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Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1β secretion in response to anti-MPO antibodies.

O'Brien EC, Abdulahad WH, Rutgers A, Huitema MG, O'Reilly VP, Coughlan AM, Harrington M, Heeringa P, Little MA, Hickey FB - Sci Rep (2015)

Bottom Line: Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3).Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production.These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells.

View Article: PubMed Central - PubMed

Affiliation: Trinity Health Kidney Centre, Department of Clinical Medicine, Trinity College Dublin, St. James' Hospital Campus, Dublin 8, Ireland.

ABSTRACT
ANCA vasculitis encompasses several autoimmune conditions characterised by destruction of small vessels, inflammation of the respiratory tract and glomerulonephritis. Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3). Clinical and experimental data suggest that pathogenesis is driven by ANCA-mediated activation of neutrophils and monocytes. We investigated a potential role for distinct monocyte subsets. We found that the relative proportion of intermediate monocytes is increased in patients versus control individuals, and both MPO and PR3 are preferentially expressed on these cells. We demonstrate that MPO and PR3 are expressed independently of each other on monocytes and that PR3 is not associated with CD177. MPO expression correlates with that of Fc receptor CD16 on intermediate monocytes. Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production. In concordance with the observed higher surface expression of MPO on intermediate monocytes, this subset produces the highest quantity of IL-1β in response to anti-MPO stimulation. These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells.

No MeSH data available.


Related in: MedlinePlus

The ANCA autoantigens MPO and PR3 are preferentially expressed on intermediate monocytes.Peripheral blood was collected from patients with AAV and the percentage of cells expressing cell-surface MPO and PR3 was examined by flow cytometry. The percentage of MPO and PR3 positive cells in each subset is shown for (A–B) anti-MPO+ AAV patients and (C–D) anti-PR3+ AAV patients. Each symbol represents a separate individual. Open circles represent patients in remission and filled triangles patients with active disease. Data are presented as the median and interquartile range. Non-parametric one-way ANOVA (Friedman test) and Dunn’s post-test were used to test for significance (*p < 0.05, **p < 0.01; ****p < 0.0001). Class: classical; Int: intermediate: NC: non-classical.
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f2: The ANCA autoantigens MPO and PR3 are preferentially expressed on intermediate monocytes.Peripheral blood was collected from patients with AAV and the percentage of cells expressing cell-surface MPO and PR3 was examined by flow cytometry. The percentage of MPO and PR3 positive cells in each subset is shown for (A–B) anti-MPO+ AAV patients and (C–D) anti-PR3+ AAV patients. Each symbol represents a separate individual. Open circles represent patients in remission and filled triangles patients with active disease. Data are presented as the median and interquartile range. Non-parametric one-way ANOVA (Friedman test) and Dunn’s post-test were used to test for significance (*p < 0.05, **p < 0.01; ****p < 0.0001). Class: classical; Int: intermediate: NC: non-classical.

Mentions: We hypothesised that surface expression levels of the MPO and PR3 autoantigens may vary between the different monocyte subsets. Using a subset of the full cohort described above and following gating on each subset, the percentage of monocytes expressing cell-surface MPO was significantly increased on intermediate cells when compared to classical and non-classical subsets (Fig. 2A,C, Supplemental Fig. S1). This finding was consistent in both test and control groups, suggesting that it is a fundamental feature of the intermediate monocyte subset. Similarly, cell-surface PR3 expression was increased on the intermediate monocyte subset in both the test and control groups (Fig. 2, Supplemental Fig. S1). Following gating of MPO/PR3 positive cells in each subset we found a significant increase in the median fluorescence intensity of MPO and PR3 on intermediate monocytes (Supplemental Fig. S2).


Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1β secretion in response to anti-MPO antibodies.

