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Keywords:

  • human leucocyte antigens;
  • histocompatibility antigens;
  • H-2 complex;
  • human leucocyte antigens complex;
  • international histocompatibility workshops (IHWSs);
  • major histocompatibility complex;
  • major immune response complex

Abstract

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

In 1958, just a little more than 50 years ago, an alloantigen present on human leucocytes was detected, which was to become the ‘first’ human leucocyte antigen (HLA); HLA-A2. Since then, we have seen a tremendous development of the HLA field, which has moved from histocompatibility to become one of the most central fields in basic and clinical immunology. This development is briefly reviewed in this article, focusing on some highlights of the history of HLA class I and II molecules and their role in immune responses. It is emphasized that the quick and extensive development of the HLA field is the result not only of excellent individual contributions by outstanding pioneers in the field, but also of an extensive international collaboration, in particular through the many international histocompatibility workshops. Admitting that it is too late to change the name now, it is concluded that instead of calling the HLA complex and similar complexes in other species the major histocompatibility complex, these gene complexes should better have been named the major immune response complex, the MIRC.

Last year was 50 years since a human leucocyte antigen (HLA) was first described as ‘MAC’, later to become HLA-A2 (1). In the following, a short account of the development of the HLA field is given, focusing on some highlights of the history of HLA class I and II antigens, or molecules as they should be called now, which I consider to be among the most important. The review is based on an invited lecture given at the opening of the 15th International Histocompatibility and Immunogenetics Workshop Conference in Rio de Janeiro on 17 September 2008. It is impossible in this short historical review to mention all who have participated in unravelling the structure and function of the HLA molecules. Thus, I must apologize to those whose important contributions could not be included due to lack of space. For a more comprehensive treatment of the subject, the reader is referred to earlier extensive reviews by others (2–4).

It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

Allogeneic tumour transplantation was often used in early experiments to study tumour biology. In the early 1900s, two US geneticists, Ernest E. Tyzzer and Clarence C. Little, performed some crucial tumour transplantations in the offspring of crosses between mice that were susceptible or resistant to an allogeneic tumour. Based on the results, they arrived at the conclusion that susceptibility to the growth of allogeneic tumours was genetically determined, possibly by as many as 15 genes [references in (2, 3)]. The nature of these susceptibility (or rather resistance) genes and their products was, however, unknown.

An antigen responsible for rejection was first discovered by the British physician and pathologist Peter A. Gorer (Figure 1) in 1936, working at that time in the Lister Institute for Preventive Medicine in London. Following a suggestion from the British geneticist J. B. S. Haldane, he studied whether resistance factors to the growth of allogeneic tumours might be associated with some blood group antigens. First, he found that his own serum contained ‘natural’ antibodies that could distinguish between erythrocytes of three inbred strains of mice (5). He next immunized rabbits with erythrocytes from the same three strains of mice and obtained antisera with which he could distinguish three different blood group antigens in mice (6):

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Figure 1. Peter A. Gorer (1907–1961).

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  • Antigen I: shared by strains A and CBA, weakly expressed in C57BL;

  • Antigen II: expressed strongly in strain A, weakly in CBA but not in C57BL;

  • Antigen III: shared by strains A, CBA and C57BL.

The rabbit antiserum-recognizing antigen II behaved similar to his own serum.

He then grafted a tumour from a mouse of strain A (carrying antigen II) into mice of strain C57BL (lacking antigen II) and into offspring of crosses between these strains. He found that mice lacking antigen II quickly rejected the tumour, while it grew well in strain A and first- and second-generation crosses between A and C57BL that expressed antigen II. Furthermore, he made the important observation that sera of mice rejecting the tumour contained antibodies against antigen II (7). Thus, antigen II, shared between malignant and normal cells, apparently was an important resistance factor to the growth of an allogeneic tumour when present in the donor and absent in the recipient. Note that these findings were made before Peter Medawar first established in 1944–1945 that rejection of allogeneic transplants was caused by an immune response against the graft (8, 9), a discovery for which he received the Nobel Prize in 1960 (shared with Frank McFarlane Burnet).

After World War II, Gorer visited the mammalian geneticist George D. Snell (Figure 2) at the Jackson Laboratory, Bar Harbor, ME. Snell was studying tumour resistance genes, which he called histocompatibility or H genes. He had previously found that mice carrying the Fu gene (causing mice to develop a deformed tail), were resistant to the growth of tumours from strain A. Thus, he concluded that there was a strong linkage between an H gene and the Fu gene. During his visit, Gorer tested various backcross strains segregating for the Fu gene with his antiserum against antigen II and found that erythrocytes of almost all mice carrying the Fu gene tested negative with his antiserum. In contrast, the presence of antigen II on erythrocytes of the host was strongly associated with growth of the tumour from strain A (10). This was further strong evidence that antigen II was encoded by a gene at an H locus in strain A and that the mice carrying the Fu gene probably carried another allele at the same locus. Their combined results indicated three alleles at this H locus (10). Because Gorer’s antiserum against antigen II was the first to detect an allele at this H locus, it became histocompatibility locus 2 or H-2.

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Figure 2. George D. Snell (1903–1996).

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The work of Gorer and Snell, extended by Snell and coworkers and others later [references in (2)], established that the H-2 locus encoded strong or major histocompatibility antigens, inducing quick rejection, compared with weaker histocompatibility antigens encoded by other loci. The H-2 locus therefore became the major histocompatibility locus in mice. Other H loci became minor H loci.

