Immunity To Protozoa.
Relatively few (less than 20) species of protozoa infect humans, but
among these are four of the most
formidable parasites of all, in terms of numbers affected and severity of
disease: malaria, the African and American trypanosomes, and Leishmania (top
left). These owe their success to combinations of the strategies found among
bacteria and viruses: long-distance spread by insect vectors (compare
plague, typhus, yellow fever), intracellular habitat (compare
tuberculosis, viruses), antigenic variation (compare influenza) and immunosuppression
(compare HIV). However, these strategies are so highly developed that
complete acquired resistance to protozoal infections is quite exceptional, and
what immunity there is often
serves merely to keep parasite numbers down (‘premunition’) and the host alive, to the advantage of the parasite.
The rationale for vaccination is correspondingly weak, especially because some
of the symptoms of these diseases appear to be brought about by the immune
response rather than the parasite itself.
In contrast, the intestinal
protozoa (bottom left) generally cause fairly mild disease, except when
immunity is deficient or suppressed. Nevertheless, together with the intestinal
worm infections described on the next page, they add up to a tremendous health
burden on the inhabitants of
tropical countries.
African trypanosomes Trypanosoma gambiense and T. rhodesiense, carried by tsetse flies, cause sleeping
sickness in West and East Africa, respectively. The blood form, although
susceptible to antibody and complement, survives by repeatedly replacing its
surface coat of glycoprotein ‘variant antigen’ by a gene-switching mechanism;
the number of variants is unknown but large (perhaps as many as 1000). High
levels of non-specific IgM, including autoantibodies, coexist with suppressed
antibody responses to other antigens such as vaccines; this may be due to
polyclonal activation of B cells by a parasite product (compare bacterial
lipopolysaccharides). Humans are resistant to the trypanosomes of rodents
because of a normal serum factor (high- density lipoprotein [HDL]) that
agglutinates them – a striking example of innate immunity.
Malaria Malaria kills more than one million people each
year, most of them children, and most of them in the world’s poorest countries.
Plasmodium falciparum (the most serious species), P. malariae, P.
vivax and P. ovale are transmitted by female Anopheles mosquitoes.
There is a brief liver stage, against which some immunity can be induced,
probably via cytotoxic T cells, followed by a cyclical invasion of red cells,
against which antibody is partially effective; anti- genic variation,
polymorphism and polyclonal IgG production may account for the slow development
of immunity. Despite over 40 years of research, there is still no 100%
effective vaccine (but see below). Vaccination protects against the red cell
stage in certain animal models, and also against the sexual gamete state.
Recently, a recombinant vaccine consisting of a sporozoite antigen fused to
hepatits B surface antigen has shown real promise in African children. Human
red cells lacking the Duffy blood group, or containing fetal haemoglobin
(sickle cell disease), are ‘naturally’ resistant to P. vivax and P.
falciparum, respectively. P. malariae is specially prone to induce
immune complex deposition in the kidney. High levels of the cytokine TNF (see
Fig.24) are found in severe cases of
malaria, and this may represent over-stimulation of macrophages by a parasite
product – a form of pathology also seen in Gram-negative bacterial septicaemia
(see Fig. 34). Malaria was one of the first diseases to be experimentally
treated by the use of anti-TNF antibody, although without success so far; in
fact TNF may also have a role in protective immunity.
Babesia spp., or piroplasms, are tick-borne cattle
parasites resembling malaria which occasionally infect humans, particularly following
removal of the spleen or immunosuppressive therapy. In cattle and dogs an
attenuated vaccine has been strikingly successful.
Theileria (East Coast fever), a cattle infection
resembling malaria, except that the ‘liver’ stage occurs in lymphocytes, is
unusual in being killed by cytotoxic T cells, i.e. it behaves essentially like
a virus.
Leishmania A confusing variety of parasites, carried by sandflies, which cause an even more bewildering array of
diseases in different parts of the tropics, although only in about 5% of
exposed individuals. The organisms inhabit macrophages, and the pathology
(mainly in the skin and viscera) seems to depend on the strength of
cell-mediated immunity and/or its balance with antibody (compare leprosy).
Cutaneous leishmaniasis in Africa is unusual in stimulating self-cure and
subsequent resistance. This example of protection has apparently been known and
applied in the Middle East for many centuries (‘leishmanization’). There is
evidence from mouse experiments that resistance is mediated by TH1 cells and
can be compromised by TH2 cells, and also that nitric oxide (see Fig. 9) may be
a major killing element.
Trypanosoma cruzi, the cause of Chagas’ disease in Central and
South America, is transmitted from animal reservoirs by reduviid bugs. It
infects many cells, notably cardiac muscle and autonomic nervous ganglia. There
is some suggestion that cell-mediated autoimmunity against normal cardiac
muscle may be responsible for the chronic heart failure, and similarly with the
nervous system, where uptake of parasite antigens by neurones and actual
similarity between host and parasite have both been shown
to occur. The organism has been killed in vitro by
antibody and eosinophils, but the only prospect for vaccination seems to be
against the blood stage. A better prospect would be to get rid of the poor
housing in which the vector flourishes.
Toxoplasma spp. T. gondii is particularly virulent
in the fetus and immunosuppressed patients, chiefly affecting the brain and
eye. It can survive inside macrophages by preventing phagolysosome formation
(compare tuberculosis), but cell-mediated immunity can overcome this. Toxoplasma
stimulates macrophages and suppresses T cells, leading to varied effects on
resistance to other infections.
Entamoeba histolytica normally causes disease in the colon (amoebic
dysentery), but can move via the blood to the liver, etc., and cause dangerous
abscesses by direct lysis of host cells. Some animals, and perhaps humans, may
develop a degree of immunity to these tissue stages but not to the intestinal
disease.
Giardia, Balantidium,
Cryptosporidium, Isospora spp.,
etc. normally restrict their effects to the gut, causing dysentery and occa-
sionally malabsorption, but can be a severe complication of AIDS (see Fig. 28).
