Only a few years ago parasite immunology looked an unattractive subject better left to the dogged specialists. Parasites and hosts had been playing chess together for a million years, and there seemed little prospect of perturbing matters in favour of the host immune system. All that has changed, for three reasons. Firstly, we have learned how to grow at least some parasites in vitro, and prospects of doing so with others are encouraging. Secondly, progress in cellular immunology has revealed the sort of loopholes in the host defence system which parasites are likely to exploit: we are learning the questions which matter about parasites as antigens. Thirdly, and most importantly, molecular genetics is being brought to bear on parasites: we can now see a real, though long-term, prospect of manufacturing practicable vaccines through bio-engineering, and more immediately it gives us the tools needed to probe the host immune responses in the form of cloned antigens.

The understanding of the mechanisms whereby intracellular parasites counteract the microbicidal processes of macrophages has progressed considerably in recent years. Various factors contribute to intracellular parasite destruction; from a biochemical standpoint, particularly important is the oxidative burst triggered by phagocytosis and by macrophage ‘activation’, that leads to the generation of toxic metabolites of oxygen. At the ultrastructural level, fusion of the parasitophorous vacuole with surrounding lysosomes appears to be a pre-requisite for the final digestion and elimination of the infecting microorganisms. The counter-measures evolved by microorganisms to escape intracellular destruction are best illustrated by studies in vitro on the interaction of parasites of the Leishmania, Toxoplasma and Trypanosoma spp. with mononuclear phagocytes. Some microbes are able to inhibit the fusion of phagosomes with lysosomes, thus avoiding the potentially harmful action of lysosomal hydrolases. Other microorganisms are able to resist the effects of such enzymes, perhaps by secreting inhibitory substances. Others still avoid lysosomes by leaving the phagocytic vacuole, to reach the cytoplasmic matrix where their development is unhindered. Particularly critical is the capacity of certain parasites to subvert the lethal effects of the oxidative burst. This can be achieved either by failing to evoke this metabolic response, or by producing scavengers that can detoxify harmful oxygen metabolites. Intracellular death or survival will thus depend on a delicate balance between the potency of macrophage cidal mechanisms, and the efficacy of the protective measures evolved by the infecting agents.

The interaction between host and infecting organism plays an important role in the survival of both of these components. The mechanisms whereby survival of one, or both, is achieved can be considered at various anatomical levels and degrees of complexity; those involving whole tissues together with events occurring at the cellular and subcellular levels. The involvement of sequestration, or the ‘standing apart’ of an invading organism from the host, as a mechanism of survival can also be examined at these various levels.

It is now well established that animal parasites elicit vigorous immune responses in their hosts and that the resistance to reinfection thus acquired is mediated through conventional humoral and/or cellular effector mechanisms. It is also recognized, however, that some parasites exhibit extreme longevity in the face of a potentially hostile or lethal environment, and it may be assumed therefore that such organisms possess a repertoire of highly sophisticated and successful evasive strategies. Of all the survival mechanisms thus far proposed, the concept of antigen sharing, or disguise, is probably the most contentious. Arguments have arisen over the nature and origin of the shared determinants and over the validity of their role in ensuring parasite survival within the fully immunocompetent host. This presentation reviews published data concerning the existence of a disguise stratagem amongst medically important parasites and evaluates experiments designed to investigate the functional importance of disguise in immune evasion.

Antigenic variation is a powerful survival strategy adapted by certain species of parasitic protozoa to allow them to survive in the immunized host. It is exemplified by the African trypanosomes, which provide far and away the best characterized and most studied system of this kind. Why have the trypanosomes developed antigenic variation to such a sophisticated level? Because the trypanosome lives its life in the bloodstream of its mammalian host and is therefore in continuous conflict with the host's immune system. Antigenic variation represents its whole survival strategy, with some help provided by its ability to immunosuppress the host. The importance of antigenic variation to the trypanosome is underscored by the estimate that up to 10% of the trypanosome genome may be devoted to variant antigen genes (Van der Ploeg et al. 1982). Most other parasitic protozoa prefer a less confrontational existence and usually adopt an intracellular home for at least a part of their life-cycle within the mammalian host. That being the case, do other parasitic protozoa need antigenic variation within their armorarium ? The answer seems to be yes, although the reasons why are by no means clear. For example, the stages in the life-cycle which exhibit antigenic variation might be expected to be those which are released free into the bloodstream – in malaria, sporozoites and merozoites, for example. Yet there seems to be no evidence for phenotypic variation at all in these stages. Rather, it is the intracellular stages which, in both Plasmodium and Babesia, seem to elaborate molecules which are expressed at the surface of the parasitized cell, and which are capable of both eliciting an immune response and of avoiding the con- sequences of such a response by phenotypic antigenic variation. Why are such antigens expressed, and what is their functional significance?