Snell received the Nobel Prize in 1980 for his contributions. At that time, Gorer had passed away (he died in 1961). If not, he would no doubt have shared the prize with Snell.

Later, the H-2 locus became more and more complex, seemingly consisting of several different ‘subdivisions’ and where each allele apparently determined many different antigens. In 1970, I first suggested that the hitherto known H-2 genes belonged to two segregant series, encoded by two different loci, D and K respectively, similar to the, at that time, two known loci in the HLA complex (11). Snell et al. arrived at a similar conclusion (12). The two-locus model for the H-2 antigens known at that time turned out to be correct. Subsequently, many additional H-2 loci were found, including those encoding the immune-response-associated (Ia) antigens. The H-2 locus became the H-2 complex, or the major histocompatibility complex, MHC, in the mouse.

Discovery of the ‘first’ HLA antigens

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

Three papers appeared in 1958 by Jean Dausset, Jon van Rood and Rose Payne and their associates, respectively (1, 13, 14), which laid the foundation of what was later to become the HLA complex. All three papers described antibodies in human sera from multitransfused patients or multiparous women, sera that reacted with leucocytes from many but not all individuals who were tested. Thus, antibodies in these sera detected a polymorphic system of antigens on human leucocytes.

The credit for discovery of the first HLA antigen goes to Dausset (Figure 3). Studying sera from patients who had received multiple blood transfusions, he found seven sera that behaved quite similarly, in that they agglutinated leucocytes from 11 of 19 individuals tested (1). Because leucocytes from the donor of the sera were also not agglutinated, the antisera obviously detected an alloantigen present on human leucocytes. He gave the name MAC to this antigen to honour three individuals who had been important volunteers for his experiments and whose names began with the initials M, A and C, respectively [Dausset in ref. 4]. Antigen MAC (later to become HLA-A2) was present in approximately 60% of the French population. At the end of the paper, Dausset wrote that ‘Finally, in a more long time perspective, the study of leucocyte antigens might become of great importance in tissue transplantation, in particular in bone marrow transplantation’ (translated from French). Thus, he was very foresighted! For his discovery, Dausset received the Nobel Prize in 1980 (shared with Snell and Baruch Benacerraf).

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Figure 3. Jean Dausset (1916–2009) discussing the complexity of human leucocyte antigens at one of the earlier International Histocompatibility Workshops.

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Both van Rood and Payne followed up their initial findings of alloantigens on human leucocytes (13, 14). Using (at that time) a sophisticated computer analysis of the reaction patterns of 60 sera from multiparous women against leucocytes from a panel of 100 donors, van Rood (Figure 4) found some sera that apparently detected a diallelic system of leucocyte antigens, which he called 4a and 4b (later to become HLA-Bw4 and -Bw6, respectively). The results were reported in his PhD thesis from 1962 (15) [see also (16)]. Two years later, Payne (Figure 5), together with Julia and Walter Bodmer (Figure 9), also using sera from multiparous women, not only detected two leucocyte antigens, LA1 (later HLA-A1) and LA2 (later HLA-A2), apparently controlled by alleles but also postulated at least one additional antigen, LA3, determined by an additional allele at the same locus (17).

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Figure 4. Jon J. van Rood (1926–) in the centre, with his long-time associate Aad van Leeuwen (1929–2009) to the left and his statistician Joe d’Amaro (1928–) to the right, at one of the earlier International Histocompatibility Workshops.

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Figure 5. Rose Payne (1909–1999), together with the author (1938–) of this review just after the fourth International Histocompatibility Workshop in 1970.

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Figure 9. Julia (1934–2001) and Walter Bodmer (1936–). Dancing has been one of the highlights at the farewell dinner of all International Histocompatibility Workshops.

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Several other investigators also made original or first identifications of leucocyte antigens in these early days of HLA. They included, among others, Bernard Amos, United States; Richard Batchelor, UK; Ruggero Ceppellini, Italy; Paul Engelfriet, the Netherlands; Wolfgang Mayr, Austria; Flemming Kissmeyer-Nielsen, Denmark; Ray Shulman, United States; Paul Terasaki, United States; Roy Walford, United States; and myself [references in (18)].

Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

The relationship between the different leucocyte (later HLA) antigens that had been identified and their polymorphism and genetics were difficult subjects to solve. No single laboratory could have carried out this alone. Therefore, very early International Histocompatibility Workshops (IHWSs) were established, where investigators in the field met to compare their reagents, techniques and results and communicate new findings.

The first three IHWSs were ‘wet’ workshops where the investigators carried out their experiments together in the same laboratory using the same panel of cells. The first IHWS was organized by Amos (Figure 6) as early as in June 1964 at Duke University, Durham, NC. Amos should be considered the ‘father’ of the workshops. He was also able to obtain funds from National Institutes of Health (NIH) to organize the first workshops. The major aim of the first IHWS was to compare different techniques to detect leucocyte antigens because a variety were in use by different investigators (leucoagglutination, the indirect antiglobulin consumption test, mixed agglutination, complement fixation, microcytotoxicity, etc). Twenty-three investigators attended the workshop testing the same sera and cells with their own techniques. Much to their dismay, most of the results were discordant (19).

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Figure 6. Bernard Amos (1923–2003).

