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Mechanisms of Immunity Metazoan Parasites
John D. Kelly, B.V.Sc., Ph.D., Department of Veterinary Pathology, University of Sydney.
INTRODUCTION
The recognition that mammals develop immunity to a wide range of protozoan and helminth parasites was first reported about 80 years ago with the observations of Smith end Kilboune (1893) that cattle recovered from Texas fever (Babesia bigemina) were immune to reinfection. The importance of such innate resistance is illustrated by the fact that, although approximately 8,000 species of protozoa parasitic for various hosts are known, only about 20 of these are significant pathogens of man (Cohen, 1974). Reports of acquired immunity to various helminth infections are numerous and these have been reviewed by Kelly (1973a).
The significance of specific acquired immunity to helminth infections has long been disputed because clinically effective responses, such as occur in bacterial and viral diseases, occur infrequently with metazoan parasites. Nevertheless, there is now abundant evidence that helminths are immunogenic and can sensitise conventional immune responses in the host. The object of this paper is to briefly outline recent developments in relation to studies of the mechanisms of host resistance to helminth infection.
CLASSIFICATION OF THE IMMUNE RESPONSE
It is generally accepted that cells of the lymphoid series are the principal cellular participants in the induction and execution of immune responses. According to the clonal selection hypothesis (Burnett, 1959), processed antigen (for example helminth antigen) reacts selectively with lymphocytes bearing appropriate surface immunoglobulin molecules (afferent or inductive phase of the immune response), resulting in the clonal proliferation of these cells. The progeny of the initial antigen reactive cells then differentiate into effector cells which: (i) produce circulating immunoglobulins, or (ii) sensitised lymphocytes which produce non-circulating immunoglobulins and/or release non-specific cyto-active substances such as lymphokines (Dumonde et al. 1969). This stage is known as the central phase of the immune response. Finally in the efferent phase of the immune response the products of the central phase (that is, circulating immunoglobulins and/or sensitised lymphocytes) react directly or indirectly with the specific antigen responsible for induction of that response. This reaction may then trigger nonspecific cellular and/or humoral factors which directly or indirectly are responsible for the manifestations of host immune response (for example, suppression of worm-egg production, worm rejection).
In general immunological responses to antigen stimuli (including helminth antigens) are broadly classified as humoral if protective immunity to challenge infection can be transferred from immune to non-immune animals with serum antibody, or cellular if transfer of immunity can only be achieved with immune, viable lymphoid cells. In the present context the terms 'humoral' and 'cellular' are restricted to immunological phenomena in which the primary event is the specific interaction between helminth antigen and circulating immunoglobulin or sensitised lymphocyte. This interaction of the products of the central phase of the immune response with specific antigen may then trigger non-specific reactions which directly or indirectly affect the parasite. Thus the terms 'cellular' and 'humoral' are used to describe the nature of the specific immunological 'trigger' of the efferent phase of the immune response.
Humoral Immunity and Helminth Infection
Variable and often inadequate degrees of protection with passively transferred antisera have been demonstrated with many host parasite systems and these have been summarised previously (Kelly 1973b). In most cases, the degree of protective immunity obtained by passive transfer is not comparable to that produced by active infection. The dominant antibody class involved in passive transfer reactions is IgG; although at the local level, the secretion of IgA, for example in the gastrointestinal tract of sheep infected with Trichostrongylus colubriformis, may be important.
IgE or reaginic antibodies are commonly associated with helminthiasis in mammals, however, their functional relationship in resistance to helminth infection is not clear (for a recent review see Dineen, 1976).
Cellular Immunity and Helminth Infection
The central role of cell-mediated or delayed hypersensitivity reactions mediated by thymus derived or T-lymphocytes) has now been reported for a wide variety of host parasite systems (Kelly, 1973b). Successful transfer of resistance with immune lymphoid cells has been demonstrated in rats infected with Hippostrongylus brasiliensis, guinea-pigs infected with T. colubriformis, mice infected with Hymenolepis nana, Trichuris muris and Trichinella spiralis and in mice and rats infected with Fasciola hepatica.
In some host-parasite systems, both antibodies and sensitised lymphocytes collaborate, e.g. in N brasiliensis in rats (Dineen et al. 1973).
The Role of Cellular and Humoral Components in the Efferent Phase of the Immune Response
Immunological responses of hosts against helminth parasites are theoretically capable of achieving parasite elimination or suppression of egg production, etc., by either a direct reaction of sensitised lymphocytes or antibody with crucial parasite, antigens or indirectly by rendering the environment unsuitable for continued parasite survival.
