HLA heterozygosity and hyperreactive malarious splenomegaly in the Upper Watut Valley of Papua New Guinea

Hyperreactive malarious splenomegaly (HMS) represents an abnormal immune response to recurrent malarial infection. In the Upper Watut Valley of Papua New Guinea, where over 80% of adult inhabitants are known to develop the disease, human leucocyte antigen (HLA) studies have demonstrated an association between the antigen DR2 and gross splenomegaly. To test the hypothesis that the magnitude of the individual immune response to malaria is also influenced by the number of different HLA antigens present, we have studied the correlation of the level of observed heterozygosity at HLA-A, -B, -C and -DR loci with the degree of splenomegaly in adult Watut subjects. Heterozygosity per se provides additional antigens for the formation of complexes between HLA and foreign antigenic epitopes, considered crucial to mounting an immune response. Multiply heterozygous individuals were found to exhibit more intense immune responses to recurrent malarial infections than did individuals with low multiple-locus heterozygosity. On the basis of the analysis presented here, we suggest that the degree of immune response to malaria is also influenced by the level of HLA heterozygosity, although the exact mechanisms remain unclear.