Jan Klein
Encyclopedia
Jan Klein is a Czech-American immunologist, best known for his work on the major histocompatibility complex
(MHC). He was born in 1936 in Stemplovec, Opava, Czech Republic. He graduated from the Charles University at Prague, in 1955, and received his M.S. (Magna Cum Laude) in Botany from the same school in 1958. He was a teacher at the Neruda High School in Prague from 1958 to 1961. He received his Ph.D. in Genetics from the Czechoslovak Academy of Sciences in 1965, and moved to Stanford University
as a postdoctoral fellow the same year. He became assistant professor in 1969, and associate professor in 1973 at the University of Michigan
. He assumed the position of professor at the University of Texas Southwestern Medical School in 1975. From 1977 to his retirement in 2004, he was the Director of the Max-Planck-Institut für Biologie at Tübingen, Germany. He is currently a Frances R. and Helen M. Pentz Visiting Professor of Science and Adjunct Professor of Biology at the Pennsylvania State University
.
, immunology
, and evolutionary biology, as well as one interface discipline: immunogenetics
. His major research focus was on the major histocompatibility complex
, (MHC or Mhc), which comprises series of gene
s, which play a critical part in the initiation of the adaptive immune response (AIS), exemplified by the production of antibodies specific for different pathogen
s.
, in which he conceived the discipline as a branch of biological sciences, rather than as a narrow province of medical studies, as it had been represented traditionally. He defined immunology
as the science of self-nonself discrimination, concerned not just with the human species
and its animal models (mouse, rabbit, and others), but with all organisms; and not just with issues of human health, but with normal physiological functions, executed with specialized body systems. He was the first to include in an immunology
textbook sections emphasizing the importance of the so-called non-adaptive immune system (NAIS; he preferred to call it non-anticipatory). He also gave immunology
a logical internal structure. Instead of organizing his textbooks into sections such as immunochemistry
, immunobiology, immunogenetics
, immunopathology
, and so on, as was then customary (i.e., according to immunology
’s interfaces with other disciplines and leaving very little for immunology
itself), he presented it as a self-contained science
. He organized it as a science
operating with specialized organs
, cells, gene
s, molecules, mechanisms, phenotype
s, and functions.
discipline. Immunogenetics
emerged in the 1930s as the study of genes controlling antigens (such as those of the various blood group systems) detected by antibodies. This was a very artificial delineation of a discipline, based essentially on a method, rather than on an internal content. In Klein’s conception, immunogenetics
was to deal with what immunology
and genetics
have in common—a set of gene
s that control and effect immune responses of any kind.
, T-cell receptor (Tcr), and B-cell receptor
(Bcr, the antibodies) proteins. Klein contributed to the study of all three systems, but his primary interest was in the Mhc
system. He developed the modern concept of the Mhc
as consisting of two principal kinds of gene
, for which he coined the designations class I and class II gene
s. The class I gene
s were discovered in 1936 (the year Jan Klein was born) as coding for blood group (red blood cell) antigen
s, which, however, were also responsible for the rejection of incompatible grafts. Klein, with his coworker Vera Hauptfeld and his wife Dagmar Klein, were the first to describe the product of the class II gene
s and identify them as the molecules that control level of antibodies synthesized in response to foreign antigen
s. Earlier, Hugh O. McDevitt and his coworkers mapped an Immune response-1 (Ir-1) locus
influencing the level of antibody
production against the synthetic polypeptide (T,G)-L—A into the Mhc
. Klein and his coworkers, finding their locus
inseparable from the postulated Ir-1 locus
, concluded that the class II antigen
s they demonstrated on the surfaces of lymphocyte
s were the product of the Ir-1 locus
. Later studies confirmed this interpretation. Genetic mapping of the loci
controlling the class I and class II antigen
s of the mouse showed them to be part of a cluster, which Klein mapped to the chromosome
17 and for which he championed the name Major histocompatibility locus
, Mhc
. The name referred to the fact that the gene
s were part of a set that controlled tissue
compatibility and in this set one cluster had the strongest (major) effect. George D. Snell named the tissue compatibility gene
s histocompatibility 1, 2, 3, etc., in the order of discovery, and since the H2 genes happened to be strongest of the set, they became the first Mhc known. All other histocompatibility genes came to be called minor.
Initially, genetic mapping of the mouse class I antigen
s suggested the existence of multiple class I loci in the H2 complex. Soon, however, inconsistencies in the assignment of certain antigen
s to loci
signaled that something was amiss with the H2 maps, as they were then drawn. Klein and Donald C. Shreffler solved the problem by demonstrating that a given antigen
could be present on molecules controlled by different loci
. Taking this finding into account, they were able to reduce the number of the class I loci
to two, H2K and H2D. This “two-locus model” played a n important part in subsequent interpretations of the Mhc
. The model was also consistent with the results of earlier Klein’s PhD work, in which he discovered that immune selection for a loss of certain H2 antigen
s on somatic cell
s was accompanied by the loss of some but not other unselected antigen
s. In this respect, the antigen
s fell into two groups as if carried by two different molecules. The discovery of the class II gene
s had been fitted into the model by the demonstration that they mapped between the H2K and the H2D. Shreffler also demonstrated the existence of another locus
mapping between the two class I loci. It coded for what he called the “serum serological” or Ss protein, present in a soluble form in the blood
fluid phase, in contrast to the class I and class II antigen
s, which were expressed on cell surfaces. At that stage, the H2 complex could be divided into four regions: class I (H2K)…Class II (Ir-1)…Ss…Class I (H2D).