Direct reactions between host antibodies and parasite antigens have been reported in a number of host-parasite systems, for example, rats infected with N. brasiliensis (Sarles and Taliaferro 1936), and mice infected with T. spiralis Jackson 1959). Regardless of the demonstration of parasite antigen-host antibody combination, no adverse effect of such a reaction on helminth infectivity, helminth metabolism or resultant host immunity has been demonstrated (Ogilvie 1970) (Castro and Fairvair 1969).
Direct reactions between cellular components of the immune response and helminths may occur, especially when developmental stages are intimately associated with host issues. Taliaferro and Sarles (1939) described cellular reactions around N. brasiliensis in immune rats, however, direct lethal action of cells on the parasite was not established. Rothwell (1969) similarly found no evidence suggestive of a direct effect of host cells (lymphoid cells) on T. colubriformis in guinea pigs, although there was a marked eosinophil and basophil response in the intestine around the site of infection. Soulsby (1967) reported the adherence of immune lymphoid cells to antibody sensitised A. suum larvae in vitro, but did not relate the phenomenon to in vivo immunity.
The failure to show that the cellular and/or humoral components of the immune response are capable of directly affecting helminths has focused attention on the possibility that these components indirectly affect the parasite by initiating non-specific host responses, for example, cellular infiltration at the site of infection. There is now an accumulating weight of evidence which suggests that the manifestations of host resistance (that is, worm expulsion, suppression of worm-egg production, etc.) are the result of a multiphasic immune response. One phase is immunologically specific (involving the interaction of specific antigen with either humoral antibody or sensitised lymphoid cells) and the other is immunologically non-specific. It is likely that at the immuno-non-specific level, either a myeloid cell response (that is, mast cells, eosinophils) with associated amine synthesis and release (that is, histamine, 5-hydroxytryptamine) is operative, or lymphocytic mediators of cellular hypersensitivity (lymphokinese.g.) may be involved.
Stewart (1953) obtained evidence in favour of a role for pharmacologically active agents in the 'self-cure' phenomenon of sheep (Gordon 1948) infected with H. contortus by showing that 'self-cure' could generally be prevented by the administration of mepyramine maleate (specific histamine antagonist). Campbell et al. (1963) working with T. spiralis in mice found that an anti-histamine (chlorpheniramine and an anti-5-hydroxytryptamine agent (1-benzyl2-methylmethozytryptamine or BAS) would prolong the intestinal phase of the infection. In guinea pigs infected with T. colubriformis in which cell-mediated immunity is functional, it has been shown that mast cells and eosinophils accumulate at the site of infection and undergo degranulation during elimination of a challenge infection (Rothwell and Dineen 1972). Furthermore, worm expulsion can be inhibited by the administration of antagonists of histamine and 5-hydroxytryptamine (Rothwell et al. 1971). Similar results have been reported for the rat — N. brasiliensis system although there is considerable controversy over the role played by mast cells in the efferent phase of the immune response (Kelly and Ogilvie 1972). It is worthwhile noting that although the administration of histamine and 5-hydroxtryptamine antagonists (for example, promethazine) could inhibit worm expulsion by antagonising histamine release and/or action, it has recently been shown that promethazine may also inhibit worm expulsion in the rat - N. brasiliensis system by an effect on lymphocyte function (Kelly and Dineen 1972).
INVOLVEMENT OF PHARMACOLOGICAL MEDIATORS, OTHER THAN HISTAMINE AND 5-HYDROXYTRYPTAMINE, IN THE EFFERENT PHASE OF THE IMMUNE RESPONSE
In view of the controversy re the role of myeloid cells and biogenic amines in the efferent phase of the immune response to some helminths (notably the gut dwelling adult stages of N. bresiliensis, T. colubriformis, T. spiralis, etc)., it has been suggested that other pharmacologically active agents, associated with both immediate and delayed hypersensitivity reactions, may be important. Recent studies (reviewed by Kelly and Dineen 1976) have draw attention to the possibility that prostaglandins may play an important role as nonspecific mediators of parasite immunity.
Prostaglandins (PG) are unsaturated hydroxy fatty acids naturally occurring in a wide variety of human and animal tissues and fluids and are prominently featured in the tissues of the gastrointestinal tract. PG are synthesised and released in this organ and are likely to be involved in helminth immunity as they drastically alter gut environment, can directly affect metabolic pathways in helminths and in addition, are capable of causing mast cell degranulation and the release of pharmacologically active amines such as histamine. Studies in Australia and the United States have clearly demonstrated a crucial requirement for PG, in the immune expulsion of at least one nematode N. brasiliensis and recent reports indicate that they are likely to be involved in other host-parasite systems. The precise nature or sequence of events linking immune lymphocytes, cells of the myeloid series and PG in the mechanism of expulsion is unknown.
