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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

PR3+ monocytes do not co-express CD177.Peripheral blood was collected from healthy control individuals, patients with AAV and disease controls and analysed by flow cytometry. Following gating on monocytes or granulocytes the percentage of PR3+ cells in each population which co-express CD177 was determined (A). Representative histograms show the median fluorescence intensity (MFI) of CD177 on monocytes and granulocytes (B). Data represent the median and interquartile range. Paired t-test was used to test for significance (**p < 0.01). Mono: monocytes; Gran: granulocytes; FMO: fluorescence minus one control.
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f4: PR3+ monocytes do not co-express CD177.Peripheral blood was collected from healthy control individuals, patients with AAV and disease controls and analysed by flow cytometry. Following gating on monocytes or granulocytes the percentage of PR3+ cells in each population which co-express CD177 was determined (A). Representative histograms show the median fluorescence intensity (MFI) of CD177 on monocytes and granulocytes (B). Data represent the median and interquartile range. Paired t-test was used to test for significance (**p < 0.01). Mono: monocytes; Gran: granulocytes; FMO: fluorescence minus one control.

Mentions: As cell-surface expression of both MPO and PR3 was increased on intermediate monocytes we investigated whether expression of the two autoantigens was linked in this cell type. The majority of autoantigen expressing monocytes were positive for either MPO or PR3 alone, indicating that MPO and PR3 are expressed independently on the cell surface (Fig. 3 and Supplemental Fig. S3). These data suggest that the mechanism for anchoring the antigen to the plasma membrane is different in each case. In neutrophils, surface expression of CD177 is linked to PR3 expression, with increased membrane expression of PR3 dependent on CD17714. We investigated whether the same mechanism accounted for surface PR3 expression on monocytes. We found little expression of CD177 on monocytes and no association between CD177 and PR3 (Fig. 4). As demonstrated previously a high proportion of PR3+ granulocytes co-expressed CD177 (Fig. 4).


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)

PR3+ monocytes do not co-express CD177.Peripheral blood was collected from healthy control individuals, patients with AAV and disease controls and analysed by flow cytometry. Following gating on monocytes or granulocytes the percentage of PR3+ cells in each population which co-express CD177 was determined (A). Representative histograms show the median fluorescence intensity (MFI) of CD177 on monocytes and granulocytes (B). Data represent the median and interquartile range. Paired t-test was used to test for significance (**p < 0.01). Mono: monocytes; Gran: granulocytes; FMO: fluorescence minus one control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: PR3+ monocytes do not co-express CD177.Peripheral blood was collected from healthy control individuals, patients with AAV and disease controls and analysed by flow cytometry. Following gating on monocytes or granulocytes the percentage of PR3+ cells in each population which co-express CD177 was determined (A). Representative histograms show the median fluorescence intensity (MFI) of CD177 on monocytes and granulocytes (B). Data represent the median and interquartile range. Paired t-test was used to test for significance (**p < 0.01). Mono: monocytes; Gran: granulocytes; FMO: fluorescence minus one control.
Mentions: As cell-surface expression of both MPO and PR3 was increased on intermediate monocytes we investigated whether expression of the two autoantigens was linked in this cell type. The majority of autoantigen expressing monocytes were positive for either MPO or PR3 alone, indicating that MPO and PR3 are expressed independently on the cell surface (Fig. 3 and Supplemental Fig. S3). These data suggest that the mechanism for anchoring the antigen to the plasma membrane is different in each case. In neutrophils, surface expression of CD177 is linked to PR3 expression, with increased membrane expression of PR3 dependent on CD17714. We investigated whether the same mechanism accounted for surface PR3 expression on monocytes. We found little expression of CD177 on monocytes and no association between CD177 and PR3 (Fig. 4). As demonstrated previously a high proportion of PR3+ granulocytes co-expressed CD177 (Fig. 4).

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