The genetic basis of hyperreactive malarious splenomegaly

Hyperreactive malarious splenomegaly (HMS) represents an abnormal immune response to recurrent malaria, characterized by excessive production of both IgM and IgG antibodies. It has both a racial and a familial distribution in various parts of the world. Immune responses to many foreign antigens, including those of malaria, are under genetic control of the major histocompatibility locus (MHC), through the influence of HLA antigens on regulatory T-lymphocyte activity. It is therefore likely that this region also contains the genetic determinants for HMS, which would be reflected in associations between HMS and particular HLA antigens or haplotypes. Genetic studies of the Watut people of Papua New Guinea have not shown any association between HMS and a wide range of red cell and serum polymorphisms. However, HMS in this group is associated with the class II HLA antigen DR2, and with high levels of HLA heterozygosity. Formal genetic analysis of family data also points to a sex-linked gene as a further determinant of overresponsiveness to malaria in the Anga. These findings suggest that more than one genetic system may be involved in the development of HMS, and that the combined effects of several genetic determinants may be responsible for the extraordinarily high frequency of HMS found in the Upper Watut Valley.