MECHANISMS OF SURVIVAL OF THE PARASITE IN IMMUNE HOSTS
Parasites provoke immune responses in their hosts but appear to have adapted to those responses in ways which ensure their continued survival and transmission from one host to the next. The possible escape mechanisms employed by parasites include:
1. Antigenic variation:
e.g. adult N. brasiliensis worms present in rats given a second large infection or in rats given low level multiple infections are less immunogenic and antigenic than adult worms present in rats undergoing primary infection. Ogilvie (1974) has termed these 'adapted' worms.
2. Parasite mediated suppression of host imune mechanisms:
e.g. infections with Ancylostoma caninum in dogs may lead to selective depression of T-lymphocyte function (Kelly et al. 1976).
In the complex multifactorial immune response to helminth infection, defective T-lymphocyte function will result in impaired cell-mediated immune responses and the host animal becomes highly susceptible to infection and reinfection.
3. Host mediated suppression of immune responsiveness:
Three types of immunologically unresponsive states occur 'naturally' in host animals, e.g. the immunological unresponsiveness of neonatal animals, parturient/lactating animals (i.e. the 'periparturient relaxation of resistance') and animals continuously exposed to helminth infection over long periods (i.e. immune paralysis or exhaustion). The epidemiological consequences of host unresponsiveness in terms of the host-parasite relationship, is that there is a rapid escalation in the numbers of parasitic stages within the host leading to a rapid increase in the number of free living stages subsequently available for reinfection.
4. Uptake and/or synthesis of host antigens:
Certain species of helminth are capable of synthesising or selectively incorporating host antigens.
e.g. host antigens contained in Schistosoma mansoni (Smithers et al. 1969; Clegg et al. 1970). The existence of such antigens either on the cuticle or in the secretions and excretions of an invading helminth would reduce the overall immunogenicity of the parasite and favour its survival in the host. In its final form, this masking or mimicry might result in identical antigens for both host and parasite.
5. Stimulation of non-protective immune responses by the host:
e.g. the secretion of the enzyme acetylcholinesterase by many nematodes results in the production of anti-acetylcholinesterase antibodies which, as far as is known, have not been demonstrated to play a role in protective immunity.
CONCLUSIONS
The degree of infection to which a host is exposed is substantially influenced by its immune status. The immune status is related to the experience of infection and can be variously modified by extrinsic (e.g. anthelmintic treatments) and intrinsic (e.g. the hormonal status of the host) factors. Although the flock or herd as a whole might be generally resistant, individuals may show varying gradations of resistance. Furthermore, it would be expected that the development and persistence of immunity in grazing animals, exposed to field infections, might be erratic.
Age alone does not confer resistance, but, in general, older animals are immunologically competent. Cattle tend to develop immunity to nematode infections earlier and their immunity appears to be stronger and more persistent than that of sheep. Nevertheless, outbreaks of Type II ostertagiasis and dictyocaulosis in adult cattle emphasise their vulnerability.
It should be remembered that immunological reactions may be inimical to the host - e.g., tissue reactions is oesophagostomosis in sheep and granuloma formation in schistosomiasis in cattle.
Immunological aberrations may occur and substantially alter the host-parasite relationship - e.g., a heavy infection early in life may lead to immunological unresponsiveness and a prolonged infection without reinfection may lead to immunological exhaustion. On the other hand, temporal discontinuities in helminth infections, particularly of grazing animals, may interfere with the maintenance and development of immunological control. The synchronisation of PPRR (peri-parturient relaxation of resistance) with neonatal susceptibility to infection represents an important means by which the effects of helminthosis can rapidly escalate in the field. The possibilities of host selection for resistance have been noted by Ross (1971).
However, considering the problems associated with selection for multiple characters, it is unlikely that deliberate genetic selection for resistance will have any practical relevance, at least with reference to helminth parasites. Nevertheless, if a breed is strain resistant to the helminth disease (e.g. the presence of an inherited factor operating against infection with H. contortus in Florida native lambs as reported by Radhakrishnan et al. 1972) possesses other desirable phenotypic characters (e.g., resistance to climatic stress) then there may be a useful application of genetic selection as a control measure.
The future prospects for vaccination against helminth disease are encouraging. At the present time, two commercially available vaccines are in use, i.e. for D. viviparus and D. filaria in cattle and sheep respectively and for A. caninum and U. stenocephala in dogs.
It is now technically possible to immunise against the following parasites, viz. D. immitis and E. granulosus in dogs and probably larval cestodes in sheep. One can envisage the widespread use of polyvalent helminth vaccines becoming an important component of disease control procedures over the next 10-20 years. The development of successful immunoprophylaxis for the control of parasitic disease will depend on a thorough understanding of the mechanisms of naturally acquired immunity in host animals.
Much more basic work is required before practical objectives such as immunoprophylaxis, mitigation of immunopathological lesions and improved techniques of immuno-diagnosis can be achieved.
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