Nobel Lecture, 8 December, 1980



University of Paris VII

Institute of Research in Blood Diseases, Paris, France


As George Snell (1) so rightly said, the supergene, the major histocompatibility

complex (MHC), is like a page from the nature book read outside of the context.

Today this context is beginning to be better understood. We would here like to

recall the evolution of concepts regarding these molecular structures found in the-.

membrane of cells. First, attention was centered on the almost botanical description

of their genetic polymorphism. Then the spotlight was turned, for several years,

on their importance in transplantation. More recently, their role in the immune

response has become more and more apparent. This, however, is probably not the

last stage in our search. We, as well as others (2-5), have suggested that the

essential function of these structures resides in self-recognition. These structures

are, in fact, the identity card of the entire organism.

We will discuss these four viewpoints successively. Far from being mutually

exclusive, they are landmarks in the stages of our thought process as we have

gained deeper knowledge of the subject.


First concept: Polymorphism and Linkage Disequilibrium


Polymorphism:Since Landsteinerís discovery of the first genetic polymorphism

in man, knowledge of polymorphic genes has not ceased to increase and will

continue to increase with DNA hybridization techniques. Most of these systems,

however, are pauci-allelic and more often than not have one very frequent allele,

one that is more infrequent, and a few variants. None of these can be compared

with the extreme polymorphism of genes in the MHC of vertebrates, and

particularly in the human lymphocyte antigen (HLA) complex

The definition of this polymorphism began to emerge in three laboratories: in

ours where the first antigen Mac (HLA-A2) was defined (6), in Van Roodís

laboratory (7) with the 4a 4b series (Bw4, Bw6), and Rose Payneís and W.

Bodmerís (8) with the two alleles HLA-A2 and -A3. Then, thanks to an intense

international effort that has spanned more than 15 years and included eight

workshops, the web began to be disentangled. The importance of this international

effort, launched by Amos in 1964 [see (9)], and followed by other workshops

directed byVan Rood (10), Ceppellini (11), Terasaki (12), Dausset (13), Kissmeyer-

Nielsen (14), Bodmer (15), and again Terasaki (16), cannot be over-emphasized

and is to the credit of the whole histocompatibility community. The four presently

welldefined, closely linked loci, HLA-A, HLA-B, HLA-C, and HLA-D/DR, have

each from 8 to 39 codominant alleles, and the number of haplotypical or

genotypical combinations already amounts to several million. It is very likely that

other closely linked polyallelic loci will be discovered, similar, for example, to the

various loci in the I region of the mouse. If one adds to this complexity the

polymorphism of other genes in the HLAregion, coding, for example, for factors

C2, C4S, C4F, and Bf

of complement, one reaches such levels of complexity that

virtually every human has a different gene combination. If one considers all the

genes of the human genome, it can be said that there is not and will never be on

earth, apart from true twins, two identical people: every person is unique.

A question that immediately comes to mind is: Why is the MHC so complex?

It is clear that a particular pressure was exerted on these genes to make them

different and to maintain this differentiation. If it is true that these structures play

a role in self-recognition and that they derive from primitive genes coding for

surface molecules, then one can conceive of this diversity quickly becoming a

necessity when living matter passed from the unicellular stage -- or from a

syncytium of identical cells able to fuse without harmful consequences -- to the

organized multicellular organism whose tissues must coexist and even cooperate

and whose cells therefore cannot even merge with the cells of an organism of the

same species.

Maintenance of this polymorphism is undoubtedly aided by the selective

advantage given to the heterozygotes, possibly through the immune functions

attributed to the MHC molecules in a subsequent stage of evolution.

The HLA system is now known to have two types of products that are very

different from each other (their single nomenclature sometimes obscures this


The products of the HLA-A, -B, and-C loci [Kleinís class I (17)] are ubiquitous,

being present at the surface of all (or almost all) cells of the organism. This wide

distribution would suggest that they play a very general biological role.

