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Hyperreactive onchocerciasis is characterized by a combination of Th17-Th2 immune responses and reduced regulatory T cells.

Katawa G, Layland LE, Debrah AY, von Horn C, Batsa L, Kwarteng A, Arriens S, W Taylor D, Specht S, Hoerauf A, Adjobimey T - PLoS Negl Trop Dis (2015)

Bottom Line: Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO.Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals.In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany; Advanced School of Medical Biology and Food Technology (ESTBA), University of Lomé, Lomé, Togo.

ABSTRACT
Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.

No MeSH data available.


Related in: MedlinePlus

Immune profiles of hyperreactive onchocerciasis individuals are associated with elevated Th2 and Th17 factors.PBMCs isolated from EN (n = 16) and O. volvulus-infected GEO (n = 16) or HO (n = 6) individuals were activated with a cell stimulation cocktail for 6 hours. Thereafter, cells were stained for CD4 and the transcription factors GATA3 (A) or RORC2 (B). Ratios of CD4+lL-17A+ vs. CD4+IL-4+ T cells (C) and CD4+RORC2+ vs. CD4+CD25hiFoxp3+ (D) were determined for each individual. Cell population frequencies were determined using flow cytometry. Graphs show percentages as box whiskers (tukey) with outliers. Asterisks show statistical differences (Kruskal-Wallis and Mann Whitney test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001). (E–G) After PBMCs were stimulated with αCD3/αCD28 (40,000 beads/ml) for 3h, RNA was extracted and transcribed into cDNA. Thereafter, PCR Arrays were performed using the RT2 Profiler PCR Array Human Th17 kit. Bars show fold change ± SEM increase in the indicated gene expression between four age-matched males presenting either GEO or HO forms of infection.
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pntd-0003414-g004: Immune profiles of hyperreactive onchocerciasis individuals are associated with elevated Th2 and Th17 factors.PBMCs isolated from EN (n = 16) and O. volvulus-infected GEO (n = 16) or HO (n = 6) individuals were activated with a cell stimulation cocktail for 6 hours. Thereafter, cells were stained for CD4 and the transcription factors GATA3 (A) or RORC2 (B). Ratios of CD4+lL-17A+ vs. CD4+IL-4+ T cells (C) and CD4+RORC2+ vs. CD4+CD25hiFoxp3+ (D) were determined for each individual. Cell population frequencies were determined using flow cytometry. Graphs show percentages as box whiskers (tukey) with outliers. Asterisks show statistical differences (Kruskal-Wallis and Mann Whitney test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001). (E–G) After PBMCs were stimulated with αCD3/αCD28 (40,000 beads/ml) for 3h, RNA was extracted and transcribed into cDNA. Thereafter, PCR Arrays were performed using the RT2 Profiler PCR Array Human Th17 kit. Bars show fold change ± SEM increase in the indicated gene expression between four age-matched males presenting either GEO or HO forms of infection.

Mentions: Correlating with the elevated IL-4 and IL-17 cytokine expression, CD4+ T cells from HO individuals had significantly higher levels of both GATA3 (Fig. 4A) and RORC2 (Fig. 4B) transcription factors. In addition, the ratio of CD4+IL-17A+/CD4+IL-4+ T cells was higher in individuals with HO (Fig. 4C) when compared to the GEO group. This trend remained when comparing the ratio CD4+RORC2+/CD4+CD25hiFoxp3+ in HO individuals with both GEO and EN groups (Fig. 4D). Using a Th17-based PCR array, we compared expression levels of Th17, Th2 and Treg related genes in GEO and HO individuals. As shown in Fig. 4E, IL-17 associated genes, such as IL17A, IL17C, IL17D, IL17F, RORC and STAT3, were all up-regulated in cells from HO individuals. The genes of cytokines known to be required for the induction of Th17 cells such as IL-6, IL-1β, TGF-β1, IL-21 and IL-23A [19], [20] and the IL22 gene were also highly up-regulated in HO persons (Fig. 4F). With regards to Th2-related genes and the Treg-associated foxp3 expression, the IL13 gene presented the strongest fold increase and correlated to the elevated gene expression of GATA3 and STAT6 (Fig. 4G). In correlation with elevated amounts of CD4+Foxp3+ cells in HO individuals, foxp3 gene expression in these patients was also upregulated (Fig. 4G).


Hyperreactive onchocerciasis is characterized by a combination of Th17-Th2 immune responses and reduced regulatory T cells.

