Immunity To Worms
Parasitic worms of all three classes (roundworms, tapeworms and flukes) are responsible for numerous human diseases, including three of the most unpleasant (upper left): onchocerciasis, elephantiasis and schistosomiasis. These worms are transmitted with the aid of specific insect or snail vectors, and are restricted to the tropics, while the remainder (lower left) can be picked up anywhere by eating food contaminated with their eggs, larvae or cysts. A feature of many worm infections is their complex life cycles and circuitous migratory patterns, during which they often take up residence in a particular organ (see figure).
Another striking feature is the predominance of eosinophils and of IgE; as a result, hypersensitivity reactions in skin, lung, etc. are common, but whether they are ever protective is still controversial. As they do not replicate in the human host (unlike protozoa, bacteria and viruses), individual worms must resist the immune response particularly well in order to survive and, as with the best-adapted protozoa (compare malaria), immunity operates, if at all, to keep down the numbers of worms rather than to eliminate them. The outlook for vaccination might seem very dim, but it is surprisingly effective in certain dog and cattle infections.
Mystifying, but provocative, is the finding that several drugs originally used against worms (niridazole, levamisole, hetrazan) turn out to have suppressive or stimulatory effects on T cells, inflammation and other immunological elements, bringing out the point that worms are highly developed animals and share many structures and pathways with their hosts. Some very effective drugs against worms act against their nervous system.
Eosinophils may have three effects in worm infections: phagocytosis of the copious antigen–antibody complexes, modulation of hypersensitivity by inactivation of mediators and (in vitro at least) killing of certain worms with the aid of IgG antibody. Eosinophilia is partly due to mast-cell and T-cell chemotactic factors; T cells may also stimulate output from the bone marrow via cytokines such as IL-5.
IgE Worms, and even some worm extracts, stimulate specific and non-specific IgE production; it has been suggested but not proved that the resulting inflammatory response (e.g. in the gut) may hinder worm attachment or entry. There is also a belief that the high IgE levels, by blocking mast cells, can prevent allergy to pollen, etc. Production of IgE is considered to reflect the activity of TH2 helper cells.
Nematodes may be filarial (in which the first-stage larva, or micro-filaria, can only develop in an insect, and only the third stage is infective to humans) or intestinal (in which full development can occur in the patient).
Filarial nematodes Onchocerca volvulus is spread by Simulium flies, which deposit larvae and collect microfilariae in the skin. Microfilariae also inhabit the eye, causing ‘river blindness’, which may be largely due to immune responses. In the Middle East, pathology is restricted to the skin; parasitologists and immunologists disagree as to whether this reflects different species or a disease spectrum (compare leprosy). Loa loa (loasis) is somewhat similar but less severe. Wuchereria ban- crofti and Brugia malayi are spread by mosquitoes, which suck microfilariae from the blood. The larvae inhabit lymphatics, causing enormously enlaged limbs and/or scrotum (elephantiasis), partly by blockage and partly by inducing cell-mediated immune responses; soil elements (e.g. silicates) may also be involved. In some animal models, microfilaraemia can be controlled by antibody.
Intestinal nematodes (Ascaris, Strongyloides, Toxocara spp.). Travelling through the lung, larvae may cause asthma, etc., associated with eosinophilia. Trichinella spiralis larvae encyst in muscles. In some animal models, worms of this type stimulate good protective immunity. Strongyloides sp. has become an important cause of disease in immunosuppressed patients, suggesting that in normal individuals it is controlled immunologically. Toxocara sp., picked up from dogs or cats, is an important cause of widespread disease in young children, and eye damage in older ones.
Guinea worms (Dracunculus) live under the skin and can be up to 1.2 m long. Hookworms (Ancylostoma, Necator spp.) enter through the skin and live in the small intestine on blood, causing severe anaemia. None of these worms appear to stimulate useful immunity.
Trematodes spend part of their life cycle in a snail, from which the cercariae infect humans either by penetrating the skin (Schistosoma sp.) or by being eaten (Fasciola, Clonorchis spp.). The latter (‘liver flukes’) inhabit the liver but do not induce protective immunity.
Schistosomes (‘blood flukes’) live and mate harmlessly in venous blood (Schistosoma mansoni, S. japonicum: mesenteric; S. haematobium: bladder), causing trouble only when their eggs are trapped in the liver or bladder, where strong granulomatous T-cell-mediated reactions lead to fibrosis in the liver and nodules and sometimes cancer in the bladder. The adult worms evade immune attack by covering their surface with antigens derived from host cells, at the same time stimulating antibody that may destroy subsequent infections at an early stage. Eosinophils, macrophages, IgG , IgE and the TH2 cytokines IL-4, IL-5 and IL-13, have all been implicated. Schistosomes also secrete a variety of molecules that destroy host antibodies and inhibit macrophages, etc., making the adult worm virtually indestructible. Nevertheless, there is evidence for the development of partial immunity, mainly directed at the skin and lung stages of the cycle. The combination of adult survival with killing of young forms is referred to as ‘concomitant immunity’. An irradiated cercarial vaccine is effective in animals, but purified antigens are also being tried.
Fasciola spp. are chiefly a problem in farm animals, where they live in the bile duct. What immunity there is appears to lead mainly to liver damage and vaccines have been disappointing.
Clonorchis sp. infects humans but otherwise resembles Fasciola spp. It may lead to cancer of the bile duct.
Cestodes may live harmlessly in the intestine (e.g. Taenia spp.), occasionally invading, and dying in, the brain (‘cysticercosis’), or establish cystic colonies in the liver, etc. (e.g. the hydatid cysts of Echinococcus spp.), where the worms are shielded from the effects of antibody. Antigen from the latter, if released (e.g. at surgery) can cause severe immediate hypersensitivity reactions (see Fig. 35). An experimental vaccine has proved effective in dogs and sheep, the primary and intermediate hosts.