These developments alerted immunologists on the one hand and transplantation biologists on the other of the Mhc’s
potential importance for their respective disciplines. The consequence was a proliferation of reports describing association of a variety of phenomena with the complex. The associations were demonstrated by testing the responses of congenic
strains differing at the H2 complex and mapping the gene
s controlling the responses within the H2 complex with the help of strains carrying H2 haplotype
s derived by intra-H2 recombination
s. These strains
were developed by George D. Snell, Jack H. Stimpfling, Donald C. Shreffler, and Jan Klein. The phenomena included control of antibody
response to a variety of antigen
s, both natural and synthetic; suppression of immune response by special suppressor cells
or soluble factors; proliferation of lymphocytes in an in vitro
culture challenged with H2-incompatible stimulating cell
(the so-called mixed lymphocyte
reaction, MLR); killing of H2-icompatible target cells by sensitized lymphocyte
s (cell-mediated lymphocytotoxicity, CML); response of transplanted immune cell
against the tissues
of the host (graft versus host reaction, GVHR); rejection of H2-incompatible grafts (skin, heart, bone marrow, etc.) by the recipients; and others. All these phenomena appeared to be controlled by different loci
within the Mhc
. As a result, the H2 complex appeared to expand by the addition of new loci
(regions). Klein’s group, however, challenged this interpretation and in a series of carefully controlled studies demonstrated that the new loci
were in reality mirages generated by various forms of interaction involving the established class I and class II loci
. In this manner, Klein contracted the H2 complex back to the version established by the serological methods, and propounded the view that the various responses (MLR, CML, etc.) were controlled by the class I and class II loci
, rather than by separate loci
. Later, other loci
were again mapped within the H2 complex and these were no phantoms. They were real but, as Klein argued, they were unrelated to the class I and class II loci
and ended up in the region by chance
. The general opinion was, however, that they represented the class III region of the Mhc
, that they were functionally related to the Mhc
by being involved in immune response, and that the complex functioned as an immune supergene
. The first of these class III loci
was the Ss locus, which was later identified as coding for complement
component 4. The C4 protein was indeed involved in immunity
by being one in a series of protein molecules that attach to a cell-bound antibody
to puncture a hole in it and thus kill it. But nobody could come up with a reason why it had to be linked
to the class I or class II gene
s to function properly. Similar arguments could be applied to the other class III gene
s. Later, Klein’s view received a strong support when his group discovered that in the fishes, which comprise more than half of jawed vertebrate
s, not even the class I and class II gene
s were in a single cluster and the class III gene
s were scattered allover the genome
. Ultimately, the modern concept prevailed against the tendencies to make the Mhc
unnecessarily nonparsimonious.
response by the Mhc
raised many question. The one on the top of immunologists’ agenda was: Why were some individuals carrying a certain H2 haplotype
high responders to a given antigen
, while others, carrying certain other haplotype
were low responders or nonresponders? The phenomenon could be reproduced in vitro
by the exposure to the antigen
. Lymphocyte
s isolated from the high responder proliferated to a much higher degree than those isolated from a low responder individual. The assay required, in addition to the thymus
-derived (T) lymphocytes, also “macrophages” or antigen-presenting cells (APCs) from the same individual. In this set-up the question reduced itself to: Are the T lymphocytes or the APCs responsible for the difference in responsiveness? Many immunologists were inclined to put the blame on the APCs, but the Klein-Nagy group, in a series of elegant experiments, falsified
this hypothesis and explained why T lymphocytes bearing different Mhc
haplotypes might differ in their response to specific antigen
s. The receptors
of the T lymphocyte
s recognize an antigen
in association with their own Mhc
molecules. The different specificities of the Tcrs
born by the individual T cells are generated by a special mechanism during the lymphocyte
development from precursor cells in the thymus
. The generation is entirely random
, so that receptors
arise against all possible antigen
s, including those borne by the individual in which the differentiation takes place (the self-molecules). The cells
with receptors
for self-molecules must be eliminated to prevent an immune reaction against the individual’s own components. The eliminated Tcrs
might, however, by chance
have had the capability of recognizing certain foreign antigen
s (nonself) in association with the nonresponder’ own
Mhc
molecules. The T-cell repertoire thus has “blind spots”, making an individual nonresponsive not only to self but also against certain foreign antigen
s.
These findings were supported by analyses of other markers, primarily chromosomal polymorphism and t-haplotypes. The karyotype of the house mouse normally consists of 40 telocentric chromosomes, but in certain regions in Europe, mice with karyotypes containing fewer than 40 chromosomes can be found. The reduction in chromosome number is due to centric fusion (Robertsonian translocation) of two telocentrics into a single metacentric. Klein’s group found populations with metacentric chromosomes in different regions of Europe, but concentrated its effort on the system of metacentrics in southern Germany. An in-depth study of these populations revealed subdivision into subpopulations, which correlated with that established by the studies of H2 polymorphism.
A t-haplotype is a designation for a chromosomal region adjacent to or encompassing the H2 complex. Three features characterize the t region: suppression of recombination over the entire length of a complete t-haplotype; segregation distortion (t/+ males transmit the t-chromosome into more than 90 percent of their progeny); and frequent presence of homozygous lethal genes. Klein group’s combined t and H2 studies on wild mice from all over the world led to the identification and characterization of a number of new t-haplotypes. Their characterization demonstrated that all the haplotypes were derived from a single ancestral haplotype; that the ancestral haplotype originated in the western European Mus domesticus; that it arose recently; and that from M. domesticus a single t-haplotype introgressed into the eastern European M. musculus, where it then underwent limited diversification.