In contrast, the products of the D/DR locus -- and probably of the ìfutureî DR

loci (class II) -- exist only at the surface of certain specialized cells, essentially

immunocompetent cells, a valuable piece of information with respect to their


We must not neglect another valuable piece of information afforded by the

major similarities between the class I products and immunoglobulins: the light

chain (the b2-microglobulin) as well as one of the domains (a3) of the heavy chain

have significant similarities with the immunoglobulins and therefore suggest the

possibility of a common ancestral gene (18, 19).

The light and heavy chains of the class II products bear no similarity either with

the class I products or with the immunoglobulins. It can be said, therefore, that

the products of the HLA complex are bipolar and are probably derived, by

duplication and successive mutation, from two very distinct genes, the function

and origin of which go far back in the evolution of the species.

At present, at least three variable regions on the heavy chain of the class I (20)

products are known. In the most distal domain (al) is the main variability zone

(between amino acids 60 to 80), which probably corresponds to the serologically

defined allelic epitope (individual antigenic determinant). This same domain

also has (between amino acids 30 to 40) an apparently variable zone that is

responsible for interaction with the influenza virus. In the median domain (a2)

is a third variable zone (between amino acids 105 to 114).

The extreme frequency of cross-reactions between the various allelic molecules

of each HLA locus is well known. Two interpretations that are not mutually

exclusive are possible: the similarity in the structure of the allelic epitopes [see

Colombani et al. (21)] or the existence of determinants common to two molecules

butdifferentfrom the epitopes; determinantswhich I, and Ivanyi (22), have called

ìantigenic factorsî (also known as supertypical antigens or public antigens):

According to our hypothesis, the molecules having an identical epitope-let us

say, for example, A2-are not identical in their composition. Some may have one

or more different antigenic factors. This variability may be found in the same

population but is more often found in different populations (23). . .

This concept suggests that the various parts of an HLA molecule might have

different functions (as is the case for the different portions of the immunoglobulin

molecule). It has recently been shown that the interaction between the HLA

molecule and the influenzavirus does not take place at the level of the serologically

distinguishable determinant since this virus has a different interaction with

molecules, which, nevertheless, have a serologically identical A2 determinant


The same hypothesis could be applied to the DR molecules and could perhaps

make it possible to solve the problem of the relations between the D and DR series.

In effect, D might be no more than a variable part of the DR molecule having a

stimulating function, since disassociated haplotypes do appear to exist-that is,

where the determinant D is not the determinant usually found with the DR

antigen (16, 25).

A second possibility, which should not be excluded, is that D in itself does not

exist but is defined by an average of allostimulation due to a certain combination

of alleles in the loci of region D, the linkage disequilibrium involving not only the

DR locus but other loci as well, equivalent to IA, IJ, IC, IE of the mouse.

A second series of DR molecules is already in the process of being defined both

by serological and cellular procedures. In particular an allelic SB series, centrometric

in relation to the DR locus, has just been described (26, 27) through the use of

mixed secondary lymphocytic cultures.

With regard to the genetic organization, we cannot yet grasp this in precise

terms, but with the aid of modern DNA hybridization techniques it will not be long

before we do understand it (28).

Linkage disequilibrium. The four loci of the HLA complex are closely linked on

the short arm of chromosome 6 (21p). They are, however, sufficiently distant for

relatively frequent recombinations to occur (0.8 percent between A and B and 1

percent between B and D/DR in man). This special situation seems presently to

be virtually unique to human genetics. It is, moreover, accompanied by a

particular phenomenon, which is the preferential gametic association between

alleles of several loci of the same complex. A linkage disequilibrium is said to exist

between these alleles. The phenomenon has given rise to numerous speculations.

Is this merely reminiscent of ancestral combinations (when populations were

isolated some 2000 to 4000 years ago) that were revealed or increased by human

migration? Could a mixture of populations temporarily set a certain haplotypical

formula that would survive for only so long as was necessary for it to be dispersed

through segregations occurring in successive generations (29)? Or is this linkage

disequilibrium really a preferential association, that is to say, selected for the

biological advantage or advantages it confers in a certain environment?

Of course, these two mechanisms can operate simultaneously.

