Research Article: Association of the Gene Polymorphisms IFN-γ +874, IL-13 −1055 and IL-4 −590 with Patterns of Reinfection with Schistosoma mansoni

Date Published: February 10, 2009

Publisher: Public Library of Science

Author(s): Michael R. Gatlin, Carla L. Black, Pauline N. Mwinzi, W. Evan Secor, Diana M. Karanja, Daniel G. Colley, Charles H. King

Abstract: BackgroundThe immunologic findings that most consistently correlate with resistance in human schistosomiasis are high levels of IgE and low levels of IgG4. We have genotyped gene and promoter polymorphisms of cytokines associated with regulation of these isotypes in a cohort of men occupationally exposed to Schistosoma mansoni in western Kenya and evaluated their patterns with respect to resistance and susceptibility to reinfection after treatment and cure with praziquantel (PZQ).Methodology/Principal FindingsIn this cohort, polymorphisms in IL-4 (−590T high IgE), IL-13 (−1055T high producer) and IFN-γ (+874A high producer) demonstrated several correlations with resistance to reinfection. Resistance to reinfection was significantly correlated with the heterozygous IL-4 −590 genotype C/T (OR 3.5, [CI 1.2, 10.2]) compared to T/T. Among men with a homozygous IL-13 genotype CC/TT, having a T allele at the IFN-γ +874 position increased the odds of resistance relative to individuals with the IFN-γ +874 A/A genotype (OR = 17.5 [CI 3.0, 101.5]). Among men with homozygous A/A IFN-γ genotype, the heterozygous IL-13 genotype C/T was associated with resistance relative to the homozygous C/C or T/T genotypes (OR = 22.5 [CI 3.5, 144.4]). No increases in odds of resistance were found in relation to the IL-13 genotype among those with a T allele in the IFN-γ gene or in relation to the IFN-γ genotype among those with a heterozygous IL-13 genotype. Calculation of the attributable proportion of resistance showed a significant synergistic interaction between IL-13 −1055 C/T and IL-4 −590 C/T.ConclusionsThe identified polymorphisms do not by themselves confer resistance or susceptibility, but we propose that these genotypes allow the resistant phenotype to be developed and expressed upon suitable immune exposure. Based on the literature, these polymorphisms contribute to the regulation of their respective cytokines, likely leading to downstream differences in the production and interrelationships of critical defense mechanisms.

Partial Text: There have been many studies of resistance to schistosome infections in humans following treatment and reinfection. Such studies involve documentation of cases of schistosomiasis, their treatment and cure, and examinations at a later date to see if reinfections occurred [1],[2],[3],[4]. Of all the immunologic findings associated with these investigations, the most consistent observation is that resistance (usually defined as lower levels of infection) correlates with high IgE and low IgG4 antibodies against schistosome antigens [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18]. Other studies have reported that production of IFN-γ and IL-5 to schistosome antigens are also correlated with resistance [19],[20],[21],[22].

The car washers in this study are part of a longitudinal study that dates back 12 years [40]. Their exposure (water contact) to infection with S. mansoni is documented by the number of cars washed for payment purposes, providing us with a unique, reliable means to quantify an individual’s exposure in an active transmission site over time. This longitudinal field setting allows us to account for water contact as a variable and pose some interesting immunologic and genetic questions with regard to what influences may play a role in determining resistance to reinfection after treatment.

Source:

http://doi.org/10.1371/journal.pntd.0000375

 

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