O'Brien EC, Abdulahad WH, Rutgers A, Huitema MG, O'Reilly VP, Coughlan AM, Harrington M, Heeringa P, Little MA, Hickey FB - Sci Rep (2015)

The ANCA autoantigens MPO and PR3 are preferentially expressed on intermediate monocytes.Peripheral blood was collected from patients with AAV and the percentage of cells expressing cell-surface MPO and PR3 was examined by flow cytometry. The percentage of MPO and PR3 positive cells in each subset is shown for (A–B) anti-MPO+ AAV patients and (C–D) anti-PR3+ AAV patients. Each symbol represents a separate individual. Open circles represent patients in remission and filled triangles patients with active disease. Data are presented as the median and interquartile range. Non-parametric one-way ANOVA (Friedman test) and Dunn’s post-test were used to test for significance (*p < 0.05, **p < 0.01; ****p < 0.0001). Class: classical; Int: intermediate: NC: non-classical.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493694&req=5

f2: The ANCA autoantigens MPO and PR3 are preferentially expressed on intermediate monocytes.Peripheral blood was collected from patients with AAV and the percentage of cells expressing cell-surface MPO and PR3 was examined by flow cytometry. The percentage of MPO and PR3 positive cells in each subset is shown for (A–B) anti-MPO+ AAV patients and (C–D) anti-PR3+ AAV patients. Each symbol represents a separate individual. Open circles represent patients in remission and filled triangles patients with active disease. Data are presented as the median and interquartile range. Non-parametric one-way ANOVA (Friedman test) and Dunn’s post-test were used to test for significance (*p < 0.05, **p < 0.01; ****p < 0.0001). Class: classical; Int: intermediate: NC: non-classical.
Mentions: We hypothesised that surface expression levels of the MPO and PR3 autoantigens may vary between the different monocyte subsets. Using a subset of the full cohort described above and following gating on each subset, the percentage of monocytes expressing cell-surface MPO was significantly increased on intermediate cells when compared to classical and non-classical subsets (Fig. 2A,C, Supplemental Fig. S1). This finding was consistent in both test and control groups, suggesting that it is a fundamental feature of the intermediate monocyte subset. Similarly, cell-surface PR3 expression was increased on the intermediate monocyte subset in both the test and control groups (Fig. 2, Supplemental Fig. S1). Following gating of MPO/PR3 positive cells in each subset we found a significant increase in the median fluorescence intensity of MPO and PR3 on intermediate monocytes (Supplemental Fig. S2).

Bottom Line: Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3).Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production.These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells.

View Article: PubMed Central - PubMed

Affiliation: Trinity Health Kidney Centre, Department of Clinical Medicine, Trinity College Dublin, St. James' Hospital Campus, Dublin 8, Ireland.

ABSTRACT
ANCA vasculitis encompasses several autoimmune conditions characterised by destruction of small vessels, inflammation of the respiratory tract and glomerulonephritis. Most patients harbour autoantibodies to myeloperoxidase (MPO) or proteinase 3 (PR3). Clinical and experimental data suggest that pathogenesis is driven by ANCA-mediated activation of neutrophils and monocytes. We investigated a potential role for distinct monocyte subsets. We found that the relative proportion of intermediate monocytes is increased in patients versus control individuals, and both MPO and PR3 are preferentially expressed on these cells. We demonstrate that MPO and PR3 are expressed independently of each other on monocytes and that PR3 is not associated with CD177. MPO expression correlates with that of Fc receptor CD16 on intermediate monocytes. Monocyte subsets respond differently to antibodies directed against MPO and PR3, with anti-MPO but not anti-PR3 leading to increased IL-1β, IL-6 and IL-8 production. In concordance with the observed higher surface expression of MPO on intermediate monocytes, this subset produces the highest quantity of IL-1β in response to anti-MPO stimulation. These data suggest that monocytes, specifically, the intermediate subset, may play a role in ANCA vasculitis, and also indicate that substantial differences exist between the effect of anti-MPO and anti-PR3 antibodies on these cells.

No MeSH data available.


Related in: MedlinePlus