One might ask whether the feature of linkage disequilibrium is specific to the

MHC or whether it is a very general feature that recurs at other points of the


HLA polymorphism and its linkage disequilibrium are valuable tools for

anthropologists and epidemiologists. They allow the former to characterize a

population; to discern its origin and draw up its genetic history. They allow the

latter to compare HLA formulas and HLA haplotypes with the particular

susceptibility of a population or groups of populations to certain diseases; and

perhaps in the future they will be able to reconstitute major diseases and epidemics

that have occurred in the past by observing the selections that have operated.

Finally, in formal genetics, the HLA complex is certainly the segment of the

human genome that is best known and is a major example of our relating a human

product to the sequence of the corresponding gene.


Second Concept: Transplantation Antigens


It is in such terms that these membrane structures are most often defined,

because at the same time that genetic polymorphism was being elucidated,

transplantation in humans was assuming great importance in therapeutics.

Our understanding of allogenic response in man has evolved rapidly. When

only the HLA-A and -B antigens were known, allogenice response amounted to

cytotoxicity on targets A and B. Thanks to admirable volunteers, the correlation

between the survival of skin graftsand the number of HLA-A and-B incompatibilities

was clearly demonstrated (30-33). The same correlation was seen in recipients of

related or non-related donor kidneys. This correlation, which was long debated,

is no longer challenged; however, the benefit of compatibility limited to these two

loci is very variable depending on the categories of patients.

When locus D was discovered (34,35), its importance in transplantation was

immediately suspected (36, 37). In fact, it was shown in vitro that lymphocytic

proliferation in allogenic culture was only possible when there was incompatibility

at the D locus (38). Clinically, a correlation has been found between the intensity

of proliferation during the mixed lymphocytic reaction, that is, between the

recipient and the related donor, and the survival of the graft. However, it has not

been possible to apply this observation to the transplantation of nonrelated organs

because of the time required for its elaboration.

In contrast, as soon as DR antigens (14, 15) could be detected by serological

means - and thus rapidly - it became possible to use this new method of selection

successfully. A DR incompatibility is accompanied by a drop in the survival rate of

grafts, both skin (39, 40) and organ transplants (41, 42). In both cases there is a

clear additive effect with those of the A and B incompatibilities (Fig. 1).

Incompatibility is in most cases both DR and D, and thus has two consequences:

1) With DR incompatibility it provides a target for cytotoxic cells. DR antigens

are true targets: they do not behave like minor antigens because they do not need

the HLA-A and -B identity between the killer cell and the target (43).

2) It induces, by the D disparity, the appearance of auxiliary cells, some of which

are helper cells and others suppressor cells. In the normal state, helper cells

dominate suppressor cells. However, it must be made clear that in certain

circumstances, the suppressor cells dominate the helper cells and the scale then

tips in favor of tolerance.

It is possible that the indisputably beneficial effect of preoperative transfusions

is due to the development of suppressor cells or factors in the recipient (44). In

fact, with Sasportes and others (45, 46) we have shown that hyperimmunization

against DR is accompanied by the in vitro appearance of a suppressive factor

capable of producing a specific feedback inhibition on its own cells. The exact

circumstances that cause the suppression invivo to sometimes dominate immunity

are unknown. However, it is known that in the monkey the beneficial effect of

transfusions has been observed onlywhere the animals are also immuno-suppressed

(47). Recipients ofkidneys are, so to speak, alwaysimmunosuppressed due to their

renal insufficiency; this would explain why, in the course of transfusions, the

immune balance leans in favor of suppression.

On the basis of the preceding considerations we have proposed (48) a

theoretical plan, of necessity provisional, for the choice of blood donors for

transfusion and organ donors. Without going into detail, it is based on the

following principles:

1) Before transplantation, a state of tolerance must be developed in the

recipient and at the same time immunization against HLA-A and B-targets must

be avoided. Thus, transfusions should be made with DR incompatible blood that

is A, B compatible. The same DR incompatibility should be used constantly in

order to increase the chances of the appearance of suppressive cells and factors

of the allogenic proliferation.