These studies became Klein’s bridge to evolutionary biology. He crossed this bridge in a series of investigations into the nature of the speciation process in Darwin’s finches and in haplochromine fishes of East Africa. With Akie Sato and collaborators, they provided molecular evidence that the 14 extant species of Darwin’s finches on the Galapagos Islands and the one species on the Cocos Island were all derived from a single ancestral species that arrived on the islands some 5 my ago. They identified the ancestral species as being related to Tiaris obscura, a species now inhabiting Ecuador and other parts of the South American continent. Using DNA markers they were able to determine phylogenetic relationships among the extant Darwin’s finches, except for the group of Ground finches. In the latter, the morphologically poorly distinguishable species were indistinguishable at the molecular level. This result could mean either that the species diverged quite recently and that the polymorphisms of their genomes have not have had enough time to sort themselves out among the species, or that the species continue exchanging genes.
Haplochromines are one of two main groups of cichlid fishes in East Africa; the other group being the tilapiine fishes. Klein and his associates studied both groups and using a variety of molecular markers contributed to the resolution of their phylogenetic relationships. They then focused on the haplochromines of both the lakes, large and small, and the rivers. The studies revealed degree of relatedness between the various groups that correlated roughly with their geographical distribution. The main focus of Klein’s group became Lake Victoria, however. The lake is the youngest of all the large lakes in East Africa, its latest refill after a desiccation dated to 14,600 years ago. The lake is inhabited with more 200 haplochromine species distinguishable morphologically and behaviorally. Contrary to earlier claims, Klein’s group demonstrated that the species are not monophyletic and are by no means pauperized in their genetic polymorphism. They fall into at least two lineages, which separated from each other 41,500 years ago, presumably outside of the lake. The lineages diverged from haplochromines inhabiting smaller lakes west of Lake Victoria more than 80,000 years ago. As in the case of the Ground finches of the Galapagos Islands, the haplochromine species of Lake Victoria are not distinguishable by any molecular markers Klein’s group used in their studies. All population genetics methods used to compute genetic distances showed no significant difference between species and between populations of the same species. In this case, however, Klein’s group was able to rule out insufficient separation time as the explanation of the data and to argue that the explanation lies in the continuation of a gene flow between the incipient species. They argue further that speciation is a protracted affair during which the arising species diverge in a few genes responsible for phenotypic differences, but continue exchanging genes until the emergence of a reproductive barrier stops the process. They argue furthermore that because of this phenomenon, many phylogenies of so-called adaptive radiations will remain unresolved. One such case is the radiation that gave rise to the tetrapods in the evolution of jawed vertebrates. In this case, Klein’s group has demonstrated that increasing the number of genes in the input database does not improve the resolution power of the output phylogenetic trees.
As for the evolution of the Mhc genes themselves, Klein’s group contributed significantly to the description of its general outline. In collaboration with Yoko Satta and Naoyuki Takahata, they developed a method for estimating the evolutionary rates of the Mhc genes and demonstrated that the rate was close to the average rate of most non-Mhc genes, and they provided evidence that the Mhc genes are subject to balancing selection. They also provided evidence that the selection leads to the independent, repeated emergence of similar or identical short sequence motifs by convergent evolution. Klein himself has long championed the view that this mechanism and mechanisms similar to it, rather than the generally favored “gene conversion”, explained the origin of the motifs.
Klein’s group demonstrated that during its evolution, the Mhc undergoes repeated rounds of expansion and contraction by gene duplications and deletions –in Klein’s terminology, an accordion mode of evolution. Thus, for example, they showed that in each of the three major primate lineages – the prosimians, the NWM and the OWM – evolution of some of the class II gene families started anew after a contraction to a single ancestral gene. And on the example of two “class III” genes, C4 and CYP21, they illustrated a mechanism by which the accordion might be expanding and contracting. The C4 gene, as already stated, codes for a component of the complement system; the CYP21gene codes for a key enzyme in the synthesis of glucocorticoid and mineralcorticoid hormones. The two genes are thus unrelated to each other and to the class I and class II genes, but they are accidentally hooked together into a module, which has been found to duplicate or triplicate as a unit during primate evolution. The hook-up seems to have arisen, when an identical short sequence motif arose by chance at both flanks of the initial C4-CYP21 doublet. Since then, an occasional misalignment of the opposite flanks has led to an unequal crossing-over and so to duplications or deletion of the module.
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC). He was born in 1936 in Stemplovec, Opava, Czech Republic. He graduated from the Charles University at Prague, in 1955, and received his M.S. (Magna Cum Laude) in Botany from the same school in 1958. He was a teacher at the Neruda High School in Prague from 1958 to 1961. He received his Ph.D. in Genetics from the Czechoslovak Academy of Sciences in 1965, and moved to Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...
as a postdoctoral fellow the same year. He became assistant professor in 1969, and associate professor in 1973 at the University of Michigan
University of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
. He assumed the position of professor at the University of Texas Southwestern Medical School in 1975. From 1977 to his retirement in 2004, he was the Director of the Max-Planck-Institut für Biologie at Tübingen, Germany. He is currently a Frances R. and Helen M. Pentz Visiting Professor of Science and Adjunct Professor of Biology at the Pennsylvania State University
Pennsylvania State University
The Pennsylvania State University, commonly referred to as Penn State or PSU, is a public research university with campuses and facilities throughout the state of Pennsylvania, United States. Founded in 1855, the university has a threefold mission of teaching, research, and public service...
.
Research interests
Klein’s scientific output encompasses 600 publications in scientific journals and a dozen of books, which he either authored or edited. It spans three major disciplines: geneticsGenetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
, and evolutionary biology, as well as one interface discipline: immunogenetics
Immunogenetics
Immunogenetics is the branch of medical research that explores the relationship between the immune system and genetics.Autoimmune diseases, such as type 1 diabetes, are complex genetic traits which result from defects in the immune system. Identification of genes defining the immune defects may...
. His major research focus was on the major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
, (MHC or Mhc), which comprises series of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, which play a critical part in the initiation of the adaptive immune response (AIS), exemplified by the production of antibodies specific for different pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s.
