In this essay I shall be discussing a specific example of how the classic TH1/ TH2 paradigm can be useful in our understanding of immunological responses to parasites. Helminths are amongst the largest types of macroparasite that our body can encounter and, using the concept of these two TH response pathways, I shall discuss how different types of helminths are dealt with by our immune system and the ways in which these parasites get around the problem in order to persist. I will then conclude by questioning the integrity of the TH1/ TH2 paradigm by discussing how fine-cut the distinction actually is between these pathways and the effector mechanisms which they employ.
The types of parasitic worms (helminths) that can infect the human body include flukes (trematodes e.g. schistosomes), tapeworms and roundworms (nematodes e.g. pinworms and hookworms). Helminths invade various parts of their host’s body where their effects can potentially be quite damaging; tapeworms and adult hookworms live in the gut, adult schistosomes live in blood vessels and some roundworms invade the lymphatic system. Like most parasites they express certain antigens that interact with our immune systems. Antigenic variation is much higher in worms than in smaller parasites and their complicated life cycles can often result in stage-specific expression of antigens. It is known that certain individuals are able to cope better against helminth invasions; the host’s genetics plays an important role in susceptibility to a certain extent, but also the behaviour of people within communities is thought to be a determining factor of the risk of attaining a high worm burden. Helminth infections are quite often chronic and during the time of infection the immune response may change, often having immunopathological effects.
The defence mounted by a host against a helminth parasite depends on many immunological effector mechanisms; complex processes arise from different cell interactions and mediators that act at different stages in the parasite’s development. Macrophage activity is especially important as a first line of defence against most parasites; often being able to produce cytotoxic factors and generate reactive oxygen intermediates that can destroy small extracellular parasites e.g. the larval stages of some worms such as schistosomes. This activity may be enhanced by specific IgG and IgE antibodies and various cytokines such as TNFá. Also important in parasite immunity are neutrophils, eosinophils and platelets. Neutrophils act in a similar fashion to macrophages to kill large and small parasites, often with a more intense respiratory burst. They are sometimes more destructive than eosinophils, which are the characteristic cells associated with worm infections. It is thought that eosinophils may have evolved to deal with the tissue stages of parasites that are too large to be phagocytosed either by limiting migration or by destroying the worms. Binding of eosinophils to the larvae of worms coated with IgG or IgE increases the release of granules containing a harmful protein onto the worm surface.
The failure of T cell-deprived mice to clear many intestinal helminth infections suggests that these components of the immune system play a crucial role in their recognition. T cells are a type of lymphocyte involved in adaptive immune responses and they recognise antigens that are presented to their specific receptors by major histocompatibility molecules (MHCs) on another cell’s surface. T cells generate their effects by releasing cytokines or by direct cell-cell interactions. The main types of T cell are the cytotoxic T cells, which destroy infected host cells, and the T helper cells (TH1 and TH2 cells) which initiate different pathways of immunological responses by interacting with other cells. The paradigm is that TH1 cells interact with different components of the immune system than do TH2 cells.
Local patterns of cytokine and hormone expression help to select the lymphocyte effector mechanism. A single TH cell precursor is able to differentiate into either a TH1 or a TH2 cell, both of which are known to be needed for specific types of immune responses. Polarized responses of CD4+ TH cells seem to be based on their profile of cytokine secretion and it is known that cytokines from TH1 cells inhibit the actions of TH2 cells and vice versa. An immune response tends to settle into a TH1 or TH2 type of response. The decision of which of these to become is crucial to effective immunity. The presence and balance of cytokines such as interleukins (IL), tumour necrosis factors (TNF), colony stimulating factors (CNF) and interferons (IFN) are involved in promoting and inducing the two pathways, along with other factors such as co-stimulatory molecules, peptide density and binding affinity of MHCs, antigen dose and antigen presentation activity.
IL-12 stimulates the production of IFNã and so initiates differentiation into TH1 cells which are associated with delayed-type hypersensitivity. TH1 cells produce IL-2 and IFNã but not IL-4 and they promote macrophage activity.TH2 cells are associated with strong antibody and allergic responses and are generated by early production of IL-4. They characteristically produce IL-4, IL-5, IL-6, IL-10 and IL-13 and do not produce IL-2 or IFNã. They are efficient at helping B cells to produce antibodies such as IgG1 and IgE and typically inhibit macrophage activity.
Some cytokines can give rise to mechanisms found in both TH cell type responses and these intermediate forms can be thought of as TH0 cells. Despite being notoriously oversimplified since put forward as a fundamental immunological textbook universality, the classic TH1/ TH2 paradigm is still a very useful way of understanding immune responses to diseases as I shall discuss. The “distinctive” polarisation of human TH1 and TH2 cells is examined by looking at the cytokines they produce and the activation markers they express; TH1- and TH2-dominated responses provide different modalities of protection against exogenous offending agents and may play a critical role in the development of other pathophysiological conditions, for example; it is well known that atopic allergies result from TH2-dominated responses to allergens. The rest of this essay will look at the changes that occur in TH1 and TH2 responses during a helminth infection of a human.
