An immunogenetic view of delayed type hypersensitivity

Tu bercle Tuber& (1991) 72. 161-167 Q Longman Group UK Ltd 1991

Review article

An immunogenetic view of delayed type hypersensitivity R. R. P. DE VRIES Department

of Immunohaematology

and Blood Bank, University Hospital, Leiden,

The Netherlands

Summary - This review, the third in the series on cellular immune reactivity to tubercle bacilli in the centenary year of Koch’s classical paper describing this phenomenon and its possible implications [l], represents an immunogenetic point of view. In fact this will be quite a broad point of view by an immunogeneticist who is not hampered by specific knowledge on therapy or prevention of tuberculosis. In this respect I probably do not differ very much from Robert Koch 100 years ago! An important difference, however, is that we think we now understand a great deal of the cellular and molecular basis of the immunological phenomena observed by Koch. Immunogenetics has contributed considerably to our current understanding and I will try to review that contribution here. Because thus far my main research interest has been in another mycobacterium, namely Myco&icterium leprae, I will use M. leprae and leprosy as an example to illustrate some ideas. The message of this review is that there is a reason for optimism: the knowledge recently gained by cellular and molecular immunologists as well as immunogeneticists has straightforward implications for the rational development of subunit vaccines and immunotherapeutic strategies.

HLA and disease

Immunogenetics was born less than 100 years ago, namely in about 1900, and grew up as a science of blood groups. Of course, the main blood group of clinical significance was, and still is, the ABO system discovered by Landsteiner [2]. About 30 years ago, Dausset, Van Rood and Payne discovered that blood groups are not only expressed on red blood cells but also on white blood cells [3-53. They coined the products of these blood groups HLA antigens. It was soon discovered that HLA antigens are not only blood group antigens, but also transplantation antiCorreqondence to: Dr Rene R.P. de Vries, Department of Immunohaematology and Blood Bank, Building 1, E3-Q, University Hospital, Postbus %oO, 2300 RC Leiden, The Netherlands.

gens and that matching for HLA is not only important in transfusion medicine but also in transplantation medicine [6]. Matching the donor and the recipient of an organ transplant for HLA antigens significantly improves the fate of the transplant in the recipient. Although HLA and ABO thus have certain aspects in common, they are at least different in one important aspect the HLA system is far more complex and polymorphic. The ABO system has one locus and the HLA system at least six. ABO has three alleles, HLA well over 100. The possible genotypes that result from combinations of these alleles are only six in the case of ABO but for HLA it is many millions. Thus the

161

162 HLA system is by far the most polymorphic genetic system known in man. The science of immunogenetics changed dramatically when it was realised that HLA antigens are not only important in transplantation and blood transfusion, but that they also play an important role in the susceptibility to many diseases, in particular immunopathological and auto-immune diseases. About 10 years before the discovery of the HLA system, the H2 system, which appeared to be the homologous system in the mouse, was put on the map by Gorer and Snell [73. It was demonstrated that these systems were coding for the main transplantation antigens and from that the name Major Histocompatibility Complex (MHC) was derived. In 1964 the American investigator Lilly discovered that the H2 system contained genes that confer resistance to a virally induced leukaemia in mice [S]. A few years later, the Frenchman Amiel reported a weak association between a certain HLA type and susceptibility to Hodgkin’s disease [9]. However, the real trigger for the avalanche of studies on HLA and disease associations that were published between then and now, was the discovery made in 1973 both in the USA and the UK that a certain HLA antigen, namely HLA-B27, appeared to be very strongly associated with ankylosing spondylitis [lo, 111. This led to several thousands of studies on the association between certain HLA types and susceptibility to several hundreds of diseases. At least 50 diseases were unequivocally shown to be associated with certain HLA types, auto-immune diseases being on the top of the list [12]. At about the same time, McDevitt and associates discovered that genes in the murine H2 system code for differences between individuals in immune reactivity to specific antigens and these genes were therefore called immune response genes or Ir-genes [13, 141. Several years later this was also confirmed in man [15-N]. An extraordinary figure in those early HLA days was Rugiero Ceppellini, who not only provided the necessary genetic background which most of the other pioneers in the HLA field lacked, but also very stimulating ideas. One of his many well formulated remarks in particular triggered my research in this field ‘There is little doubt, however, that the motivation of nature in selecting for a genetic polymorphism of this complexity was not an u priori hostility against transplantation surgeons’. And one could add that there is even less doubt that the HLA system was not meant to confer susceptibility to disease. Ceppellini went on to say that ‘to find the selective mechanism that has allowed the establishment during evolution of such