Redefinition of Immunology
In his textbooks and other writings, Klein introduced a new concept of immunologyImmunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
, in which he conceived the discipline as a branch of biological sciences, rather than as a narrow province of medical studies, as it had been represented traditionally. He defined immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
as the science of self-nonself discrimination, concerned not just with the human species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
and its animal models (mouse, rabbit, and others), but with all organisms; and not just with issues of human health, but with normal physiological functions, executed with specialized body systems. He was the first to include in an immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
textbook sections emphasizing the importance of the so-called non-adaptive immune system (NAIS; he preferred to call it non-anticipatory). He also gave immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
a logical internal structure. Instead of organizing his textbooks into sections such as immunochemistry
Immunochemistry
Immunochemistry is a branch of chemistry that involves the study of the reactions and components on the immune system.Various methods in immunochemistry have been developed and refined, and been used in scientific study, from virology to molecular evolution....
, immunobiology, immunogenetics
Immunogenetics
Immunogenetics is the branch of medical research that explores the relationship between the immune system and genetics.Autoimmune diseases, such as type 1 diabetes, are complex genetic traits which result from defects in the immune system. Identification of genes defining the immune defects may...
, immunopathology
Immunopathology
Immunopathology is a branch of medicine that deals with immune responses associated with disease. It includes the study of the pathology of an organism, organ system, or disease with respect to the immune system, immunity, and immune responses....
, and so on, as was then customary (i.e., according to immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
’s interfaces with other disciplines and leaving very little for immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
itself), he presented it as a self-contained science
Science
Science is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe...
. He organized it as a science
Science
Science is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe...
operating with specialized organs
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
, cells, gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, molecules, mechanisms, phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s, and functions.
Redefinition of Immunogenetics
In his experimental work, his 25 years as a director of the Immunogenetics Division of the Max Planck Institute of Biology, and nearly the same period of time at the helm of the journal Immunogenetics, Klein strived to redefine the immunogeneticsImmunogenetics
Immunogenetics is the branch of medical research that explores the relationship between the immune system and genetics.Autoimmune diseases, such as type 1 diabetes, are complex genetic traits which result from defects in the immune system. Identification of genes defining the immune defects may...
discipline. Immunogenetics
Immunogenetics
Immunogenetics is the branch of medical research that explores the relationship between the immune system and genetics.Autoimmune diseases, such as type 1 diabetes, are complex genetic traits which result from defects in the immune system. Identification of genes defining the immune defects may...
emerged in the 1930s as the study of genes controlling antigens (such as those of the various blood group systems) detected by antibodies. This was a very artificial delineation of a discipline, based essentially on a method, rather than on an internal content. In Klein’s conception, immunogenetics
Immunogenetics
Immunogenetics is the branch of medical research that explores the relationship between the immune system and genetics.Autoimmune diseases, such as type 1 diabetes, are complex genetic traits which result from defects in the immune system. Identification of genes defining the immune defects may...
was to deal with what immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
and genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
have in common—a set of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s that control and effect immune responses of any kind.
Discovery of Class II Genes and the Concept of Mhc
In the adaptive immune system, the three preeminent sets of genes are those that code for the MhcMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
, T-cell receptor (Tcr), and B-cell receptor
B-cell receptor
The B-cell receptor is a transmembrane receptor protein located on the outer surface of B-cells. The receptor's binding moiety is composed of a membrane-bound antibody that, like all antibodies, has a unique and randomly-determined antigen-binding site...
(Bcr, the antibodies) proteins. Klein contributed to the study of all three systems, but his primary interest was in the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
system. He developed the modern concept of the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
as consisting of two principal kinds of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, for which he coined the designations class I and class II gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. The class I gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s were discovered in 1936 (the year Jan Klein was born) as coding for blood group (red blood cell) antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s, which, however, were also responsible for the rejection of incompatible grafts. Klein, with his coworker Vera Hauptfeld and his wife Dagmar Klein, were the first to describe the product of the class II gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and identify them as the molecules that control level of antibodies synthesized in response to foreign antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s. Earlier, Hugh O. McDevitt and his coworkers mapped an Immune response-1 (Ir-1) locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
influencing the level of antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
production against the synthetic polypeptide (T,G)-L—A into the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
. Klein and his coworkers, finding their locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
inseparable from the postulated Ir-1 locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, concluded that the class II antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s they demonstrated on the surfaces of lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s were the product of the Ir-1 locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. Later studies confirmed this interpretation. Genetic mapping of the loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
controlling the class I and class II antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s of the mouse showed them to be part of a cluster, which Klein mapped to the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
17 and for which he championed the name Major histocompatibility locus
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
, Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
. The name referred to the fact that the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s were part of a set that controlled tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
compatibility and in this set one cluster had the strongest (major) effect. George D. Snell named the tissue compatibility gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s histocompatibility 1, 2, 3, etc., in the order of discovery, and since the H2 genes happened to be strongest of the set, they became the first Mhc known. All other histocompatibility genes came to be called minor.
Initially, genetic mapping of the mouse class I antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s suggested the existence of multiple class I loci in the H2 complex. Soon, however, inconsistencies in the assignment of certain antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s to loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
signaled that something was amiss with the H2 maps, as they were then drawn. Klein and Donald C. Shreffler solved the problem by demonstrating that a given antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
could be present on molecules controlled by different loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. Taking this finding into account, they were able to reduce the number of the class I loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
to two, H2K and H2D. This “two-locus model” played a n important part in subsequent interpretations of the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
. The model was also consistent with the results of earlier Klein’s PhD work, in which he discovered that immune selection for a loss of certain H2 antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s on somatic cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s was accompanied by the loss of some but not other unselected antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s. In this respect, the antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s fell into two groups as if carried by two different molecules. The discovery of the class II gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s had been fitted into the model by the demonstration that they mapped between the H2K and the H2D. Shreffler also demonstrated the existence of another locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
mapping between the two class I loci. It coded for what he called the “serum serological” or Ss protein, present in a soluble form in the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
fluid phase, in contrast to the class I and class II antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s, which were expressed on cell surfaces. At that stage, the H2 complex could be divided into four regions: class I (H2K)…Class II (Ir-1)…Ss…Class I (H2D).