Infection by helminths is typically associated with TH2-type cytokine responses i.e. IL-4 production, high levels of IgE, eosinophilia and mastocytosis. Evidence for this comes from individuals who are resistant and susceptible to the intestinal helminth Trichuris muris where it was found that TH2 responses were protective but that a dominant TH1 response could lead to a chronic infection. IgE and eosinophils can indeed kill parasites, but to assume that destruction of all large extracellular invaders is carried out simply by initiating a characteristic TH2 response at any time is incorrect. It is known that IL-4 can induce the expulsion of some worms from the gut, but it is very difficult to find evidence that the classic phenotype associated with TH2 responses is responsible for detrimental effects on the parasites and indeed many worms appeared to be unaffected by adjusted IL-4 levels in experiments performed on mice. This suggests that immunity may rely on specific combinations of T-cell factors and non-T-cell factors depending on the host and the parasite and on the timing of immune response initiation. Unravelling the role of IL-4 in the control of helminth infections in the gut is therefore crucial if we are to understand how TH2 cells are involved in protection against these extracellular parasites.
One fact that has been recognised in TH2 responses against intestinal worms is that there is no single effector mechanism for expulsion; instead an effective defence is dependent not only on the species of worm, but on the anatomical position of the parasite within the gut and the immune status of the host. It is known that there is a range of effector mechanisms and that they can be either T-dependent (activation and proliferation of effector cells e.g. B cells) or T-independent (non-specific inflammatory molecules such as TNF and IL-1 contribute to goblet cell proliferation causing an increased level of mucus to be secreted into the lumen of the gut).
The level of complexity increases when dealing with tissue-dwelling helminths. Existing evidence for the TH2 pathway being the most important aspect of immunity against tissue dwelling helminth species is merely circumstantial and quite often the opposite response is seen. Also it would be foolish to assume that one immune response alone would be sufficient to combat every stage of the parasite’s life cycle. This complexity is illustrated by the case of schistosomiasis; in humans it seems as if IgE and eosinophil activity correlates with protective immunity but in some studies of mice it appears as though the TH2 response actually benefits the parasite and in some way enhances the infection. The induction of the TH2 cytokine IL-10 downregulates TH1 responses that, as well as being damaging to the parasite can often be damaging to the host (e.g. cyst formation and fibrosis) and so there is a balance whereby both host and parasite are favoured. It seems though that both pathways are harmful and so it is likely that a general downregulation of overall immune responsiveness (rather than controlling selectivity for one type) occurs in schistosomiasis. Evidence for this theory comes from the elevated TH1 and TH2 responses that often follow chemotherapy and the removal of live parasites.
A successful parasite will have evolved to get the most out of its host by evading the immune system. Helminth parasites do exactly this and even exploit cells and molecules of the immune system to their own advantage e.g. production of eggs by S. mansoni is actually promoted by host TNFα and T. brucei actually uses IFNγ as a growth factor. Interference with the immune system is also common by the release of free antigens by the worms that can combine with components of the immune system such as B cells, antibodies, macrophages and T cells inducing immunosuppression. Helminths can also have immunopathological consequences e.g. the gross changes that occur in individuals with elephantiasis are immunopathological responses to adult filariae in the lymphatics.
Quite bizarrely it seems looking at all the evidence that although it is likely that TH2 type responses evolved as a way of protecting against helminth infections, the parasites are not only adapted to avoid these responses, but some have also evolved to be able to take advantage of the cross-regulatory properties of the TH pathways and to use them to enhance their own survival within their specific hosts. This has given rise to exquisite and dynamic relationships between individual parasites and their hosts that cannot be used to make inferences about other cases, even in closely related organisms.
Conclusion: Helminths are a fine example of how the immediate characterisation of an immune response as being either TH1 or TH2 type should be avoided. It also demonstrates however that it is still useful to bear the paradigm in mind when considering immunological phenomena as it describes clearly observable phenotypes with regards to the sets of cytokines produced, even allowing us to consider TH1 and TH2 as two extremes on a continuum of cytokine profiles. The paradigm has aided in the realisation that the mechanisms that infer immunity against some helminths can actually be immunopathological against others.
Immunology (6th edt)
The Th1/Th2 paradigm
Bibliography
Roitt, Brostoff and Male
Immunology Today 18 (6) 263-266
Sergio Romagnani
Th1-Th2: reliable paradigm or dangerous dogma?
Immunology Today 18 (8) 387-392
Judith E. Allen and Rick M. Maizels