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systems in many, possibly all, vertebrates represents a challenging aim for biology’ [19]. Actually it was Rugiero Ceppellini himself who, together with Piazza and other collaborators, was the first to take the challenge by going to Sardinia and showing that malaria is not only a selective agent for the thalassaemia gene but has also exerted a signiticant selection on the HLA system [20]. A few years later I demonstrated that an epidemic of typhoid fever had acted as a selective agent on the HLA system [21]. This led to the following hypothesis: the HLA system is meant to confer resistance to infectious diseases, which by exerting a strong selective pressure on the HLA system, generated and maintained the polymorphism as we see it today. The other side of the coin is, however, that the same HLA polymorphism that plays a useful role in conferring resistance to infectious diseases, is also the price that some people have to pay through increased susceptibility to some immunological diseases. Because such diseases are not usually killers and occur after the reproductive age, they do not have a significant effect in terms of selection. In other words, one might say that the HLA polymorphism is a kind of life insurance for the species against premature extinction by infectious diseases and that the premium for that life insurance is paid by the few people who suffer from HLA-associated allergic and immunopathological diseases. HLA class II immune response genes Since 1974 we know, through the work of Rolf Zinkemagel, the function of HLA molecules: they present antigens to T-cells [22, 231. A few years later, McDeviu, Benacerraf and others showed that the same molecules are the products of immune response genes [24,25]. In other words, their polymorphism results in differences in antigen presentation capacity. In the last 10 years the molecular basis of these two discoveries has been claritied. In order for a protein antigen to be recognised by T-cells it has to be broken down or processed in an antigen-presenting cell to a peptide [26] which then binds to a pocket in an HLA molecule which is specifically ‘designed’ to bind peptides [27]. This binding usually takes place in the cell. The complex of HLA and bound peptide is then transported to the cell surface where it may be recognised by a T-cell receptor that is specific for that particular combination. CD8 and CD4 molecules are accessory molecules for this interaction, binding respectively to HLA class I and class II molecules [28]. The molecular basis of immune response genes

163

IMMUNOOEh’ETICS OF DTII

is thus that various HLA molecules differ in their binding capacity for peptides. Accordingly, compared to an antibody or a Bcell which recognise a specific epitope in a native molecule or on a whole microorganism, the situation is more complicated for T-cells. Although the question was not introduced at the beginning of this review, I think it is appropriate at this point to ask: ‘Why is the T-cell so complicated if the B-cell has shown that it can also be done in an easy way’. There are at least three good reasons for this. The first is that once a microbe is in a cell (and that is of course very pertinent for intracellular parasites like mycobacteria) it cannot be recognised by an antibody. This system therefore protects the host from parasites hiding in cells. The second reason is that, in contrast to B-cells which produce antibodies that can swim around the body, the T-cell produces lymphokines which are locally acting and short-lived molecules. In other words, for the T-cell to do its job it has to be focused. I-ILA molecules provide this focus very efficiently. The third reason is a bit more complicated, but I mention it because it is important to understand why HLA genes are so polymorphic. The T-cells not only need HLA molecules in order to recognise foreign antigens but also to survive during their ontogeny. In the thymus, a Tcell has to recognise a self-HLA molecule, otherwise it will die there. This process is called positive selection. On the other hand, they also have to be tolerant for self, so T-cells that recognise self-HLA molecules too well are deleted and that process is called negative selection [29]. This means that we end up with ‘holes’ in our T-cell repertoire and the solution to that handicap is the HLA polymorphism, as I will try to explain. Different individuals carrying the products of different HLA alleles will bind different peptides for presentation to their T-cells. This may result in differences between individuals in immune reactivity to peptides. We do not have an immune system that can present all peptides with one type of HLA molecule, because every individual would then have the same ‘holes’ in his T-cell repertoire and the population might be wiped out by one pathogen that would find such a hole. The HLA polymorphism thus generates variation in the ‘holes’ of each individual T-cell repertoire, thus spreading the risk for the population. HLA class II immune response genes and leprosy 100 years ago, leprosy was still endemic in a few pockets of Europe and, in particular, in Norway. Until Armauer Hansen discovered Mycobacterium leprue, leprosy was generally considered to be a hered-