These developments alerted immunologists on the one hand and transplantation biologists on the other of the Mhc’s
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
potential importance for their respective disciplines. The consequence was a proliferation of reports describing association of a variety of phenomena with the complex. The associations were demonstrated by testing the responses of congenic
Congenic
In genetics, two organisms that differ in one locus are defined as congenic or coisogenic.-Generating congenic strains:Congenic strains are generated in the laboratory by mating two inbred strains , and backcrossing the descendants 5-10 generations with one of the original strains, known as the...
strains differing at the H2 complex and mapping the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s controlling the responses within the H2 complex with the help of strains carrying H2 haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
s derived by intra-H2 recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
s. These strains
Congenic
In genetics, two organisms that differ in one locus are defined as congenic or coisogenic.-Generating congenic strains:Congenic strains are generated in the laboratory by mating two inbred strains , and backcrossing the descendants 5-10 generations with one of the original strains, known as the...
were developed by George D. Snell, Jack H. Stimpfling, Donald C. Shreffler, and Jan Klein. The phenomena included control of antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
response to a variety of antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s, both natural and synthetic; suppression of immune response by special suppressor cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
or soluble factors; proliferation of lymphocytes in an in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
culture challenged with H2-incompatible stimulating cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
(the so-called mixed lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
reaction, MLR); killing of H2-icompatible target cells by sensitized lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s (cell-mediated lymphocytotoxicity, CML); response of transplanted immune cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
against the tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of the host (graft versus host reaction, GVHR); rejection of H2-incompatible grafts (skin, heart, bone marrow, etc.) by the recipients; and others. All these phenomena appeared to be controlled by different loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
within the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
. As a result, the H2 complex appeared to expand by the addition of new loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
(regions). Klein’s group, however, challenged this interpretation and in a series of carefully controlled studies demonstrated that the new loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
were in reality mirages generated by various forms of interaction involving the established class I and class II loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. In this manner, Klein contracted the H2 complex back to the version established by the serological methods, and propounded the view that the various responses (MLR, CML, etc.) were controlled by the class I and class II loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, rather than by separate loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. Later, other loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
were again mapped within the H2 complex and these were no phantoms. They were real but, as Klein argued, they were unrelated to the class I and class II loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
and ended up in the region by chance
Randomness
Randomness has somewhat differing meanings as used in various fields. It also has common meanings which are connected to the notion of predictability of events....
. The general opinion was, however, that they represented the class III region of the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
, that they were functionally related to the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
by being involved in immune response, and that the complex functioned as an immune supergene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The first of these class III loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
was the Ss locus, which was later identified as coding for complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
component 4. The C4 protein was indeed involved in immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
by being one in a series of protein molecules that attach to a cell-bound antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
to puncture a hole in it and thus kill it. But nobody could come up with a reason why it had to be linked
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
to the class I or class II gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s to function properly. Similar arguments could be applied to the other class III gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. Later, Klein’s view received a strong support when his group discovered that in the fishes, which comprise more than half of jawed vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, not even the class I and class II gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s were in a single cluster and the class III gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s were scattered allover the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. Ultimately, the modern concept prevailed against the tendencies to make the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
unnecessarily nonparsimonious.
Nature of the Mhc-controlled Immune Response
The control of antibodyAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
response by the Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
raised many question. The one on the top of immunologists’ agenda was: Why were some individuals carrying a certain H2 haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
high responders to a given antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
, while others, carrying certain other haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
were low responders or nonresponders? The phenomenon could be reproduced in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
by the exposure to the antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
. Lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s isolated from the high responder proliferated to a much higher degree than those isolated from a low responder individual. The assay required, in addition to the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
-derived (T) lymphocytes, also “macrophages” or antigen-presenting cells (APCs) from the same individual. In this set-up the question reduced itself to: Are the T lymphocytes or the APCs responsible for the difference in responsiveness? Many immunologists were inclined to put the blame on the APCs, but the Klein-Nagy group, in a series of elegant experiments, falsified
Falsifiability
Falsifiability or refutability of an assertion, hypothesis or theory is the logical possibility that it can be contradicted by an observation or the outcome of a physical experiment...
this hypothesis and explained why T lymphocytes bearing different Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
haplotypes might differ in their response to specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s. The receptors
Immune receptor
An immune receptor is a receptor, usually on a cell membrane, which binds to a substance and causes a response in the immune system.-Types:...
of the T lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s recognize an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
in association with their own Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules. The different specificities of the Tcrs
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
born by the individual T cells are generated by a special mechanism during the lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
development from precursor cells in the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
. The generation is entirely random
Randomness
Randomness has somewhat differing meanings as used in various fields. It also has common meanings which are connected to the notion of predictability of events....
, so that receptors
Immune receptor
An immune receptor is a receptor, usually on a cell membrane, which binds to a substance and causes a response in the immune system.-Types:...
arise against all possible antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s, including those borne by the individual in which the differentiation takes place (the self-molecules). The cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
with receptors
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
for self-molecules must be eliminated to prevent an immune reaction against the individual’s own components. The eliminated Tcrs
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
might, however, by chance
Randomness
Randomness has somewhat differing meanings as used in various fields. It also has common meanings which are connected to the notion of predictability of events....
have had the capability of recognizing certain foreign antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s (nonself) in association with the nonresponder’ own
Mhc
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules. The T-cell repertoire thus has “blind spots”, making an individual nonresponsive not only to self but also against certain foreign antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s.