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These disappointing results, coupled with the fact that van Rood at the first IHWS had also presented evidence for other clusters of leucocyte antigens in addition to 4a and 4b, prompted van Rood to organize the second IHWS which was held in August, 1965 at the University of Leiden, the Netherlands. Here, investigators from 14 different groups tested their own antisera, using their own techniques, on cells from a common panel of 45 individuals. The main aim was to see if ‘local’ specificities defined in one laboratory correlated with those defined in other laboratories. Most encouragingly, it was now found that several local specificities were indeed identical or almost identical (20). These included the specificities MAC (of Dausset), LA2 (of Payne and the Bodmers), 8a (of van Rood), B1 (of Shulman) and Te2 (of Terasaki), later to become HLA-A2. Furthermore, Dausset et al. (21) and van Rood et al. (22) also presented work suggesting that most of the antigens they could identify were controlled by a single chromosomal complex.

The third IHWS was organized by the well-known human geneticist Ruggero Ceppellini (Figure 7) at the University of Turin, Italy, in June 1967. The main aim was to study the genetics of the hitherto identified leucocyte antigens. Thus, the organizers included blood from 11 families, including monozygotic twins, that were tested ‘blindly’ by the different investigators with their own typing antisera and techniques. Several investigators were now using the quicker and more reliable microcytotoxicity test, initially developed by Terasaki (Figure 10) and McClelland (23), which later became the standard serological typing technique for HLA antigens. The results showed strong correlations between 13 local specificities. But more importantly, it was now fully established that most of these specificities were encoded by closely linked genes at one chromosomal region. This led to the designation HL-A for this chromosomal region, that is human leucocyte, locus A (24). This was later changed to HLA (without the hyphen), where A is now interpreted to mean antigen.

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Figure 7. Ruggero Ceppellini (1917–1988), giving a talk at one of the earlier International Histocompatibility Workshops.

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Figure 10. Paul I. Terasaki (1929–).

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Just after the third IHWS, in 1968, an HLA Nomenclature Committee was established (first sponsored by World Health Organization, (WHO)) consisting of leading investigators in the field. This committee, which still exists, is responsible for giving official names to HLA specificities and loci. In the early days, an officially recognized or ‘accepted’ HLA specificity was a specificity that could be recognized by several different investigators using their own serological reagents. An account of the lively discussions at their first meeting in New York in September 1968 is given by Walford in ref. 4. By quickly establishing a common uniform nomenclature and thus avoiding a long list of various local specificities, the committee has played a major role in unravelling the complexity of HLA genes and their products.

Several loci in the HLA chromosomal region

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

The first to propose two HLA loci were Bodmer and Payne and their associates (25). They called the two loci ‘LA’ (adapted from the LA antigens of Payne and coworkers) and ‘4’ or ‘four’ (adapted from the 4a and 4b antigens of van Rood). At the third workshop in Turin, Ceppellini et al. also proposed that there were two different mutational sites within the HLA chromosomal region (26). It was, however, the work of Kissmeyer-Nielsen (Figure 12) and associates, which firmly established that there were two HLA loci (27). In extensive studies of unrelated individuals and families, they showed that the two loci, LA (later named HLA-A) and 4 (later named HLA-B), were closely linked and contained at least seven and eight alleles, respectively.

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Figure 12. Some members of the Scandinavian group studying their data at the fourth International Histocompatibility Workshop meeting in 1970. The leader of the group, Flemming Kissmeyer-Nielsen (1921–1991), is seen (with glasses) in the centre.

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There had been suggestions in 1969 from Dausset, Terasaki and Walford and their associates also of a third locus in the HLA chromosomal region. The strongest evidence came, however, from the studies by a Scandinavian group of an antiserum detecting a ‘new’ leucocyte antigen, AJ, which in population and family studies behaved as if it was encoded by another HLA locus separate from LA and 4 (28). Later, we were able to show in cell membrane capping experiments that antigen AJ indeed was independent of antigens encoded by the LA and 4 loci, which firmly showed the existence of a third HLA locus (29). This was first called the AJ locus (from its first antigen) but was later named HLA-C.

In 1964, two groups, Bach and Hirschorn (30) and Bain et al. (31), independently described morphological transformation and cell division if leucocytes from two different individuals were mixed. This was to become the mixed lymphocyte culture (MLC) reaction. Fritz Bach (Figure 8) together with Amos then showed that the MLC reaction was governed by the HLA chromosomal region. Cells from siblings who were genotypically HLA identical generally did not respond to each other in reciprocal MLC tests (32). Later, Amos and Bach also obtained results indicating that the HLA determinants stimulating in the MLC test might not be identical to the serologically defined HLA-A and -B antigens (33). This was fully confirmed by Yunis and Amos (34) who showed that there was a separate ‘MLC locus’ in the HLA chromosomal region responsible for the determinants inducing the MLC response. From their studies in mice, Bach et al. (35) then proposed that there were two different types of determinants encoded by genes in the H-2 complex, serologically defined (SD) and lymphocyte-defined (LD) determinants, the latter being responsible for stimulation in the MLC test, a concept that was also adapted for man.

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Figure 8. Fritz H. Bach (1934–).