itary disease. One of the proponents of the hereditary aetiology of leprosy was Hansen’s father in law, Danielssen, a Norwegian dermatologist who wrote a classical book on the disease [30]. By his discovery, Hansen thought that he had definitely won the argument between him and, amongst others, his father in law. He literally said that ‘a bacillary disease cannot be inherited’ [3 11.Of course that is true, but we know now that the leprosy bacillus is virtually non-toxic and that most of the symptoms of leprosy are caused by the immune response of the host rather than by the mycobacterium itself. We also know that the differences between individuals in immune reactivity to the bacillus are, to a great deal, controlled by genetic host factors. So both Hansen and his father in law Danielssen were right. The immunology of leprosy may be briefly summarised as follows. After infection with M. feprue, the host mounts an immune response which can be a cellular or an antibody response. Because M. feprue is an intracellular parasite, immunity is not mediated by antibodies but by T-cells. In most cases the cellular or T-cell mediated immune response is adequate in the sense that it leads to protective immunity and the host does not develop leprosy. However, in some individuals the same T-cell mediated immune response that confers immunity is also causing immunopathology, namely delayed type hypersensitivity (DTH). The type of disease that is associated with DTH is called tuberculoid leprosy. At the other pole of the leprosy spectrum is the individual that does not mount a T-cell response but nevertheless produces antibodies reactive with M. feprue. These antibodies have no role in protective immunity but they do have a role in immunopathology and the type of leprosy that is associated with immune complex or antibody-mediated immunopathology is called lepro matous leprosy [32J.

Table Leprosy and HLA Swceplibildy IO:

Linkage

Leprosy per se Tubercvloid leprosy Lepromatous leprosy

+ +

Association -

These different host responses are genetically controlled and one of the responsible genetic factors is located in the HLA system. The Table is a heroic condensation of many genetic-epidemiological studies by our group and by others on HLA and leprosy

164

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[33-391. What it shows is that the susceptibility to infection with Mycobucterium leprae is not controlled by HLA linked genes. Thus there is neither linkage in families nor an association at the population level. However, the susceptibility to certain types of immunopathology which is reflected as different types of leprosy is clearly linked to HLA and associated with several HLA alleles, in particular HLA class II alleles. Classical examples are I-LA-DR3, which in some populations is associated with tuberculoid leprosy, and I-LA-DQl, which is universally associated with lepromatous leprosy. Similar observations have been made in tuberculosis [4045]. M.leprae epitope

T-cell

immunity

TOK

+

TDTH

+

Ts

-

leprosy

T

Fig. 1 HLA class II k-genes and the type of leprosy. Antigen-presenting cells (APC) of three individuals differing for HLA class II present different M. leprac epitopes to T-cell receptors (TCR) of functionally different T-cells: TOK is a helper T-cell that confers protective immunity, the same is ttue for T~H which, however, also causes immuuopathology (delayed-type hypersensitivity) seen in tuberculoid leprosy, and Ts is a suppressor T-cell responsibIe for the M. leprac -specific non-responsiveness seen in lepromatous leprosy.