2) In selecting the organ donor one must avoid providing targets againstwhich

the recipient could be immunized. Thus, priority should be given to HLA-DR

compatibility in patients who have not produced antibodies against HLA-A and

-B antigens in the coarse of transfusions (nonresponder recipients). On the other

hand, priority should be given to HLA-A and -B compatibility in those who have

been sensitized in the course ofpreoperative transfusions (responder recipients).

Indeed, for the former there is little chance of immunization occurring against A

or B antigens, but the appearance of helper cells and a supply of DR targets should

be avoided. Conversely, in the responders, helper cells are already present and

their action must be neutralized by not contributing incompatible A and B targets.

Very precise and detailed treatment protocols will be necessary to verify or

disprove the validity of this plan.


Third Concept: Role in the Immune Response


This third concept is essentially based on our knowledge of animals since

systematic experiments are ethically difficult and thus rare in man(49). Nonetheless,

to date, the parallelwith the H-2 complex is striking. Here again we find the bipolar

division of the functions of the products of the HLA complex:

1) Class I products appear to serve as targets when a cell is either infected by a

virus or covered with a hapten.

2) Class II products appear to serve as a regulator between the various cell

subgroups involved in the immune response.

In both cases, a phenomenon of restriction is most often observed, that is to say,

an identity with class I or II products is apparently necessary between the

cooperating cells.

Thus a phenomenon of restriction exists in the cytotoxicity of a killer T

lymphocyte cell against a cell carrying a virus (50,51), a hapten (52) such as the

DNP, or a normal antigen such as the H-Yantigen (53). The killer cell must have

at least one identity with the HLA-A and -B (class I) antigens of the target cell in

order for the lysis to be effective, or else the killer must have matured in the

presence of the histocompatibility antigens of the target.

Similarly, when an antigen such as PPD is presented by human macrophages

(54), the presence of a DR identity (class II) is apparently necessary for the

presentation to be effective and for lymphocytic proliferation to occur. This

restriction is not absolute, however, and a certain number of proliferative

reactions that can be explained by cross-reactions between DR antigens has been


As in the mouse, where soluble factors carry antigens from the I region that

convey a specific message to another T or B cell population, so in man there is

evidence of a certain number of soluble factors of this type (55,56). Undoubtedly,

when we have a better understanding of the various products of region D in man,

numerous specific and aspecific factors, either restricted or unrestricted, will be


The restriction phenomenon is probably the most direct proof of the role of

the products of the HLA complex in the immune response of man.

Indirect proof has been sought in the numerous associations between HLA and

diseases. Based on the murine model, the first study of associations between HLA

and disease was done in our laboratory on acute lymphoblastic leukemia (57). A

slight but definite increase of A2 has now been demonstrated in numerous

worldwide studies (58). Likewise, the Al antigen is slightly increased in Hodgkinís

disease. These two observationswould suggest thatagene acting on hematopoiesis

may exist near locus A (58).

However, most of the diseases indisputably associated with HLA are neither

tumorous nor obviously infectious (59). These are chronic or subacute diseases

having a definite familial though mild character, that are of unknown etiology and

are not included in any of the major classifications. For a good number of these

there is an obvious autoimmune component.

We will give only two examples to illustrate once again the bipolar nature of the

functions of HLA products. In the first example, class I products may still be

considered as possible targets; in the second example, class II products may be

considered as regulators of the immune response.

Articular and more especially sacropelvic disorders that are strongly associated

with B27 seem to require the molecule HLA-B itself to play an essential role. In fact,

the same B27 antigen is found in a series ofdisorders (Reiterís syndrome, ankylosis

spondylarthritis, psoriatic rheumatism) which tend to affect the articulations of

the sacrum and pelvis. Further, this same predisposition is found in all populations

of the globe. However, it has now been clearly demonstrated that the same

pathological manifestations can also affect a small number of individuals who are

B27 negative. The B27 epitope is therefore not indispensable. At least two

hypotheses may be advanced: either the responsible gene in all populations is

strongly linked with the B27 antigen, or molecule B27 has a variable part (an

antigenic factor) that is responsible for susceptibility; this antigenic factor would

not always be present on all B27 molecules and could be found on other HLA

molecules probably having cross-reactions with B27 (in keeping with our concept

explained above).