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This started an extensive hunt for the LD determinants in man. It was Mempel et al. (36) who first suggested that MLC-stimulating cells that were homozygous at the LD locus could be used to type for LD determinants in man, in that non-responsiveness of the responding cells would indicate that the stimulating and responding cells shared the same LD determinant(s). Several investigators showed that this indeed was possible, and multiple LD determinants were identified by what was generally called MLC typing. This was also a major topic at the sixth IHWS in 1975, organized by Kissmeyer-Nielsen in Aarhus, Denmark. By exchange of 62 LD homozygous typing cells, eight different LD determinants were clearly defined by MLC typing by the different participating laboratories, of which six LD determinants were accepted by the Nomenclature Committee and provisionally (by the prefix ‘w’ = workshop) named HLA-Dw1–6 (37). The corresponding ‘locus’ was named HLA-D. Sheehy et al. (38) reported that LD (or Dw) determinants could also be identified by priming lymphocytes against given LD determinants, which was called primed LD typing. Later studies showed that the provisional HLA-D locus consisted of several different closely linked loci, which encoded three different series of determinants, DR, DQ (previously called DC) and DP (previously called SB).

In the early 1970s, several groups reported that some sera containing HLA antibodies were able to inhibit the MLC reaction [(39) and refs therein]. This was confirmed by van Leeuwen et al. who also obtained suggestive evidence that the responsible antibodies recognized antigens present on B cells but not on T cells or platelets (40). Thus, these antisera might serologically detect HLA-D determinants. This was therefore made a major topic at the seventh IHWS in 1977, organized by Julia and Walter Bodmer (Figure 9), in Oxford, UK. Using 177 selected antisera recognizing antigens on B cells, antisera that had been exchanged between the participating laboratories, it was possible to convincingly identify seven different B-cell antigens that correlated closely to the HLA-Dw1–7 determinants and that therefore were named HLA-DRw1-7 (DR = D Related) (41).

In the early 1980s, the overall picture was that the HLA chromosomal region, found to be present on the short arm of chromosome number 6, encoded six different very polymorphic series of determinants, A, B and C that were present on most nucleated cells and DR, DQ and DP that were mainly present on B cells, monocytes and dendritic cells. In 1967, Ceppellini had introduced the term HLA haplotype for the genetic information carried by each of the two HLA chromosomal regions of an individual. Klein (42) introduced the terms class I to describe the A, B and C antigens and class II to describe the DR, DQ and DP antigens (and the corresponding antigens in other species), a nomenclature that has since been followed. Furthermore, after the discovery of additional class I antigens, HLA-G, -E and -F, with a more limited tissue distribution, the latter were named non-classical HLA class I antigens, while the HLA-A, -B and -C antigens were named classical HLA class I antigens.

Later, many additional loci were detected in the HLA chromosomal region or the HLA complex as it is called now. As a matter of fact, in the extended HLA complex covering a total of 7.6 Mb, as many as 252 genes have been found expressed, of which approximately 28% may have immune functions (43). A further treatment of this development of the HLA complex, including the finding of some complement genes, cytokine genes, RING (really interesting new genes), BING (bloody interesting new genes) and many others, is outside the scope of this short review (see Horton et al. (43) for a complete gene map of the extended HLA complex).

The HLA class I and II antigens are strong histocompatibility antigens

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

From skin grafting experiments in the early 1960s, both Dausset and coworkers and van Rood and coworkers had obtained evidence that the HLA antigens are strong histocompatibility antigens. This was confirmed and extended in studies by Ceppellini et al. (44) and Amos et al. (45). They showed that first-set skin grafts between HLA-identical siblings (who had inherited the same HLA haplotypes from both parents) had a significantly longer survival time than skin grafts between siblings differing for one or two HLA haplotypes. Because skin grafting resulted in the production of antibodies against HLA antigens of the donor, this was also an evidence that the HLA antigens were important histocompatibility antigens [references in (46)].

The first data suggesting a correlation between HLA matching and kidney allograft survival were presented by Terasaki (Figure 10) and coworkers as early as in 1965 (47). These early results are quite remarkable, given the broadly reacting typing reagents available at that time and just typing for a few HLA-A and -B antigens. Other references to early work on the impact of HLA matching on clinical kidney transplantation are found in Brent (3) and Kissmeyer-Nielsen and Thorsby (46). Taken together, the results from skin and clinical kidney grafting, together with other evidence [references in (46)], showed that the HLA complex indeed was the MHC in man, as it had been previously shown for H-2 in mice.

At the start of the 1970s, it had become accepted that the survival of kidneys transplanted between HLA-identical siblings was superior to all other combinations. HLA typing to obtain such or other well-matched combinations in kidney transplantations from living-related donors became of general use. Following several reports of better survival also of HLA-matched compared with HLA-mismatched kidneys from cadaveric donors [references in (46)], HLA typing to obtain well-matched kidneys in such unrelated combinations was also used in many centres. However, the benefits of the latter application were hit hard by a presentation by Terasaki’s group at the Third Congress of the International Transplantation Society in Hague, the Netherlands, in 1970. While HLA matching was found to be of great importance using living-related donors, they reported no effects of HLA matching when instead cadaveric donors were used. The results raised such a storm at the congress that their paper was not included in its proceedings. Instead, it was published separately in this journal (48), accompanied by comments by its editor at that time, Kissmeyer-Nielsen (49), discussing reasons for the discrepancy between the disappointing results reported by Terasaki’s group compared with the beneficial effects of HLA matching in cadaveric donor transplantation as reported by several others. The result was, however, that HLA matching in cadaveric donor transplantation went into a state of limbo. The differences in survival found between grafts from HLA-matched and HLA-mismatched cadaveric donors were considered by many surgeons to be too small to matter.

