immunological in a normal Philipp who in the as Landsteiner in the Vienna University these in 1901 1901), his own results of human sera for and on normal human red cells. He had noted that cells were by their own serum. Eisenberg was that the agglutinins or antibodies were not for and not for diagnostic purposes. He the agglutinins were the result of the resorption of red cells. It was after in the Wiener klinische Wochenschrift that Landsteiner's paper on the agglutination of normal human blood groups for the first appeared in the was the to Landsteiner's of In 1901, at the of the of and in rejected a role for agglutinins in the and as with function for 1901). He what it that are in the blood circulation directed against which normal can into the and is it to the it has in its blood directed against the red cells or against of other antibodies had and were part of a of in different and in different physiological processes. a of different for antibodies on cell with his the reaction was for the metabolic survival of the cells or for to other his Karl was born in Vienna on 14 Landsteiner was a in Vienna, a of in which both the and Landsteiner, of was a and is often as the of modern He had as a for in and been a in at the University of In the year of the he had to Vienna and for a few the of himself. at the of when Karl was only Karl by his who from a from in 2002). The to be an and the in the of Vienna, an for classical of which was The a from into and as as a to In Karl Landsteiner his medical studies at the at the Vienna Medical He with a to his in and his at the Second for Internal one of the medical at the University of Vienna. the who is known for the first description of was of this The between and found Landsteiner his studies in in with who the Nobel Prize in in and in he his first as an in von in Vienna of Landsteiner was to the on the fundamental of and between and The working at the of caused to in to the in Landsteiner was only at the for a he to the Department of Pathological Anatomy in the of working as an for the first This was by (the of the of Landsteiner for the of in in but was and at the Department of Pathological Anatomy the of He what was one of the most productive periods of his with such as and the who discovered the Landsteiner himself and than in his own this he published which were of a serological 12 with and and with and than for about one of the in the his from Landsteiner and his had to a for because were only to in the Landsteiner was to a his to that had been for on a for in Vienna that might have in his to this for to his later to and in the his own and his from the Landsteiner's to he had been in the of that he had of the Department of Pathological Anatomy and of the which is still one of the in Vienna, with over His at the for 12 and of his of were published this time. the of in Landsteiner was a of the but to after their had one who was to a in the of in Vienna was with and were such in Landsteiner was that he was to his and as the at the but with The their own or for other reasons to with a to the of His was a factor in to a but the that from his intellectual curiosity the of research was a for He a at the in The the of his but his of the 12 he published this were in He in for a to to Vienna but an to to the with and their with who was the of the and had earlier Landsteiner's he the in and his by the in to of the The Landsteiner in the Landsteiner for He only had a small his Nobel Prize a laboratory and His at this was in the and immunological of and with he that to certain is by by of these with in which cells from a were into a normal were the of studies on the of and other the of years, Landsteiner as an of the He a heart at the and 2 later on after the of his Landsteiner's discovery that red cells from people are by serum from was the of the Blood had been as the of and and medical The the of and is with and is also the of the he of and the of the The of blood as a for from blood to blood was Landsteiner's In the than 12 of plasma for factor and Landsteiner a to the of medicine. He the antigenic properties of chemically modified proteins, and to antigens by small organic which he named & Landsteiner, The of to immunological research the into the of sites, antigenic determinants and antibody–antigen binding forces. In only 3 after his on the blood Landsteiner, with a to the of & Landsteiner, Landsteiner research on in which led to the of for the of with the of antibodies for diagnostic as as et al, His concept of the specificity of serological was in his The of this a for (Landsteiner, Landsteiner's were the in and His were the for in for the of in the (Fig A by intellectual is to in of (A and A Dr Karl The in circulation the of the 1 the of physiology and to which Landsteiner devoted his Landsteiner a Landsteiner to the of A of a Landsteiner from to and that the causing to a group of A of an for his to He was the first to antibodies by blood groups from the discovery of blood a of his The of the was by The to and for their The this in their The in this not the of this was a cell the first description by and by and Landsteiner by and of was This described the of to red cell agglutination in