The hypothesis that we have developed to explain the association between certain HLA class II types and the type of leprosy is graphically illustrated in Figure 1, and is basically an extension of the Ir-gene scenario depicted in the previous section. The extension is that we invoke different T-cell subtypes. The first T-cell subtype confers immunity, and is usually activated in the course of an infection with M. leprae. A second T-cell subtype also confers immunity but also causes immunopathology, namely DTH, and tuberculoid leprosy. Finally, there is a suppressor T-cell that is shutting off both these two types of T-cells, but not the production of (specific) antibodies, and leads to lepromatous leprosy. Of course, this hypothesis implies that these three patterns are related to differences

in HLA type: the T-cell responsible for DTH and tuberculoid leprosy would preferrentially ‘see’ certain M. leprae peptides presented by HLA-DR3 and the suppressor T-cell resulting in lepromatous leprosy would ‘see’ other M. leprae epitopes presented by HLA-DQl [46]. In the next three paragraphs I will briefly review some data that support this hypothesis. The best studied M. ieprae antigen is a 65kDa heat shock protein (hsp): 24 T-cell epitopes have now been mapped on this particular protein. All these epitopes are presented to (helper) T-cells by I-LA class II and almost all by I-LA-DR molecules [46,47]. However, each epitope is exclusively presented to Tcells by the product of one particular I-LA allele. In other words, the T-cell reactivity to this 65kDa hsp is under strict HLA class II immune response gene control. The basis for this immune response gene control has, at least in a few instances, been shown to be due to differences in binding of these epitopes (peptides) to different HLA molecules (unpublished data). A second important question is whether there is a correlation between a specific peptide and/or the presenting HLA class II alleles and the T-cell receptor used to recognise it. This may indeed be the case. In one individual, all T-cells that reacted with mycobacterial antigens and that were restricted by either DR3 or DR2 used two out of the about 20 VPT-cell receptor genes that were shown to be used by his peripheral blood T-cells. Moreover, all the DR3-restricted clones used a VP 5 gene product and most of the DR2-restricted clones used a V/3 18 gene product (unpublished data). Thus this is a very dramatic example of preferential VP gene usage. This preference is specific for the individual, because when we looked at other individuals we again saw preferential V gene usage, but different VP genes (unpublished data). The third set of data relates to the question of different T-cell subsets, in particular differences in lymphokine production. Mosmann et al. have described two helper T (Th) subsets in the mouse, differing in their lymphokine secretion profile. The first subset (Thl) produced IL-2 and EN-y and the second (Th2) IL-4, but no IL-2 and IFN-?I [48]. Thus far, there has not been much evidence in man for differences in lymphokine production by different Tcells. However, in the case of antimycobacterial Tcells there is now very good evidence for a Thl-like human T-cell subset. Most of the antimycobacterial class II restricted CD4 positive T-cells can specifically kill targets pulsed with mycobacterial antigens [49]. When we compare the cytokine production by T-cells reactive with mycobacterial antigens with that of T-cells reactive with non-mycobacterial antigens,

165

IMMUNOOENETICS OF DTH

the tirst produce large amounts of IFN-y and no or very little IL-4, in contrast to the latter [SO].Evidence for Thl and Th2 patterns of cytokine secretion in lesions from, respectively, tuberculoid and lepromatous patients has also been presented (Modlin, personal communication). In the mouse THY,but not ‘I’+, cells were shown to be responsible for protective immunity to intracellular microorganisms as well as for DTH reactions. Injection of IL-2 or IFN-y produced an increased cellular immune reactivity in lepromatous leprosy patients and induced DTH reactions [51-533. Since IL-10 has been shown to inhibit IFWy and IL-2 production by THY cells [54, 551, there might be a place for such an antagonist in the immunotherapy of DTH reactions in mycobacterial disease. Implications for development of a subunit vaccine Bloom and colleagues have put forward the idea of developing a recombinant mycobacterial vaccine that is capable of inducing cell-mediated immunity as well as antibodies to multiple pathogens. Such a vaccine would be an excellent adjuvant, safe (based on experience of BCG) and could be given as one shot at birth [56]. However, to develop such a recombinant vaccine one needs to know which (parts of) genes of the different pathogens are coding for protective antigens. Our hypothesis (Fig. 1) has obvious impli-

