PAST,
PRESENT, AND FUTURE CONCEPTS
Nobel
Lecture, 8 December, 1980
by
JEAN
DAUSSET
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
difference).
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
functions.
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
(24).
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
genome.
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
observed.
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
described.
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
receptors.
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
system.
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. . .
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