It seems, moreover, that for these diseases there is a factor that triggers

infection. In fact, it is known that some acute intestinal infections caused by Gramnegative

bacteria such Shigella, Salmonella, and Yersinia are complicated by ankylosing

spondylarthritis mainly in patients who are B27 positive. Recently, a direct

relationship was suggested between the B27 antigen and a type of Klebsiella

(KlebsiellaB43). The antibodies against Klebsiella would be capable of recognizing

specificallyanantigenpresenton the lymphocytes of B27 positivepatientsaEected

by ankylosing spondylarthritis. Further, lysates from this infectious agentwould be

capable of transforming lymphocytes in B27 normal individuals and of making

them sensitive to the antibodies against Klebsiella (60, 61). Although clinically the

link between a Klebsiella infection and ankylosing spondylarthritis is still unclear,

this observation, not yet confirmed, suggests that certain infectious agents would

be capable of modifying HLA antigens and of apparently making them similar to

those in patients. It is not impossible that this type of mechanism may one day

explain the linkages with other microorganisms referred to above. These

microorganisms would be capable of modifying the B27 antigen and perhaps

certain other HLA molecules as well (to take into account B27 negative patients),

and of making them privileged targets for T-immune autolymphocytes. Although

this hypothesis is enticing, it cannot yet explain the very special localization of

lesions, since the B27 antigen, like all HLA antigens, is practically ubiquitous.

If we now consider disorders associated with HLA-D/DR, one is at the outset

struck by the large number of them that are associated with Dw3/DR3 and, more

especially in Caucasians, with the Al, B8, DR3 haplotype. For the most part, there

are diseases with a strong autoimmune component and a low family penetrance,

such as myastheniagravis, Gravesí disease, Addisonís disease, Sj-grenís syndrome,

disseminated lupus erythematosus, and active chronic hepatitis. It appears that

this haplotype, in strong linkage disequilibrium, has a gene or perhaps a series of

genes that are conducive to autoimmunization.

Insulindependentjuvenile diabetes (IDD) , itself associated with Al, B8, DR3

and also with B18, DR3, and B15, DR4 is in this respect very instructive (62, 63).

.The viral etiology of IDD is highly suspected: experimental models of the disease

do exist and specific observations in some cases in man incriminate the B4

Coxsackie virus. One can therefore infer that the virus has destroyed a certain

number of islets of Langerhans and triggered a process of cellular autoimmunity

where cytotoxic lymphocytes persist in the organism against antigens modified by

or associated with a virus. The disease would thus be self-sustained. In this

hypothesis the D region products would have been incapable of inducing an

adequate immune reaction against the virus causing the disease. In contrast,

individuals who are DR2 positive (most frequently A3, B7, DR2), who appear to

be ìprotectedî against IDD would have a more effective immune response against

the responsible agent.

This is only a working hypothesis which would have the advantage of applying

to other diseases associated with HLA-DR such as multiple sclerosis (DR2) and

chronic polyarthritis (DR4) orjuvenile rheumatism (DR5).

The reality, however, is certainly far more complex. In fact, in no case is the

association complete with a DR antigen. This is generally explained by a linkage

disequilibrium between a simple susceptability gene for the disease and a DR

allele. Here too, however, one might think there are polymorphic parts to DR

molecules other than the epitopes presently known and that these might have a

particular immune function. Even better, it could be assumed that the interaction

of two (or more than two) genes from the D region would be conducive to an

adequate immune response. This interaction could take place in the &position

(64 ) between genes of the same haplotype (as in the interaction between I-A b and

I-Eb to form an I-E molecule in the mouse) or in the trans (65) position between

two haplotypes (such as I-Akand 1-Ab) complementation in the mouse).

