How an anti-hero of the immune system protects from malaria

Malarial disease and autoimmune disease share a strange relationship. Both are best avoided, however when one is infected with the Plasmodium parasite it may be beneficial to have a propensity for autoimmunity. Kelly Hagadorn and colleagues, at institutes including the National Institute of Health in the US, have sought to explain and clarify this mysterious link.

The immune system is a finely balanced network. B cells, which detect pathogens and can then produce targeted antibodies, must generate a plethora of different receptors so that among them will be one that is specific for the attacking infection. This can go wrong when one of these receptors just so happens to bind one of our own proteins – initiating an immune response against the self. Although there are mechanisms to prevent this, people with autoimmune disorders (such as lupus) will attest to the fact that some self-reactive B cells slip through the cracks. These B cells are causing damage through the autoantibodies they secrete, binding and damaging one’s own tissue. Although some unlucky patients are born with these autoantibodies, they can also be triggered by infection, such as Covid-19. It isn’t too much of a surprise that a pathogen may lead to a greater chance of autoantibody production – activating the immune system always risks some part of the process going wrong. What has perplexed researchers, however, is whether autoantibodies actually help protect from some diseases.

Face of a man with lupus erythematosus
Watercolour of the face of a man with lupus erythematosus, an autoimmune disease. Credit: Wellcome.

One prominent example of this is in malaria. Infections by the most severe causative species, Plasmodium falciparum, can lead to autoantibodies appearing in the blood of patients. Different studies have shown mixed results as to whether these molecules are protective or not. Although parts of the genome associated with resistance to malaria are also associated with susceptibility to autoimmune disease, and autoantibodies correlate with a lower parasitaemia and less severe anaemic symptoms, these same antibodies correlate also with a higher chance of cerebral malaria (inflammation impacting neural function). Are the rogue cells of the immune system actually a misunderstood antihero in malaria endemic areas? Kelly Hagadorn and colleagues, led by Peter Crompton and Christine Hopp, set out to establish a clearer link by following and testing patients across an entire season of P. falciparum infection.

The investigators assembled a cohort of patients in the minor commune of Kalifabougou in Mali (with the assistance of local colleagues led by Boubacar Traore of the University of Sciences, Technique and Technology of Bamako). Here, malaria transmission is intense but seasonal, so during the dry season there is a negligible rate of infection. It is at the end of this dry season, on the precipice of malaria’s return, that autoantibodies were first assessed in the healthy study participants. Despite this, around half the patients were still PCR positive for parasite presence, indicating a high rate of chronic infection latent from the last wet season. Assays for antinuclear antibodies were used (although these also capture other autoantibodies), an established procedure for diagnosing lupus and other autoimmune conditions. These autoantibodies, which bind components of the cell nucleus including DNA, sound like a particularly nasty thing to keep in the blood. However, they are surprisingly common – it is only at high levels that they cause a problem. Autoantibodies tend to increase with age, and there was no exception found in this cohort; there was no antinuclear antibody signal in children under the age of 2, while over 60% of adults had medium-to-high levels. A cohort from the US demonstrated how stark a difference this was to a location where malaria is not endemic; only 10% of adults had medium-to-high levels of autoantibody, while nearly 80% of lupus patients did. None of the Malian participants in this study had a diagnosis of an autoimmune condition.

Six images showing the different kinds of antinuclear antibody binding patterns: speckled, homogeneous, mixed, nucleolar, centromere, and peripheral.
The binding patterns of antinuclear antibody can be used to diagnose patients using guides like this. Credit: J Al-Mughales 2022, edits by M Häggström

By monitoring over the ensuing wet season, the researchers could address which groups of people were the least susceptible to malaria infection. Indeed, those with the highest amount of existing autoantibodies appeared to be the most protected from infection, even after controlling for other influencing factors such as age. In children between the ages of 3 months and 12 years, a crucial period of developing immunity to malaria, this protection amounted to a 41% lower risk of developing clinical disease. 

Confident now that they had observed a protective effect of the antinuclear antibody, the investigators sought to find a mechanism of this inhibition. They extracted the antibodies from the participants sera and applied them to P. falciparum being cultured in vitro to see how they impacted the parasites’ ability to invade and replicate in red blood cells. Growth of the parasite was impeded by an average of 16%, and this was from utilising antibody levels at fifth of the concentration found in the patients. The potency of the effect was underlined by the experimenters comparing this result to that of diluted total antibody from the Malian cohort (which showed no effect despite years living in a malaria endemic area, likely due to the dilution) and that of specific anti-falciparum antibodies (a higher but comparable inhibition). By fluorescently tagging the autoantibodies, it was then possible to see where they were binding and interfering with parasite development. They very specifically bound to infected red blood cells, forming dotted islands of fluorescence across the cell surface. In fact, it wasn’t just the Malian, malaria-exposed, autoantibodies that showed this pattern. Quite incredibly, the US autoantibodies, from lupus patients, also bound the infected red blood cells (although similar results have been observed before). 

Fluorescent images showing the 'dotted' patterns of autoantibody binding on infected red blood cells
Fluorescent images showing the ‘dotted’ patterns of autoantibody binding (in green) on infected red blood cells. Credit: Hagadorn et al., 2024.

This punctate pattern on the infested erythrocyte is typical of so-called knob structures that the parasite produces to aid sequestration around the circulation. However, by staining the cells with another antibody specific for a knob protein (you get an idea of how central antibodies are for modern science!), it was evident that the autoantibodies were binding something else. A screen was performed with this sera and a vast range of P. falciparum proteins to systematically assess which ones they stuck to. The candidates found were not expanded upon much in this paper, but they include a number of invasion proteins produced by the parasite at different times of development, perhaps providing a hint to their mechanism of action. Of course, these antibodies are defined for their self-binding nature, so a similar screen was performed to identify with human proteins they could target. Again, the results were not discussed in detail, giving others the opportunity to explain these observations in detail, although there was strong overlap with autoantigens present in autoimmune diseases like myositis.

Perhaps a link between these self-destructive autoantibodies and protection from malaria infection is beginning to become clearer. They may be binding and blocking the parasite from entering their major host cell – the red blood cell, either by targeting the pathogen’s invasion proteins or the human receptors that permit their entry. Once again one of humanitys’ most ancient foes has demonstrated its powerful, lasting influence, over our genetics and health.

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