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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

MPO and CD16 expression are correlated on intermediate monocytes.Peripheral blood was collected from patients with AAV and analysed by flow cytometry. Following gating on intermediate monocytes the MFI of CD16 was plotted against that of MPO or PR3. Data presented show (A–B) anti-MPO+ AAV patients, (C–D) anti-PR3+ AAV patients. Each symbol represents an individual patient. Open circles represent patients in remission and filled triangles show patients with active disease. Correlation was tested by Spearman Rank Test.
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f5: MPO and CD16 expression are correlated on intermediate monocytes.Peripheral blood was collected from patients with AAV and analysed by flow cytometry. Following gating on intermediate monocytes the MFI of CD16 was plotted against that of MPO or PR3. Data presented show (A–B) anti-MPO+ AAV patients, (C–D) anti-PR3+ AAV patients. Each symbol represents an individual patient. Open circles represent patients in remission and filled triangles show patients with active disease. Correlation was tested by Spearman Rank Test.

Mentions: As CD16 positivity is the criterion for differentiation between classical and intermediate monocytes, as well as being a potential signalling mechanism for ANCA in monocytes, we investigated the relationship between CD16 and MPO/PR3. Following gating on intermediate monocytes, we assessed whether the MPO/PR3 median fluorescence intensity was correlated with that of CD16. We found that surface MPO, but not PR3, was significantly correlated with CD16 (Fig. 5). Neither antigen was correlated with CD16 in healthy controls, but it was correlated in disease controls (Supplemental Fig. S4), suggesting that this may be a feature of either renal dysfunction or systemic inflammation.


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)

MPO and CD16 expression are correlated on intermediate monocytes.Peripheral blood was collected from patients with AAV and analysed by flow cytometry. Following gating on intermediate monocytes the MFI of CD16 was plotted against that of MPO or PR3. Data presented show (A–B) anti-MPO+ AAV patients, (C–D) anti-PR3+ AAV patients. Each symbol represents an individual patient. Open circles represent patients in remission and filled triangles show patients with active disease. Correlation was tested by Spearman Rank Test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: MPO and CD16 expression are correlated on intermediate monocytes.Peripheral blood was collected from patients with AAV and analysed by flow cytometry. Following gating on intermediate monocytes the MFI of CD16 was plotted against that of MPO or PR3. Data presented show (A–B) anti-MPO+ AAV patients, (C–D) anti-PR3+ AAV patients. Each symbol represents an individual patient. Open circles represent patients in remission and filled triangles show patients with active disease. Correlation was tested by Spearman Rank Test.
Mentions: As CD16 positivity is the criterion for differentiation between classical and intermediate monocytes, as well as being a potential signalling mechanism for ANCA in monocytes, we investigated the relationship between CD16 and MPO/PR3. Following gating on intermediate monocytes, we assessed whether the MPO/PR3 median fluorescence intensity was correlated with that of CD16. We found that surface MPO, but not PR3, was significantly correlated with CD16 (Fig. 5). Neither antigen was correlated with CD16 in healthy controls, but it was correlated in disease controls (Supplemental Fig. S4), suggesting that this may be a feature of either renal dysfunction or systemic inflammation.

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