As a corollary to these gene interactions we propose that each HLA haplotype,

and especially those in linkage disequilibrium that are found most frequently in

the numerous diseases associated with HLA, has its own gene configuration that

confers on it a particular capacity for immune response, which may be favorable

in certain environmental conditions and unfavorable in others (for example the -

A3, B7, DR2) haplotype gives a susceptibility to multiple sclerosis and protects

against IDD) Thus, each HLA complex would be composed of a set of genes that

have subtle interactions among one another (such as gene C2 with the two C4

genes) thereby giving them a specific identity in immunological terms.

Likewise, every individual possessing two HLA haplotypes has his or her own

immunological capacitywhich is conferred on him by the two particular haplotypical

formulas inherited from his two parents, but which is also the result of the genetic

interaction or complementation between the these two complexes. Thus each

individual has a personal immune response that makes him either susceptible or

resistant to certain diseases. Here again each haplotypical combination may be

beneficial or harmful depending on the type of challenge to which the individual

is subjected.

In terms of the population, we can thus conceive that certain individuals are or

were more exposed and thus are or were more easily eliminated than other

individuals more resistant to past and present epidemic or endemic diseases. But

it is not the same individuals who are susceptible or resistant to the different

attacks; this is what makes the survival of a population possible, and thus the

perpetuation of the human species.

MHC products are distributed on the surface of cells. Those of class I are

virtually ubiquitous. Class II products may be found on immunocompetent cells

but also on endothelial and other specialized cells. Their location suggests that

they play a role in the social organization of cells of the same organism.

This assumption is strongly supported by the following observation: it appears

to be necessary for MHC products to share an identity in order for cooperation to

be etablished between two populations of cells in the same organism or in two

different organisms. This is the restriction phenomenon which we discussed

above, and which is valid for the two classes of products. Results confirming this

apparent need for identity are accumulating very rapidly in both animals and in

man and are no longer limited solely to immunocompetent cells. The same is true,

for example, in the adhesion phenomenon between fibroblasts and especially in

the ìhomingîphenomenon in ganglia. Degos and others (66) have observed that

splenocytes injected intravenously must share an identity with the cells of the

capillary endothelium with regard to class I products so that homing can occur.

The identity of class II products does not intervene (Fig. 2).

Fig. 2. Homing in lymph nodes according to identities (a) or differences (0) Labeled lymphocytes

were injected intravenously into mice under different genetic conditions: allogenic (first line),

syngenic (second line), congenic where the difference involves only one or several genes of the H-

2 complex (all other lines). The average value of r (percentage of horning from which the control

value has been deducted) is high wherever there isidentity (0) with H-2D or H-2K; H-21 identity has

no influence (66).

We are thus faced with a very general phenomenon with such a consistent

record that it is difficult to escape the conclusion that the two types of molecules

have a common function. They could serve as a recognition signal (recognizers)

among cells of the same organism; a signal necessary but probably insufficient to

permit effective cooperation between the two subpopulations of cells because it

would be the same, at least at class I, for all cells of the organism (2-5).

The passive or negative discrimination of self implies that the cells ìignoreî one

another. This seems improbable in view of the cohesion of tissues and of their

interaction. Without self-recognition, each specialized cell and each tissue would

be isolated and incapable of surviving. These considerations thus suggest that selfrecognition

is an active phenomenon.

The subjacent mechanism of self-recognition is still unknown. At least three

possibilities come to mind. The most orthodox is the complementarity between

two different molecules. But one cannot exclude recognition by identity, whether

that recognition takes place between two identical molecules or through a ligand.

This fascinating problem has been discussed in detail elsewhere (67). Suffice it to

mention here just two remarks in relation to complementarity:

lIf a second molecule (receptor) existed with the same immunogenicity as the

HLA determinant, a second allelic system as complex as the former would have

been found. To date no such system has been found. However, one should remain

aware of the weak immunogenicity of the idiotypes which could represent these


lIf the receptor and the determinant were coded by two different genets, any

mutation and selection of one should correspond to the mutation and selection -

of the other. This is unlikely. Here again, however, one might envisage, according

to Jerneís theory, that each individual has all possible receptors, the appropriate

receptor being selected in early life, perhaps in the thymus. This is probably what

occurs, for example, in the growth of allophenic mice in which cells carrying

different H-2 antigens coexist.