Following the identification of the HLA-DR antigens, the picture changed. Three independent studies, published in 1978, one by Ting and Morris (50), the second from our own group in Oslo (51) and the third from the group in Leiden (52), all showed beneficial effects of matching for the HLA-DR antigens in cadaveric kidney transplantation. Our own studies (53) also showed that the HLA-DR matching effect was seen irrespective of matching for the HLA-A and -B antigens (Figure 11). The impact of HLA-DR matching was later also confirmed in studies by many others.

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Figure 11. Influence of HLA-DR matching in 96 transplants from a cadaveric donor. Left part shows the overall data, and the right part shows the data for transplants mismatched for one or two HLA-A or -B antigens. Reprinted from Albrechtsen et al. (53), copyright 1978, with permission from Elsevier. HLA, human leucocyte antigen.

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The further developments in this area and the present use of HLA matching in clinical organ transplantation are outside the scope of this short historical review. It suffices to say that in many centres the best possible match between donor and recipient for HLA-A, -B and -DR antigens is an important factor considered, when using both living and cadaveric donors of kidneys. In sensitized patients with HLA antibodies, it is generally accepted that the crossmatch between serum from the recipient and lymphocytes from the organ donor must be negative, as tested by the microcytotoxicity test.

While the role of HLA matching in clinical organ transplantation, in particular using cadaveric donors, has continued to be a much discussed issue, the role of optimal HLA matching in bone marrow transplantation (BMT) is universally accepted. Graft-vs-host disease is a major barrier to successful BMT. Early successful BMTs to children with inborn immunodeficiencies (54, 55) and patients with aplastic anaemia (56) were obtained by using HLA-identical siblings as donors. It was also shown that it was particularly important that the MLC test between donor and recipient was negative (57), that is their class II antigens had to be matched. Together, this has resulted in the formation of large international registries of HLA-typed volunteer bone marrow donors and banks of HLA-typed cord blood, which have made it possible to offer HLA-matched BMTs to most patients in need of this treatment. The more recent developments in this area, that is ‘intelligent mismatching’ to promote ‘graft-vs-leukaemia’ effects, is outside the scope of this short review.

HLA antigens are associated with diseases

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

Already at the third IHWS in 1967, Amiel reported that an HLA antigen, 4C (later shown to be a ‘broad’ antigen including several different HLA-B locus antigens), was found significantly more frequently in patients with Hodgkin’s disease (51%) than among healthy individuals (27%) (58). The association was not strong, the relative risk, RR (i.e. how much more frequently the disease occurs among individuals carrying the antigen under study compared with those lacking it) was just 2.8 and the observation has been hard to reproduce by others. It led, however, to an extensive hunt for other HLA-associated diseases.

In 1973, came the ‘big bang’. Brewerton et al. (59) and Schlosstein et al. (60) independently reported a very strong association between HLA-B27 and ankylosing spondylitis. The studies found that 88%–96% of the patients carried HLA-B27 compared with 8%–4% of healthy controls, respectively. These data were later confirmed by many other groups, giving an RR of >100 to develop ankylosing spondylitis in individuals being positive for HLA-B27. The reason for this very strong association was unknown, but the authors of one of these papers (60) speculated that because the association was so strong, either an immune response (Ir) gene in strong linkage (disequilibrium) to HLA-B27 was involved or there was a cross-reaction between HLA-B27 and the aetiologic agent causing the disease. Later, the same year, Jersild et al. (61) first reported a strong disease association to an HLA class II antigen. Multiple sclerosis was found to be more strongly associated to a determinant as established by MLC typing, LD-7a (later to become HLA-Dw2, now HLA-DR2), than HLA-B7.

Since then, many diseases have been found to be associated to given HLA antigens, in particular autoimmune diseases (62). Autoimmune diseases are the combined result of predisposing genes and precipitating environmental factors, and in almost all autoimmune diseases, the strongest genetic predisposition is associated to one or more HLA antigens. Fine mapping of the HLA complex genes involved in these diseases and the possible mechanisms behind the associations are therefore now major research fields [see a recent review in this journal (63)].

Role of the IHWSs (II)

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

Science is of course to a large extent driven by competition between individual investigators. This has also been the case in the HLA field. However, there must be very few other scientific fields where international collaboration has played such a major role for the progress, mainly through the many IHWSs. They have had an extremely important unifying influence on the HLA field. They laid the ground for a continuous open and friendly collaboration between involved investigators all over the world, which is an important mark distinguishing this research field from many others. As reported above, the first three IHWSs were wet workshops where the investigators carried out their investigations in the laboratory of the workshop chairman. From the fourth IHWS, however, the project studies have been carried out locally in the laboratories of the investigators, to a large extent using exchanged reagents, followed by a joint workshop meeting to discuss the results (Figure 12). More recently, a conference for a broader audience has also been arranged in conjunction with the workshop meetings, where not only the workshop results have been summarized but also individual scientists have presented their most recent research on HLA, its applications and related topics.