Mhc Polymorphism, Variation in Chromosome Numbers, and t-haplotypes
Typing of inbred strains suggested that the Mhc might manifest unusually high variability (polymorphism). Inbred strains were, however, not suited for determining polymorphism, because assessing it required measuring gene frequencies in populations. There were all sorts of problems associated with such an effort, most of which could, however, be alleviated by transferring a sample of H2 haplotypes from wild mice onto inbred (C57BL/10 or B10) background and thus producing a set of congenic B10.W lines. These lines proved to be essential for the complete characterization of the new haplotypes; for the identification of natural intra-H2 recombinants; and for their use as a tool for mapping H2-associated traits. Using a variety of methods, Klein and his colleagues were able to characterize H2 polymorphism in populations of wild mice from different parts of the world. The studies revealed that the polymorphism was indeed staggering, both in the number of alleles and haplotypes (a haplotype being a particular combination of alleles borne by a particular chromosomal segment) that occurred in appreciable frequencies in the populations. Exceptions from the high polymorphism were found only in certain island populations and in populations that have passed recently through a bottleneck phase. The H2 polymorphism, in combination with other markers, could then be used to characterize a population. H2- typing of the global wild mice population revealed it to be fragmented into a large number of small subpopulations (demes), which differed in the presence and frequencies of alleles at the individual loci. Skin grafting and other methods indicated inbreeding within the demes, but sharing of certain alleles between the demes suggested a continuous gene flow between demes.These findings were supported by analyses of other markers, primarily chromosomal polymorphism and t-haplotypes. The karyotype of the house mouse normally consists of 40 telocentric chromosomes, but in certain regions in Europe, mice with karyotypes containing fewer than 40 chromosomes can be found. The reduction in chromosome number is due to centric fusion (Robertsonian translocation) of two telocentrics into a single metacentric. Klein’s group found populations with metacentric chromosomes in different regions of Europe, but concentrated its effort on the system of metacentrics in southern Germany. An in-depth study of these populations revealed subdivision into subpopulations, which correlated with that established by the studies of H2 polymorphism.
A t-haplotype is a designation for a chromosomal region adjacent to or encompassing the H2 complex. Three features characterize the t region: suppression of recombination over the entire length of a complete t-haplotype; segregation distortion (t/+ males transmit the t-chromosome into more than 90 percent of their progeny); and frequent presence of homozygous lethal genes. Klein group’s combined t and H2 studies on wild mice from all over the world led to the identification and characterization of a number of new t-haplotypes. Their characterization demonstrated that all the haplotypes were derived from a single ancestral haplotype; that the ancestral haplotype originated in the western European Mus domesticus; that it arose recently; and that from M. domesticus a single t-haplotype introgressed into the eastern European M. musculus, where it then underwent limited diversification.
Trans-species Polymorphism
Dictionaries define genetic polymorphism as the presence, in appreciable frequencies, of two or more alleles at a locus in a species. Hence H2 polymorphism was expected to have arisen by an unusually high mutation (evolutionary) rate in the house mouse after its divergence from its nearest relative. There was, however no indication that this was the case. On the contrary, Klein and his co-workers found, by the methods then available, indistinguishable alleles in the two European house mouse species, Mus domesticus and M. musculus, which diverged from each other some 1–2 million years (my) ago. Similarly, in M. domesticus populations, whose divergence times could be dated, they found no new variants. Klein’s group could also not find any new Mhc (HLA) variants in isolated human populations such as those of the South American Indians and the indigenous populations of Siberia. These and other observations led Klein to the formulation of the trans-species polymorphism (TSP) hypothesis positing that the divergence of similar Mhc alleles predates the divergence of the species in which they occur. The original detection of trans-species polymorphism relied on serological (antibody-based) identification of antigenic molecules. Later, however, the identity of alleles in different species could be confirmed by peptide-mapping analysis of the antigenic proteins. Ultimately, DNA-sequencing not only confirmed the results obtained with the earlier methods, but also introduced a new dimension into the TSP studies. The tests revealed that closely related species such as M. domesticus and M. musculus, the many haplochromine fish species in East African lakes and rivers, or Darwin’s finches on the Galapagos Islands, shared many alleles at not only the Mhc, but also at some of the non-Mhc loci. In more distantly related species, such as human and chimpanzee or the house mouse and the Norwegian rat, sharing of identical alleles could no longer be demonstrated, but shared related alleles were clearly in evidence. This finding led to the concept of allelic lineages, in which members of a given lineage in one species were more similar to members of the same linage in another species than they were to other alleles in either of the two species, TSP of Mhc and other loci has since been documented in many species and found applications to a variety of issues in evolutionary biology.Applications of the TSP Concept in Evolutionary Biology
The essence of the TSP concept is that a certain number of alleles at a locus must pass through the speciation phase from the ancestral to the descendant species to assure the retention of the ancestral polymorphism in the new species. If this number is known, the size of the founding population of the emerging species can be estimated. The TSP thus provides a window into the otherwise poorly accessible phase of evolution. Klein’s group used the TSP concept to estimate the founding population sizes of several species. For the human species, the size estimated from the HLA polymorphism was 10,000 breeding individuals. Similarly large founding populations had to be postulated for the two lineages from which most of the hundreds of species inhabiting Lake Victoria in East Africa had diverged. And even for Darwin’s finches, widely believed to have arisen from a single pair of founders, Vincek and his colleagues came to the conclusion that the founding flock was at least 30 heads strong.These studies became Klein’s bridge to evolutionary biology. He crossed this bridge in a series of investigations into the nature of the speciation process in Darwin’s finches and in haplochromine fishes of East Africa. With Akie Sato and collaborators, they provided molecular evidence that the 14 extant species of Darwin’s finches on the Galapagos Islands and the one species on the Cocos Island were all derived from a single ancestral species that arrived on the islands some 5 my ago. They identified the ancestral species as being related to Tiaris obscura, a species now inhabiting Ecuador and other parts of the South American continent. Using DNA markers they were able to determine phylogenetic relationships among the extant Darwin’s finches, except for the group of Ground finches. In the latter, the morphologically poorly distinguishable species were indistinguishable at the molecular level. This result could mean either that the species diverged quite recently and that the polymorphisms of their genomes have not have had enough time to sort themselves out among the species, or that the species continue exchanging genes.