Infective larvae, adults and newborn larvae of Trichinella spiralis were surface labelled with radioactive iodine, and the surface material was solubilized in the mild detergent sodium deoxycholate. The radio-isotope labelled products were stage-specific glycoproteins that were few in number (2–4 components) and antigenic in infected mice and rats. Antibodies synthesized in infected animals against these biochemically defined surface antigens may or may not interact with the surface of the living worm. The latter type of antibody is unlikely to be involved in the initial phase of parasite rejection and is therefore another example of a non-protective host antibody response. The stimulus for its synthesis must be the observed release of surface antigen. A monoclonal antibody to a surface glycoprotein of newborn larvae protected against infection, and also promoted eosinophil killing in vitro. This observation emphasizes the importance of surface antigens in protection against infection, suggests a role for granulocytes in vivo, and provides encouragement for the possible use of nematode surface antigens in protection. An example of regional specialization of the nematode cuticle was given by a monoclonal antibody reactive with only the surface of the male intromittent organ and not the female or remainder of the male. The same stages were labelled in vitro with radioactive methionine, and the secreted proteins were also found to be stage-specific. Some, but not all, were antigenic in infected mice. The total concanavalin A-binding somatic glycoproteins of each stage exhibited considerable individuality, and hence stage specificity, when resolved by two-dimensional gel electrophoresis. These results extend our knowledge of stage-specific components of T. spiralis, and allow a rational approach towards protection and the construction of diagnostic procedures.

In common with a number of parasite surface antigens about which we have heard, the influenza haemagglutinin is a membrane glycoprotein which varies in antigenicity.

A question which often arises concerns the contribution of the carbohydrate side-chains to antigenicity, and we have recently observed that a number of monoclonal antibodies are able to discriminate between glycosylated and nonglycosylated haemagglutinin molecules. Specifically these antibodies select antigenic variants with haemagglutinins which contain asparagine substitutions in the sequence asparagine–cysteine–threonine and the asparagine is glycosylated. By infecting cells incubated in medium containing tunicamycin non-glycosylated variant haemagglutinin can be obtained, and it is possible to show that such molecules are precipitated by the antibodies used to select the variant. These results directly indicate that carbohydrate side-chains can modulate the antigenic properties of glycoproteins and may be involved in antigenic variation.

Many parasitic diseases are accompanied by an immunosuppression which may affect only parasite-specific responses in some infections or lead to a general dysfunction of the immune system in others. African trypanosomiasis causes a particularly severe disorder of the immune system and this serves as a model system for analysis of the cellular basis of a parasite-induced general immune dysfunction affecting nearly all T- or B-lymphoid cell subpopulations. The nature of the parasite products causing havoc in the immune system may well vary in different infections and still remains to be defined. Trypanosome membrane fractions are active in vitro or in vivo but we have no evidence for a direct action on B- or T-cells. In vitro, both in man and mouse, T-cells are stimulated, but only in the presence of accessory cells. This points to the importance of host-derived immunosuppressive factors in the immune dysfunction. We have evidence that macrophages, after uptake of parasites in the presence of antibodies, are at least one target cell for parasite action. They can mediate immunosuppression and undergo changes in phenotype and mediator release during the course of infection. The macrophages show all the characteristic signs of activation, which can also be induced by other means and other infective agents such as BCG. Thus, macrophage activation would provide a common pathway for induction of a general immunosuppression in different infections.

