Th17-Treg Antagonism: Impact on Disease Outcome in Helminth Infections
Final Report Abstract
During filarial infections both clinical and basic research have shown that regulatory T cells play an essential role in maintaining homeostasis and coordinating immune regulatory networks. Expanding on our previous research our current studies continue to highlight the association of Treg‐IgG4‐IL‐10 in contributing to a regulated immune state during filarial infections. First, our field studies with W. bancrofti‐infected individuals revealed differences in immune profiles and gene expression profiles by microarrays in Treg populations from asymptomatic MF+ and MF‐ individuals. These studies have opened new avenues of research into how host immune responses, MF‐ individuals hinder transmission. Further immunoepidemiological studies in O. volvulus endemic areas compared frequencies of different cell populations in infected individuals with or without disease‐related dermal manifestations (GEO vs. HO). This work revealed for the first time that there is a dominant Th2/Th17 profile in HO individuals (those displaying pathology). Here both IL‐17A+‐ and RORC+CD4+ T cell populations were elevated and gene expression profiling via PCR arrays also showed up‐ regulation of Th17‐related genes. Moreover, when compared to GEO or EN cohorts, TCR‐activation of PBMC cultures from HO individuals also showed increased IL‐17A production. Additional immunoepidemiological and multivariate regression analysis in O. volvulus endemic areas that had had differing rounds of mass drug administration showed that areas with a lowered infection pressure due to MDA‐IVM appear to influence Onchocerca‐specific and bystander responses in community members even if they have not regularly participated in the therapy. One of our research foci has been to decipher how individuals infected with the same helminth develop polar extremes of infection. Our in vitro studies clearly demonstrated that isolated Treg from human PBMC suppress B cell activity by moderating CD69 and MHCII up‐regulation upon CD40L activation. As a consequence of this suppression B cell antibody production is shifted towards IgG4. Interestingly, TLR activated B cells become resistant to Treg control and corollary produce less IgG4 while increasing IgE, IgG2 and IgG1 production despite the presence of activated Treg. Furthermore, co‐culture of LPS or CpG but not Pam3Cys activated B cells with isolated Treg leads to the induction of IL‐17 production within the Treg population. This IL‐17 production was accompanied by a significant up‐regulation of RORC2 suggesting a phenotype shift of Treg towards Th17. However the transformed T cells retained Foxp3 expression and residual suppressive properties. This transformation of Treg cells into a Th17 like phenotype was IL‐6 and TGF‐β dependent. These data provide a novel facet into the interaction of Treg and B cells during innate stimuli and demonstrate that such radical behaviour by Treg themselves could have drastic consequences on developing responses to infection. Thus, under conditions like bacterial or viral infections, B cells can escape Treg control, and provides an explanation as to why patients suffering from allergy or helminth infections display polar immunopathological symptoms despite being exposed to the same agent.
Publications
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2012. Elevated adaptive immune responses are associated with latent infections of Wuchereria bancrofti. PLoS NeglTrop Dis. 6: e1611
Arndts K, Deininger S, Specht S, Klarmann U, Mand S, Adjobimey T, Debrah AY, Batsa L, Kwarteng A, Epp C, Taylor M, Adjei O, Layland LE, Hoerauf A
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2014. Co‐activation through TLR4 and TLR9 but not TLR2 skews Treg‐mediated modulation of Igs and induces IL‐17 secretion in Treg: B cell co‐cultures. Innate Immun. 20: 12‐23
Adjobimey T, Satoguina J, Oldenburg J, Hoerauf A, Layland LE
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2014. Immunoepidemiological profiling of onchocerciasis patients reveals associations with microfilaria loads and ivermectin intake on both individual and community levels. PLoS Negl Trop Dis. 8: e2679
Arndts K, Specht S, Debrah AY, Tamarozzi F, Klarmann‐Schulz U, Mand S, Batsa L, Kwarteng A, Taylor M, Adjei O, Martin C, Layland LE, Hoerauf A
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Helminth Infections and their Impact on Global Public Health. Editor Bruschi. Springer Publishing. ASIN: B00K5J5PHE
Hübner MP, Layland LE, Hoerauf A
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2015. Hyperreactive onchocerciasis is characterized by a combination of Th17‐Th2 immune responses and reduced regulatory T cells. PLoS Negl Trop Dis. 9: e3414
Katawa G, Layland LE, Debrah AY, von Horn C, Batsa L, Kwarteng A, Arriens S, D WT, Specht S, Hoerauf A, Adjobimey T
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2015. Reductions in microfilaridermia by repeated ivermectin treatment are associated with lower Plasmodium‐specific Th17 immune responses in Onchocerca volvulus‐infected individuals. Parasit Vectors. 8: 184
Arndts K, Klarmann‐Schulz U, Batsa L, Debrah AY, Epp C, Fimmers R, Specht S, Layland LE, Hoerauf A
