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People living in malaria endemic areas tend to be infected repeatedly. Over time, they gradually acquire an immunity to malaria. This immunity includes the development of mechanisms that can kill parasites or inhibit the replication of parasites.
Equally important, however, is the development of another type of immunity: one that will limit the body's own immune response to the parasite. Without this latter type of immunity, the immune system can go into overdrive in its attempts to kill the parasites, and acute febrile symptoms and severe malaria can result. Children, who have yet to develop this immunity, are thus at greater risk of clinical malaria, severe disease and death than adults.
Although this seems quite straightforward, it likely to be an oversimplified view. Cerebral malaria – a common and particularly dangerous manifestation of severe malaria – typically occurs in children who have already acquired a significant degree of anti-malarial immunity. One potential explanation for this is that cerebral malaria is in part mediated or caused by the human immune system: the first infection 'primes' the system, and re-infection leads to an overenthusiastic, damaging response.
Another paradox is found in travellers from non-endemic areas who move to endemic areas and catch malaria: in this case, severe malaria is more common in adults than in children. Indeed, death rates are five times higher in people over the age of 20 than in those under 20. What might be priming the immune system of these adults to cause severe malaria during their first malaria infection?
The human immune system is an remarkably sophisticated defender of the body. It has an array of protective cells that can be mobilised to tackle an invader, with cells of the innate immune system forming the first line of defense, and those of the adaptive immune system arriving later but with extremely specific weaponry.
Coordinating this response are the messengers, chemical agents called cytokines. A plethora of cytokines can be produced, working together – or in opposition – in exquisitely sensitive and complex ways with the protective cells. There are many gaps to be filled in our understanding of the immune response to malaria, and how immunity develops. Yet we can begin to fit what we do know into a model of how immunity develops.
The trigger for the immune response is the release of parasite molecules into the bloodstream when malaria-infected red blood cells rupture. These foreign materials activate or stimulate macrophages, cells which play an important role in killing of some bacteria, protozoa and tumour cells, releasing cytokines that stimulate other cells of the immune system, and 'presenting' the foreign antigens to the rest of the immune system.
The parasite molecules directly induce the production of low levels of the inflammatory cytokine tumour necrosis factor-a (TNF-a). At these levels, TNF-a is anti-parasitic, working together with interferon-g to induce production of nitric oxide and other toxic radicals.
Yet too much TNF-a seems to be a bad thing, as patients with severe malaria often have high levels of TNF-a (and other inflammatory cytokines such as interleukin-1 and interleukin-6) in their bloodstreams. What causes the macrophages to ramp their production of TNF-a to excessive levels? A second stimulus, in addition to malarial molecules, appears to be required.
An obvious candidate for this stimulus is the macrophage-activating factor, interferon-g. For example, we have found that the first infection with malaria leads to a low-level production of interferon-g, initially by 'natural killer cells' (part of the innate immune system) and later by T cells. The infection induces few clinical symptoms and parasites are cleared from the body.
It appears that T cells are primed by the first infection because upon reinfection with malaria, they produce much higher levels of interferon-g. This interferon-g synergises with malarial molecules to increase the production of TNF-a by macrophages to much higher levels. This leads to an increased risk of severe malaria and, in particular, cerebral malaria.
Further infections induce anti-parasitic immune mechanisms which reduce the numbers of parasites in the body, and hence the amounts of parasite molecules that could stimulate the macrophages. As the levels of these stimulatory molecules declines, the immune system switches its focus from T cells that produce interferon-g to T cells that produce anti-inflammatory cytokines (such as TGF-b or interleukin-10).
Interferon-g production drops back down to low levels, and the anti-inflammatory cytokines dampen down the effects of the inflammatory cytokines. The clinically immune individual can now clear the infection without running the risk of overproducing dangerous inflammatory mediators. So the risk of severe malaria may well depend on how quickly the different components of the anti-malarial immune response develop.
If the T cells need to be primed by the first malaria infection, producing high levels of interferon-g only upon a later infection, why do non-immune adults often get severe malaria upon their first infection?
A convincing explanation is that the T cells are in fact primed by molecules from another pathogen – whether another parasite, bacteria or fungus. The older the person, the wider the range of common pathogens and other microorganims the system will have encountered, and the larger the population of 'generic', primed T cells will be.
The complexity of the immune system presents particular challenges to the development of malaria vaccines. There are not only many different components to an immune response and to immunity, but the balance between the components is also crucial.
So while interferon-g and its associated cellular responses are clearly required to clear parasites from the body, they need to be induced in a limited, site- or organ-specific manner in order to avoid systemic disease.
Professor Eleanor Riley is at the Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
Page of 3; 2/9/04
[WTD023881] Malaria and the human immune system.doc