CAMBRIDGE, United Kingdom—A gene polymorphism associated with systemic lupus erythematosus (SLE) reduces susceptibility to malaria, which might account for the higher prevalence of certain lupus-associated mutations in Asians and Africans. Menna R. Clatworthy and colleagues at research centers in the United Kingdom and in Kenya report in Proceedings of the National Academy of Sciences that SLE-associated defects in the inhibitory receptor FcγRIIb in genetically engineered mice enable the mice to clear malarial parasites more quickly and reduce the severity of malaria.¹

 

Senior author Kenneth G. C. Smith, MD, told CIAOMed that his group's most important finding is that the lupus mutation, which is most common in areas where malaria is endemic, has likely been maintained in humans because it is protective against malaria. Dr. Smith is genzyme professor of experimental medicine and honorary consultant physician at the Cambridge Institute for Medical Research, and the department of medicine, Addenbrooke's Hospital, in Cambridge, UK.

 

Populations with high rates of the polymorphism are from malaria-prone areas

The investigators began studying the FcγRIIb^T/T232 polymorphism because it is 10 times more prevalent in South and East Asian populations than in populations of European origin, because these groups also have a much higher prevalence and severity of SLE, and because the areas where this polymorphism is most common are also areas with high rates of malarial infection, a major cause of death in these locations.

 

"If FcγRIIb deficiency increased pathogen clearance, this could explain the high frequency of SLE-associated mutations and thus, a predisposition to autoimmunity in Africans and Asians, similar to the effect of malaria on the selection of thalassemia or sickle cell anemia," Dr. Smith suggests.

 

To address this possibility, the researchers determined FcγRIIb^T/T232 genotypes in DNA samples from Kenya, and then studied the results of infection with the nonlethal murine malarial parasite Plasmodium chabaudi chabaudi in FcγRIIb-deficient and control mice. They also examined the effect of FcγRIIb deficiency on the ability of macrophages to phagocytose malarial parasites in vitro, measured TNF-α production by these macrophages after ingestion of malarial parasites, measured antimalarial antibody titers in FcγRIIb-deficient mice, and finally examined the effect on human monocyte phagocytosis of Plasmodium falciparum-infected erythocytes in vitro, using a FcγRIIb-negative human monocytic cell line.

 

Gene polymorphism improves clearance of malaria parasite

 

The experiments showed that mice deficient in FcγRIIb had lower parasitemia, less anemia, and less severe disease when infected with malaria. The mice also had higher levels of phagocytosis, TNF-α, and antimalarial antibodies.

 

"Thus, individuals expressing the defunctioned FcγRIIb receptor on phagocytes are better able to clear malarial parasites and may therefore have increased resistance to infection. This resistance would explain the increased frequency of the FcγRIIb^T/T232 genotype in populations living in malarial endemic areas. Although malaria affects all age groups, it is the young who bear the brunt of malaria-associated mortality. Therefore, it is likely to act as a powerful evolutionary pressure in determining the selection of immune polymorphisms which confer resistance to infection," the authors write.

 

Dr. Smith told CIAOMed that studies to confirm this hypothesis are under way. "Our current approach is focused on a genetic study to formally demonstrate an association between the inactivating polymorphism [and important promoter polymorphisms] and malaria. We are doing this in collaboration with a Wellcome Trust funding group in Kilifi, Kenya. The genetics of this is complex, however, as the region of chromosome 1 containing FcγRIIb also contains a host of other low affinity Fc receptors, many of them implicated in both infection and autoimmunity. One [receptor], in particular, also has variable copy number. Sorting out the relative contributions of these different neighboring genes is proving to be quite a challenge," he said.

 

Malaria also may reduce risk of lupus

 

The picture is made even more complex by the observation by Hentati and colleagues that infecting lupus-prone mice with malaria retards the development of their lupus, because IgM and IgG autoantibodies "attempt, at least transitorily, to rescue a natural autoantibody network that is deficient in the [lupus-prone] mice."²

 

"The fact that malaria appears to reduce the subsequent risk of lupus is indeed intriguing. The initial observation that this is the case is now 30 years old, and yet we are not much closer to dissecting the molecular mechanisms underlying it. If we were able to do so, I think that this information could be very useful for designing new therapies to prevent, or even treat, autoimmunity." Dr. Smith said.

 

References

1. Clatworthy MR, Willcocks L, Urban B, et al. Systemic lupus erythematosus-associated defects in the inhibitory receptor FCγRIIb reduce susceptibility to malaria. Proc Natl Acad Sci USA. 2007;104:7169-7174.
2. Hentati B, Sato MN, Payelle-Brogard B, et al. Beneficial effect of polyclonal immunoglobulins from malaria-infected BALB/c mice on the lupus-like syndrome of (NZB x NZW) F1 mice. Eur J Immunol. 1994;24:8-15.