The role of some of the earlier workshops for identification of the first HLA-A, -B and -D/DR antigens has been mentioned above. However, all workshops have been instrumental for the development of the HLA field and its application in research and clinical medicine. To just mention a few achievements, the fifth IHWS showed that HLA typing would become an important tool in anthropology; in the eighth IHWS, the role of HLA matching in clinical renal transplantation was an important aim; the ninth IHWS introduced various new techniques for studies of the polymorphism of HLA; as a result of the 10th IHWS, a reference panel of well-typed cell lines was established, which has been of great help for many investigators; and as a result of the 13th IHWS, a publicly accessible database was established, which now contains a huge amount of data for future research. And so on, the list of what has been accomplished in the 15 workshops so far organized is long, very long. The work laid down by the workshop chairmen and their associates in organizing these workshops has been extensive and so has also been the work of the participants. It is, however, impossible in this short review to give a comprehensive account of all projects that has been studied in these workshops and the results obtained, for which I apologize to all workshop organizers and participants. Table 1 just gives a very short and incomplete summary of some important aims and results. For more details, the reader should consult the proceedings from the various workshops (listed in Table 1), which not only contain the ‘Joint reports’ that summarize the results of the various workshop projects but also contain many important results of research on HLA and its applications by individual investigators, presented at the workshop conferences. These proceedings are thus a rich source of information and also show the extensive development that has taken place during the 45 years since the very first workshop was organized.

Table 1.  Some major aims and results from the IHWSsa
WS numberDatePlaceChairmanSome important aims and resultsReference
  • BMT, bone marrow transplantation; HLA, human leucocyte antigen; IHWGs, International Histocompatibility Working Groups; IHWSs, International Histocompatibility Workshops; MHC, major histocompatibility complex.

  • a 

    The first three IHWSs were ‘wet’ workshops, where participants carried out their investigations together in the laboratory of the workshop chairman. From the fourth IHWS, the participants carried out their investigations locally in their own laboratories, often using exchanged reagents. The investigators then met at the workshop meeting to discuss the results.

1June 1964Durham, NC, USAD. Bernard AmosComparison of different typing techniques64
Results: very little consistency!
2August 1965Leiden, HollandJon J. van RoodComparison of different ‘local’ specificities65
Results: strong correlations between several
3June 1967Turin, ItalyRuggero CeppelliniEstablish the genetics of leucocyte antigens66
Results: strong correlations between more ‘local’ specificities; most are encoded by genes at one chromosomal region; HLA
4January 1970Los Angeles, CA, USAPaul I. TerasakiFurther definition of HLA specificities67
Eleven HLA specificities accepted
5May 1972Evian, FranceJean DaussetUse of HLA in anthropology68
Established HLA frequencies in different populations
6June 1975Aarhus, DenmarkFlemming Kissmeyer-NielsenFocus on HLA LD antigens by exchange of homozygous typing cells. HLA-Dw1-6 accepted69
More HLA-A and -B antigens and five -Cw antigens accepted
7September 1977Oxford, UKJulia and Walter F. BodmerFocus on antigens expressed on B cells70
HLA-DRw1-7 accepted, strong correlations to corresponding HLA-Dw antigens
8February 1980Los Angeles, CA, USAPaul I. TerasakiFocus on applications71
A possible beneficial effect of HLA matching in renal transplantation from unrelated donors
Strong HLA-DR associations to some diseases
9May 1984Munich, GermanyEkkehard D. Albert and Wolfgang R. MayrFurther dissection of HLA polymorphism by family studies, also using monoclonal antibodies and biochemistry72
More HLA specificities accepted
Beneficial effects of both HLA-A, -B and -DR matching in renal transplantation from unrelated donors
10November 1987Princeton, NY, USABo DupontTheme: Molecular genetic basis of HLA polymorphism73
Comparison of HLA specificities detected by different assays
Established a IHWS reference cell line panel
11November 1991Yokohama, JapanKimiyoshi Tsjui, Miki Aizawa, and Takehiko SasazukiEstablishment of DNA typing of HLA (PCR SSO)74
New data on the role of HLA in transplantation, disease associations, anthropology, etc.
12June 1996Saint-Malo, FranceDominique CharronTheme: Genetic diversity of HLA75
Extensive DNA typing, many new HLA variants detected
More data on applications
13May 2002Victoria, BC, CanadaJohn A. HansenTheme: immunobiology of the human MHC76
New data on applications
Establishment of different IHWGs
Establishment of a publicly accessible MHC database
14November 2005Melbourne, AustraliaJim McCluskeyNew results of work by the different IHWGs and others77
New data on KIR–HLA and applications, in particular in BMTs
15September 2008Buzios, BrazilMaria Elisa Moraes and Maria Gerbase-DeLimaFurther results of the work by the different IHWGs and others78
New data on applications in clinical medicine, anthropology, etc.

If I should try to very briefly summarize some important achievements of the workshops, I would list the following:

  • 1
    They have been instrumental for solving the complexity of HLA. This has been the case for all workshops, but in particular the early ones.
  • 2
    They have been necessary in order to carry out investigations that need large international collaboration involving many different centres. These projects include, among many others, the role of HLA matching in renal transplantation and in BMTs, the role of antibodies in chronic rejection, studies of HLA-associated diseases and use of HLA in anthropology.
  • 3
    They have been biobanks long before this term was coined, that is for collection of reliable typing reagents, important patient sera, reference cell line panels, oligonucleotides and complementary DNA probes and for generation of publicly accessible HLA databases, all of which have been instrumental for workers in the field.
  • 4
    They have been platforms for further research and developments in individual laboratories. Many new and original contributions by individual investigators have been based on workshop results or reagents provided by the workshops.
  • 5
    They have played an important educational role, making quick technology transfer possible. Many less experienced laboratories have by participation been actively trained and learned new techniques.

The bottom line is that, without these workshops, we would not have been where we are today with respect to our knowledge of the HLA complex and its applications in research and clinical medicine.