Haplochromines are one of two main groups of cichlid fishes in East Africa; the other group being the tilapiine fishes. Klein and his associates studied both groups and using a variety of molecular markers contributed to the resolution of their phylogenetic relationships. They then focused on the haplochromines of both the lakes, large and small, and the rivers. The studies revealed degree of relatedness between the various groups that correlated roughly with their geographical distribution. The main focus of Klein’s group became Lake Victoria, however. The lake is the youngest of all the large lakes in East Africa, its latest refill after a desiccation dated to 14,600 years ago. The lake is inhabited with more 200 haplochromine species distinguishable morphologically and behaviorally. Contrary to earlier claims, Klein’s group demonstrated that the species are not monophyletic and are by no means pauperized in their genetic polymorphism. They fall into at least two lineages, which separated from each other 41,500 years ago, presumably outside of the lake. The lineages diverged from haplochromines inhabiting smaller lakes west of Lake Victoria more than 80,000 years ago. As in the case of the Ground finches of the Galapagos Islands, the haplochromine species of Lake Victoria are not distinguishable by any molecular markers Klein’s group used in their studies. All population genetics methods used to compute genetic distances showed no significant difference between species and between populations of the same species. In this case, however, Klein’s group was able to rule out insufficient separation time as the explanation of the data and to argue that the explanation lies in the continuation of a gene flow between the incipient species. They argue further that speciation is a protracted affair during which the arising species diverge in a few genes responsible for phenotypic differences, but continue exchanging genes until the emergence of a reproductive barrier stops the process. They argue furthermore that because of this phenomenon, many phylogenies of so-called adaptive radiations will remain unresolved. One such case is the radiation that gave rise to the tetrapods in the evolution of jawed vertebrates. In this case, Klein’s group has demonstrated that increasing the number of genes in the input database does not improve the resolution power of the output phylogenetic trees.
Evolution of the Mhc
Three critical assumptions underlie the study of Mhc evolution: First, the Mhc is absent in all non-vertebrates. Second, jawless vertebrates (Agnatha) are monophyletic and are a sister group of jawed vertebrates (Gnathostoma). And third, jawless vertebrates lack the Mhc, which is present in all the jawed vertebrates. Klein’s group contributed significantly to the current general acceptance of these suppositions. The absence of the Mhc in non-vertebrates became apparent when scrutiny of non-vertebrate genomes failed to identify homologs of Mhc genes. Klein’s group provided strong support for agnathan monophyly by cloning, sequencing, and analyzing long DNA stretches of the representative agnathan and gnathostome species. And they isolated, in collaboration with Max Cooper’s group, lymphocyte-like cells, cloned, sequenced, and analyzed genes expressed in these cells, and found no evidence for expressed Mhc gene homologs. They did find, however, evidence for gradual evolution of the adaptive immune system. They could demonstrate the presence in jawless vertebrates of several auxiliary components and pathways, which the AIS co-opted when the three central receptors (Mhc, Tcr, and Bcr) emerged in the jawed vertebrates. They also contributed evidence for the omnipresence of Mhc genes in jawed vertebrates by identifying such genes in a wide range of species from bony fishes [zebrafish (Danio rerio), cichlid Aulonocara hansbaenschi, tilapia (Oreochromis niloticus), carp (Cyprinus carpio), guppy (Poecilia reticulata), threespine stickleback (Gasterosteus aculeatus), swordtail (Xiphophorus)]; through coelacanth (Latimeria chalumnae), African lungfish (Protopterus aethiopicus); birds [Bengalese finch (Lonchura striata), Darwin’s finches and their South American relatives]; to metatherian mammals [red-necked wallaby (Macropus rufogriseus) and eutherian mammal [rodents such as the mole rat (Spalax ehrenbergi)] and a variety of primates including prosimians, New World monkeys (NWM, Platyrrhini), Old World monkeys (OWM, Catarrhini) and apes]. In several of these species they worked out also the organization of the Mhcs, most notably in the zebrafish.As for the evolution of the Mhc genes themselves, Klein’s group contributed significantly to the description of its general outline. In collaboration with Yoko Satta and Naoyuki Takahata, they developed a method for estimating the evolutionary rates of the Mhc genes and demonstrated that the rate was close to the average rate of most non-Mhc genes, and they provided evidence that the Mhc genes are subject to balancing selection. They also provided evidence that the selection leads to the independent, repeated emergence of similar or identical short sequence motifs by convergent evolution. Klein himself has long championed the view that this mechanism and mechanisms similar to it, rather than the generally favored “gene conversion”, explained the origin of the motifs.