Katawa G, Layland LE, Debrah AY, von Horn C, Batsa L, Kwarteng A, Arriens S, W Taylor D, Specht S, Hoerauf A, Adjobimey T - PLoS Negl Trop Dis (2015)

Immune profiles of hyperreactive onchocerciasis individuals are associated with elevated Th2 and Th17 factors.PBMCs isolated from EN (n = 16) and O. volvulus-infected GEO (n = 16) or HO (n = 6) individuals were activated with a cell stimulation cocktail for 6 hours. Thereafter, cells were stained for CD4 and the transcription factors GATA3 (A) or RORC2 (B). Ratios of CD4+lL-17A+ vs. CD4+IL-4+ T cells (C) and CD4+RORC2+ vs. CD4+CD25hiFoxp3+ (D) were determined for each individual. Cell population frequencies were determined using flow cytometry. Graphs show percentages as box whiskers (tukey) with outliers. Asterisks show statistical differences (Kruskal-Wallis and Mann Whitney test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001). (E–G) After PBMCs were stimulated with αCD3/αCD28 (40,000 beads/ml) for 3h, RNA was extracted and transcribed into cDNA. Thereafter, PCR Arrays were performed using the RT2 Profiler PCR Array Human Th17 kit. Bars show fold change ± SEM increase in the indicated gene expression between four age-matched males presenting either GEO or HO forms of infection.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288720&req=5

pntd-0003414-g004: Immune profiles of hyperreactive onchocerciasis individuals are associated with elevated Th2 and Th17 factors.PBMCs isolated from EN (n = 16) and O. volvulus-infected GEO (n = 16) or HO (n = 6) individuals were activated with a cell stimulation cocktail for 6 hours. Thereafter, cells were stained for CD4 and the transcription factors GATA3 (A) or RORC2 (B). Ratios of CD4+lL-17A+ vs. CD4+IL-4+ T cells (C) and CD4+RORC2+ vs. CD4+CD25hiFoxp3+ (D) were determined for each individual. Cell population frequencies were determined using flow cytometry. Graphs show percentages as box whiskers (tukey) with outliers. Asterisks show statistical differences (Kruskal-Wallis and Mann Whitney test) between the groups indicated by the brackets (*p<0.05, **p<0.01, ***p<0.001). (E–G) After PBMCs were stimulated with αCD3/αCD28 (40,000 beads/ml) for 3h, RNA was extracted and transcribed into cDNA. Thereafter, PCR Arrays were performed using the RT2 Profiler PCR Array Human Th17 kit. Bars show fold change ± SEM increase in the indicated gene expression between four age-matched males presenting either GEO or HO forms of infection.
Mentions: Correlating with the elevated IL-4 and IL-17 cytokine expression, CD4+ T cells from HO individuals had significantly higher levels of both GATA3 (Fig. 4A) and RORC2 (Fig. 4B) transcription factors. In addition, the ratio of CD4+IL-17A+/CD4+IL-4+ T cells was higher in individuals with HO (Fig. 4C) when compared to the GEO group. This trend remained when comparing the ratio CD4+RORC2+/CD4+CD25hiFoxp3+ in HO individuals with both GEO and EN groups (Fig. 4D). Using a Th17-based PCR array, we compared expression levels of Th17, Th2 and Treg related genes in GEO and HO individuals. As shown in Fig. 4E, IL-17 associated genes, such as IL17A, IL17C, IL17D, IL17F, RORC and STAT3, were all up-regulated in cells from HO individuals. The genes of cytokines known to be required for the induction of Th17 cells such as IL-6, IL-1β, TGF-β1, IL-21 and IL-23A [19], [20] and the IL22 gene were also highly up-regulated in HO persons (Fig. 4F). With regards to Th2-related genes and the Treg-associated foxp3 expression, the IL13 gene presented the strongest fold increase and correlated to the elevated gene expression of GATA3 and STAT6 (Fig. 4G). In correlation with elevated amounts of CD4+Foxp3+ cells in HO individuals, foxp3 gene expression in these patients was also upregulated (Fig. 4G).

Bottom Line: Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO.Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals.In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Bonn, Germany; Advanced School of Medical Biology and Food Technology (ESTBA), University of Lomé, Lomé, Togo.

ABSTRACT
Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4+ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4+CD25hiFoxp3+ regulatory T cells. These profiles included increased IL-17A+, IL-4+, RORC2+ and GATA3+CD4+ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis.

No MeSH data available.


Related in: MedlinePlus