Immunobiological function of the HLA class I and II antigens

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

But what was the immunobiological function of the HLA class I and II antigens? It was clear very early that they were strong histocompatibility antigens, hence the name MHC for the HLA and analogous complexes in other species. But, this could not be their real immunobiological function! The first answers mainly came from studies in the mouse.

First, Benacerraf and colleagues reported in 1963 that the antibody response in guinea pigs to a particular synthetic polypeptide antigen (PLL) was controlled by a single gene (79). Genes controlling specific immune responses were later called Ir genes. Benacerraf received the Nobel Prize in 1980 (shared with Snell and Dausset) for his contributions on Ir genes. Then, in 1968, came the first data that would lead to an understanding of the immunobiological function of the MHC antigens. Hugh McDevitt (Figure 13) together with Marvin Tyan then first showed that the ability of mice to make an antibody response to a series of synthetic polypeptide antigens was a genetic trait that was closely linked to the H-2 complex (80). These results were confirmed and extended in further experiments by McDevitt and Chinitz the next year (81). Using 33 different inbred strains of mice that were of eight different H-2 types but where mice having the same H-2 type had different genetic backgrounds, they showed that all strains being H-2b responded strongly to the synthetic antigen (T,G)-A--L, while strains of other H-2 types did not respond or responded much more weakly. In contrast, when they instead used another synthetic antigen, (H,G)-A--L, different mouse strains being H-2a or H-2k responded strongly, strains being H-2b responded poorly and strains having other H-2 types did not respond or responded variably. Thus, genes closely linked to the H-2 complex controlled specific immune responses! The authors concluded that their results were compatible either with multiple Ir gene loci or with a single Ir gene locus with multiple alleles but in both cases closely linked to the H-2 complex.

image

Figure 13. Hugh McDevitt (1930–).

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MHC-linked Ir genes were later identified in several species, and the mechanism of their function became much discussed. It was speculated that they might be identical to the MHC genes themselves, that is the genes encoding the MHC class I antigens, and that the MHC antigens on immunocompetent cells in one way or another might modify the antigen receptors on these cells. Alternatively, the Ir genes might be different from the genes encoding the MHC class I antigens and represent a new set of antigen receptors on T cells (82). Later studies showed that the murine Ir genes were separate from and mapped to a position between H-2D and H-2K and that some antisera recognized the corresponding gene products called Ia antigens [references in (83)]. These antigens were later shown to be encoded by two different loci in the H-2 complex, I-A and I-E, corresponding to HLA-DQ and -DR, respectively, that is the class II antigens of mice.

In 1972, it was first shown that cooperation between T and B cells required MHC compatibility between the interacting cells (84). The next year, it was shown that the same was true for the interaction of macrophage-associated antigen with T cells (85). That the MHC antigens were directly involved in T-cell recognition of antigens was, however, first shown in 1974 by Rolf Zinkernagel and Peter Doherty, when they worked together in Canberra, Australia. A very interesting account of how they discovered this was given by Zinkernagel and Doherty (86). The results of their initial experiments were reported in two short and yet momentous letters in Nature (87, 88).

Very briefly, using mice infected with lymphocyte choriomeningitis virus (LCMV), they observed that T cells from the H-2k strain were only able to kill LCMV-infected target cells from the H-2k strain and not LCMV-infected target cells from the H-2d strain. The reverse was true when they instead used T cells from LCMV-infected H-2d mice, which were only able to kill LCMV-infected target cells from H-2d mice and not LCMV-infected target cells from H-2k mice. Thus, T-cell recognition of antigen from the virus was restricted by the MHC antigens of the T-cell donor, which was called MHC restriction. They proposed two explanations for their results, either the antigen-specific receptor on T cells, the T-cell receptor (TCR), recognizes MHC antigens that have been modified by the virus or the TCR recognizes a complex formed between virus and MHC antigens. They later proposed a unifying hypothesis that T-cell recognition by cytotoxic (CD8) T cells and by helper (CD4) T cells involved similar mechanisms, involving MHC class I and class II antigens, respectively, and that this may explain the experiments summarized above on Ir gene effects and the need for histocompatibility between interacting immune system cells. Furthermore, they proposed that this may also explain how the MHC antigens are strong histocompatibility antigens and may predispose to diseases (89). Although the exact mechanism how the MHC antigens were involved in T-cell recognition could not be shown by their experiments, Zinkernagel and Doherty came very close (see subsequently). They received the Nobel Prize in 1996 for their seminal observations (Figure 14).

image

Figure 14. Peter Doherty (1940-) left and Rolf Zinkernagel (1944-) receiving the Nobel Prize in 1996.

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In 1986, it was first shown that MHC restriction, not surprisingly, was also the case for human T-cell-mediated immune responses, as shown by Goulmy et al. for cytotoxic T cells (90) and by Bergholtz and myself for helper T cells (91).

Structure of HLA resolved; the pieces come together

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

During the 1960s and 1970s, many studies on the structure of MHC antigens, both H-2 and HLA, appeared [references in (2, 3)]. By the early 1980s, it had been established that the class I antigens are composed of two chains, a glycoprotein heavy chain anchored in the cell membrane of molecular weight (mw) of approximately 45 000, varying in its membrane distal part between different class I molecules, which is non-covalently associated with β-2 microglobulin (mw about 12 000), which is constant in all class I molecules. In contrast, the class II antigens consist of two glycoprotein heavy chains (α and β) of mw of approximately 34 000 and 29 000, respectively, both anchored in the cell membrane and where the β chain varied between different HLA-DR antigens.