cations for the development of such a vaccine. For a rational design of such a so-called subunit vaccine it is first necessary to characterise disease-inducing epitopes of a microorganism and to delete them from a vaccine, leaving only the immunity-inducing epitopes. Secondly, it is necessary to take care of the fact that certain individuals will only respond to certain immunity-inducing peptides, so you may either have to combine several immunity-inducing peptides or to find a peptide that is binding to all or most of the DR molecules. Implications for immunotherapy of immunopathological diseases The knowledge of cellular and molecular immunology and immunogenetics described in this review can also be applied to immunotherapy of immunopathological diseases, for instance those resulting from DTH reactions. As was implicit in what I have discussed thus far, the helper T-cell, which is a class II restricted CD4 positive T-cell, plays a central role in orchestrating the immune response. The way it does this is by producing cytokines or iymplhokines, which regulate all the other activated (by antigen) players of the immune system. Interference with the production or effects of cytokines has been discussed above and in a previous review in this series by Rook and Al At-

APC

antibodies

to

other blocking compounds

A

tolerance induction with 4

antibodies to

antibodies to -e TCR

T DTH Fig. 2 Antigen recognition by disease-inducing helper T-cells as a target for immunotherapy and prevention of inununopathological diseases. APC: antigen-presenting cell, T~H: helper T-cells that induces a DTH reaction.

166 tiyah [573. However, the most specific and efficient immunotherapy for an immunopatbological disease is to turn off the switch that specifically operates the disease-inducing helper T-cell. That switch, as we have discussed, is the HLA molecule presenting a disease/immunopathology-inducing epitope to the Tcell receptor of a disease-inducing T~~ell. How this switch for e.g. DTH inducing T-cells may be turned off has been shown in experimental animal models and is summarised in Figure 2. The first strategy would be to prevent the HLA molecule from binding and presenting a peptide that induces DTH. In particular, if certain HLA alleles are exclusively or preferentially presenting such an epitope, this can be done in at least two ways; one is the use of antibodies against the I-LA molecule [58] or, more specifically, against a particular combination of peptide and HLA [59], and the second is the design of peptides or other compounds that prevent the disease-inducing epitope from binding to the disease-related HLA molecule [60]. If we know the disease-inducing antigen, we can try to induce tolerance, for instance by delivering that antigen in such a way that it does not induce a detrimental immune response but instead turns off the immune response to that antigen [61]. In particular, if certain T-cell receptors are preferentially used to recognise a certain peptide-HLA combination (like in the leprosy model), we can use antibodies [621 or, even better, active strategies such as vaccination with attenuated disease-inducing T-cells [63] or T-cell receptor peptides [64]. The last strategy, which at first glance seems to be less specific, involves the use of an antibody directed against the CD4 molecule used by the helper Tcell to recognise the HLA class II molecule [65]. Thus today there are enough possibilities for specific immuno-intervention in a DTH caused by M. tuberculosis. These interventions are based on solid knowledge of the cellular and molecular mechanisms underlying this immunopathological reaction. Quite a different situation compared with 100 years ago! Whether and which of these potential immune intervention strategies will prove useful for the treatment and prevention of disease caused by mycobacteria remains to be seen. Ten years or, more likely, 25 years from now may be a good time for an evaluation.

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Acknowledgements ‘lhe author would like to thank Amelle van Loenen for editorial assistance and the Netherlands Leprosy Relief Association (NSL), World Health OrganirationlIMMLEP working grcup (WHO/lMMLBP), European Econanic Communities (EEC) and the Netherlands Organization of Scientific Research (NWO) for suppotting the studies discussed in this review.

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