Whatever the mechanism, the fact remains that self-recognition is a general

and active phenomenon of any cell that is at least partially, linked to the MHC. We

suggest that class I products are responsible for individuality, for integrity, and

perhaps for the general cohesion of the being and that class II products are an

example of cellular cooperation, thanks to self-recognition at the level of the

differentiated cells of the immune system, allowing the immune system to

function harmoniously.


Future Prospects


Thus the increasingly deep understanding of the MHC in man opens up

exhilarating prospects both in public health and in basic science.

With regard to organ transplantation, we do not feel that the choice of the most

compatible donor will be the last word. On the contrary, our aim must be to

provoke in the recipient a specific tolerance to incompatible donor antigens

without at the same time diminishing his or her immunological defenses. It seems

that with preoperative transfusions the way has been opened to this type of

preparation. We must now attempt to unravel its detailed mechanism so that the

method can be used more generally. This will be the objective of the years to come,

and we have no doubt that it will be achieved.

Although organ and bone marrow transplantations mark a milestone and have

already brought help to numerous patients, they should not be considered an end

in themselves. Etiological treatment should progressively replace them.

The discovery of more than 50 diseases associated with or linked to HLA is

perhaps still more promising, and although the diagnostic or prognostic benefits

to practising physicians are still limited, physicians recognize the validity of this

approach. They know that correction of the abnormalitywhich provokes a disease

is close at hand when the gene responsible has been located and its function

defined. Thanks to the astounding possibilities offered by genetic engineering it

will henceforth be possible to know the exact DNA sequence in the vicinity of the

HLA genes. The latter will serve as markers and will make it possible to discern

anomalies of susceptibility genes. We must emphasize the possibility that in some

cases no anomaly will be found because a gene (or combination of genes) may be

perfectly active in the defense against certain antigens but totally inactive in the

defense against others. Thus an inventory of the immunological capacities of each

individual will need to be drawn up. This inventory will show the weaknesses

(susceptibility), the excesses (autoimmunization), and the good capacities

(protection) afforded by each type of gene combination. In this way, preventive

medicine of high precision will be possible; a personalized medicine that will be

more efficient and less burdensome for the community than the present mass


At the same time, researchers now have the means with which to approach the

crucial problem represented by the subtle organization of manís immune system.

The cascade of interrelationships, and the language, between different

immunocompetent cells will be clarified; the place of the ìspecificî and the

ìnonspecificî will be recognized; the role of HLA products in messages between

welldefined cells will be determined. This deeper understanding of manís

immune response will quickly have major repercussions in pathology. It will

perhaps provide the key to the irritating problem of the treatment of cancer, and

may also provide a simple means of inducing graft tolerance at will. It will also

perhaps lead to an immunological treatment of the major parasitic diseases that

still afflict such a large part of mankind.

Finally, the discovery of the primary function of the molecules of the MHC

found at the surface of all, or almost all cells of the organism will be a decisive step

in our understanding of the differentiation and social organization of cells.

The way already trod is but a simple introduction. They are still many

marvellous pages to be written. . .


References and Notes


1. G. D. Snell, Havey Lect, 74, 49 (1979).

2. , Folio Biol. (Prague) 14, 335 (1968).

3. N. K. Jerne, 1 Eur.J. Immunol. 1, 1 (1971).

4. J. Dausset, A. Lebrun, M. Sasportes, C. R. Acad. Sci. Paris 275, 2279 (1972).

5. W. F. Bodmer, Nature (London) 237, 139 (1972).

6. J. Dausset, Acta Haematol. 20, 156 (1958).

7. J. J. Van Rood and A. Van Leeuwen, J. Clin. Invest. 42, 1382 (1963).

8. R. Payne, M. Tripp, J. Wiegle, W. Bodmer, J. Bodmer, Cold Spring Harbor Symp. Quant. Biol. 29,

285 (1964)

640 Physiology or Medicine 1980

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