The studies by Zinkernagel and Doherty summarized above, and studies by many others later, had shown that T cells recognize foreign antigens associated with MHC antigens or MHC molecules as we should call them from now on. It was shown by Ziegler and Unanue (92) that CD4 T cells recognize fragments of antigens in association with MHC class II molecules in macrophages and by Townsend et al. (93) that CD8 T cells recognize peptide fragments of antigen in association with MHC class I molecules in target cells. But what was the mechanism?

In 1987, two papers by the Strominger/Wiley group were published back to back in Nature, which provided the explanation and caused a paradigm shift not only in the HLA field but also in immunology in general. In an article to the memory of Don Wiley (1944–2001), Strominger has given a very interesting account on how the group arrived at their results (94). In the first Nature paper, Bjorkman et al. (95), using X-ray crystallography, showed that the part of the HLA-A2 molecule proximal to the cell membrane contains two domains with immunoglobulin folds that are paired in a novel manner. However, more importantly, they also showed that the membrane distal domain is a platform of antiparallel β-strands topped by two α-helices, which together form a large grove that provides a binding site for processed antigen, probably a peptide. They also showed that an unknown peptide material was found in this site in crystals of HLA-A2 (Figures 15 and 16, which for many years were the most frequent shown pictures in any lecture on HLA or immunology). Thus, HLA molecules were peptide-presenting molecules!

image

Figure 15. Schematic representation of the four domains of human leucocyte antigen HLA-A2. Reprinted with permission from Macmillan Publishers Ltd, copyright 1987 (95).

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image

Figure 16. Surface representation of the top of the human leucocyte antigen HLA-A2 molecule, showing (a) the deep groove identified as the antigen recognition site and (b) the electron density found in this site, probably a peptide. Reprinted with permission from Macmillan Publishers Ltd, copyright 1987 (95).

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In the accompanying paper, Bjorkman et al. (96) discussed how some of the polymorphic amino acid residues in the groove of HLA class I molecules, and by inference also in the groove of class II molecules [which was, however, first shown 6 years later (97)], would interact with a peptide, while other polymorphic residues of HLA molecules would interact with the TCR.

This explained the phenomenon of MHC or HLA restriction, that is a given T cell recognizes a particular peptide–HLA complex, where both the peptide and the presenting HLA molecule constitute the ligand. This would also explain allorecognition, which might involve T-cell recognition of complexes of allogeneic peptides bound by self HLA-molecules but also of allo-HLA molecules and their bound peptides. The data also suggested that there would be limitations in the ability of a given HLA molecule to bind all types of peptides [which were amply confirmed in later studies by others of peptide binding to HLA molecules (98)]. The MHC or HLA class I and II molecules of an individual will to a large extent determine which peptides will be bound and displayed and therefore recognized by his or her CD8 or CD4 T cells, respectively. This explained the MHC-linked Ir gene effects caused by different peptide-binding repertoires of various MHC molecules. It also provided a probable explanation for many HLA-associated autoimmune diseases. The strong HLA associations might be caused by preferential binding by the disease-associated HLA molecules of particular immunogenic peptides, which would be able to trigger an autoimmune response, given the necessary precipitating environmental factors. The pieces had come together.

It is interesting to note that the first HLA molecule whose structure was fully shown was the same as the very first HLA molecule discovered in man, that is MAC or HLA-A2, discovered by Dausset 29 years previously (1).

Concluding remarks

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References

It is now just a little more than 50 years since Dausset first discovered a leucocyte antigen in man, which became the first HLA antigen, HLA-A2. Since then, the field has moved from histocompatibility to become one of the most central fields in basic and clinical immunology in general. As a matter of fact, the term MHC for the HLA complex and similar genetic complexes in animals should rather be considered a misnomer because the role of the HLA class I and II molecules as histocompatibility antigens is more a side-effect of their immunobiological function. Given the instrumental importance of class I and II molecules, and adding the function of many other HLA complex gene products, both in innate and in adaptive immune responses, a better name for the complex would be the major immune response complex; the MIRC. But, it is too late to change this now!

There are several reasons for the quick and extensive developments of the field. First and foremost are the instrumental contributions by its many pioneers. Some of them have received the Nobel Prize (Snell, Dausset, Benacerraf, Zinkernagel and Doherty), but several others would also have been excellent candidates. That such a relatively large number of Nobel Prizes has gone to pioneers in this field witnesses its importance. But another factor that must not be underestimated is the extensive international collaboration, which has taken place since the early days of HLA, in particular the IHWSs. Together, the pioneers and the extensive international collaboration are responsible for the giant progress we have seen in this field during the past 50 years.

References

  1. Top of page
  2. Abstract
  3. It started in the mouse: discovery of histocompatibility antigen II and the H-2 complex
  4. Discovery of the ‘first’ HLA antigens
  5. Solving the complexity through international collaboration: role of the International Histocompatibility Workshops (I)
  6. Several loci in the HLA chromosomal region
  7. The HLA class I and II antigens are strong histocompatibility antigens
  8. HLA antigens are associated with diseases
  9. Role of the IHWSs (II)
  10. Immunobiological function of the HLA class I and II antigens
  11. Structure of HLA resolved; the pieces come together
  12. Concluding remarks
  13. Acknowledgments
  14. References
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