Klein’s group demonstrated that during its evolution, the Mhc undergoes repeated rounds of expansion and contraction by gene duplications and deletions –in Klein’s terminology, an accordion mode of evolution. Thus, for example, they showed that in each of the three major primate lineages – the prosimians, the NWM and the OWM – evolution of some of the class II gene families started anew after a contraction to a single ancestral gene. And on the example of two “class III” genes, C4 and CYP21, they illustrated a mechanism by which the accordion might be expanding and contracting. The C4 gene, as already stated, codes for a component of the complement system; the CYP21gene codes for a key enzyme in the synthesis of glucocorticoid and mineralcorticoid hormones. The two genes are thus unrelated to each other and to the class I and class II genes, but they are accidentally hooked together into a module, which has been found to duplicate or triplicate as a unit during primate evolution. The hook-up seems to have arisen, when an identical short sequence motif arose by chance at both flanks of the initial C4-CYP21 doublet. Since then, an occasional misalignment of the opposite flanks has led to an unequal crossing-over and so to duplications or deletion of the module.
Honors/Awards
- 2003 Gregor Johann Mendel Medal, Moravian Museum, Brno
- 1994 Jan Evangelista Purkyne Medal
- 1990 Glaxo Prize for Medical Writing
- 1986 James W. Mclaughlin Medal
- 1986 6th J.F. Heremans Memorial Lecture, Institute of Cellular and Molecular Pathology
- 1985-1990 Member, Institute Scientific Council, ICP
- 1985 5th Maude L. Menten Lecturer, University of Pittsburgh School of Medicine
- 1985 Culpepper Lecturer, University of North Carolina
- 1985 Francois 1er Fonde le College de France Medal
- 1981 Rabbi Shai Shacknai Memorial Prize in Immunology and Cancer Research, Hebrew University of Jerusalem
- 1979 Elisabeth Goldschmid Memorial Lecture, Hebrew University of Jerusalem
Memberships
- 1997-1998 Immunogenetics Honorary Editor
- 1991 International Mammalian Genome SocietyInternational Mammalian Genome SocietyThe International Mammalian Genome Society is a professional scientific organization that promotes and coordinates the genetic and genomic study of mammals...
founding member
- 1990-1993 Mammalian GenomeMammalian GenomeMammalian Genome is a peer-reviewed journal that publishes research and review articles in the fields of genetics and genomics in mouse, human and related organisms. As of July 2009 its editors-in-chief are Joseph H. Nadeau and Steve D. M. Brown...
Editor-in-Chief
- 1989–Present Folia Biologica Member, Editorial Board
- 1989-1991 EMBO Journal Member, Editorial Board
- 1988-1995 Cambridge Studies in Evolutionary Biology Member, Editorial Board
- 1987-1995 Molecular Biology and Evolution Associate Editor
- 1987 CRC Critical Reviews in Immunology Member, Editorial Board
- 1987 National Institutes of Health Member, National Advisory Council of Immunology
- 1985-1990 Mouse Newsletter Member, Editorial Board
- 1984-1991 International Reviews of Immunology Member, Editorial Board
- 1984-1990 Bioscience Research Reports, Immunology Series Member, Editorial Board
- 1983-1997 EOS, Journal of Immunology and Immunopharmacology Member, Editorial Board
- 1983-1996 Immunological Reviews Member, Editorial Board
- 1983-1987 Cell Member, Editorial Board
- 1982–Present Scandinavian Journal of Immunology Member, Editorial Board
- 1981-1990 Journal of Craniofacial Genetics and Developmental Biology Member, Editorial Board
- 1981-1987 Transplantation Society Councilor
- 1977-1991 European Journal of Immunology Member, Editorial Board
- 1977-1983 Developmental and Comparative Immunology Member, Editorial Board
- 1977-1980 Current Topics in Microbiology and Immunology Member, Editorial Board
- 1974-1997 Immunogenetics Editor-in-Chief
- 1974-1978 National Institutes of Health Member, Immunology Study Section
- 1974-1976 Transplantation Member, Editorial Board
- 1974-1975 Journal of Immunology Member, Editorial Board
- 1982 European Molecular Biology Organization Member
- American Association of Immunologists Honorary Member
- Scandinavian Society of Immunology Honorary Member
- French Society of Immunology Honorary Member
- American Association for Advancement of Science Fellow Member
- American Association for the Advancement of Science Fellow
- American Association of Immunologists Honorary Member
- Societas Scientarum Bohemica Honorary Member
Books
- Klein, J. The Use of Tissue Incompatibility in the Genetics of the Somatic Cell. Academia, Praha 1966 (in Czech).
- Klein, J. Molekulární základy dedicnosti (Molecular Basis of Heredity). Orbis, Praha 1964 (in Czech).
- Klein, J., Vojtíšková, M., and Zelený, V. (eds.) Genetic Variations in Somatic Cells. Academia, Praha 1966.
- Klein, J. Biology of the Mouse Histocompatibility-2 Complex. Principles of Immunogenetics Applied to a Single System. Springer-Verlag, New York 1975.
- Klein, J. Immunology. The Science of Self-Nonself Discrimination. Wiley, New York 1982.
- Klein, J. Natural History of the Major Histocompatibility Complex. Wiley, New York 1986.
- Klein, J. Immunology. Blackwell, Oxford 1990.
- Klein, J. and Klein, D. (eds.) Molecular Biology of the Major Histocompatibility Complex. Springer-Verlag, Heidelberg 1991
- Blancher, A., Klein, J., and Socha, W.W. (eds.). Molecular Biology and Evolution of Blood Group and MHC antigens in Primates. Springer-Verlag, Berlin 1997.
- Klein, J. and Horejsi, V. Immunology. 2nd edn. Blackwell Science, Oxford 1997.
- Klein, J. and Takahata, N. Where Do We Come From? Springer-Verlag, Heidelberg 2002
External links
- Jan Klein at Penn state University
- Jan Klein at ISI HighlyCitedISI highly cited researcherISI Highly Cited is a database of "highly cited researchers"—scientific researchers whose publications are most often cited in academic journals over the past decade, published by the Institute for Scientific Information...
- Jan Klein telling his life story at Web of Stories
- Jan Klein at timms