It is proposed that, for many species of parasites, evasion of the host immune response may be achieved passively through enhanced survival within host individuals that have a genetically determined low responsiveness to infection. Evasion by this means may contribute significantly to continued transmission of infection in man and domestic animals and influence the severity of pathology. Low responsiveness plays an important role in determining over-dispersion of parasites within host populations, and the common occurrence of this form of distribution is seen as supporting evidence for the proposition, although few of the examples available provide conclusive proof. The extensive individual and strain variation in response to parasitic infection in laboratory strains of mice is tak as a homologue of the natural situation and allows analysis of the mechanisms underlying low responsiveness. Two examples are considered in detail. In Leishmania infections both non-H-2 and H-2-linked genes influence resistance, but the primary expression of genetically determined low response is at the level of the macrophage. Genetic influences upon acquired immunity regulate macrophage–T-cell interactions. In Trichinella spiralis H-2-linked and non-H-2 genes influence development of the intestinal responses necessary for expulsion of the adult worm, the former through the response of helper T-cells to worm antigen and the amplification of this response through other T-cells, the latter through an effect upon the response of myeloid stem cells to T-cell signals. Modification of genetically determined low responsiveness is discussed in terms of (a) improving host responsiveness through vaccination or non-specific immunostimulation and (b) altering host genotype through selective breeding or the introduction of resistance alleles into a population.

The antibody response of the appropriate hosts (cattle) to Taenia saginata larvae was compared with that of an inappropriate host (Balb/c mice) using gel electrophoresis followed by immunoelectrotransfer blot techniques (Western blotting). Three groups of cattle were included, those known to be resistant to challenge infection because of repeated oral challenge with T. saginata eggs over a 1-year period, a previously infected but known susceptible group and a group of uninfected controls. Serum from the mice and the two groups of infected cattle contained antibodies recognizing different ‘target’ antigens, some of which may be related to host resistance. The potential value of the technique of Western blotting in dissecting the humoral response of a particular host species to parasitic infection and in the identification of those antigens suitable for the production of effective vaccines is discussed.

The following brief survey considers various manoeuvres which can be applied to manipulate the immune response to parasitic infections in vivo. The examples quoted largely concern malaria, babesiosis, schistosomiasis and leishmaniasis, predominantly in inbred mouse strains. Since my own relevant research experience has been restricted to leishmaniasis, this will receive undue emphasis, although it does illustrate particularly well points I wish to stress. The types of intervention described do not all provide the precision of interpretation with which they are sometimes credited. Thus, effects of immunosuppression or T-cell depletion alone can usually only implicate the specific immune response (in its broad sense) in shaping the natural history and outcome of an infection or in underlying the effect of prophylactic immunization. Nevertheless, more precise delineation of lymphocyte subset involvement can be obtained by cell replacement studies in some of these models or by exclusion of antibody. The outcomes of these approaches have been (or are) predictable in most cases. More fascinating, however, are the various instances which will be stressed where totally unpredicted and contrary observations have been made which led (or may lead) to fresh insight into the disease. These serendipitous findings illustrate at the same time the value of applying the manoeuvres, even though they imply that the logical immunologist cannot yet always outsmart the parasite by design.

In the preceding paper Howard (p. 665) has given a very elegant presentation on ways in which the host immune system may be manipulated to provide valuable information about immunoregulation of parasitic infection in vivo. In our laboratory we have used some of the same manoeuvres to study immunoregulation of genetically controlled responses to Leishmania donovani infection in inbred mouse strains (Ulczak & Blackwell, 1983; Crocker, Blackwell & Bradley, 1984). As has been Howard's experience, the results obtained have not always been as one might have predicted at the outset.

When I first began to think about this presentation I flirted with the idea of reversing the title to read: ‘Immunologists as Parasites’. I could clearly see some of the sectional headings such as ‘The Spreading Cancer of Tumour Immunology’ and ‘Does the International Immunology Scene represent an IDIOT-ype–Anti-IDIOT-ype network’?. But although this might have been fun it would certainly have been unfair to those immunologists who are currently working on Parasite Immunology, a very difficult and demanding field.