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Impaired clearance of early apoptotic cells mediated by inhibitory IgG antibodies in patients with primary Sjögren's syndrome.

Manoussakis MN, Fragoulis GE, Vakrakou AG, Moutsopoulos HM - PLoS ONE (2014)

Bottom Line: Compared to HBD, approximately half of SS and SLE patients studied (but not RA) manifested significantly reduced ApoCell-phagocytosis (p<0.001) and MB-phagocytosis (p<0.003) by blood-borne phagocytes that correlated inversely with disease activity (p≤0.004).In cross-admixture assays, healthy monocytes showed significantly reduced ApoCell-phagocytosis when fed with apoptotic cells that were pretreated with sera or purified serum IgG preparations from SS and SLE patients (p<0.0001, compared to those from HBD or RA).Such aberrant effect of the SS and SLE sera and IgG preparations correlated linearly with their content of IgG antibodies against apoptotic cells (p≤0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece; Hellenic Pasteur Institute, Athens, Greece.

ABSTRACT

Objectives: Deficient efferocytosis (i.e. phagocytic clearance of apoptotic cells) has been frequently reported in systemic lupus erythematosus (SLE). Todate, patients with primary Sjögren's syndrome (SS) have not been assessed for phagocytosis of apoptotic cells (ApoCell-phagocytosis) and of particulate targets (microbeads, MB-phagocytosis).

Design: ApoCell-phagocytosis and MB-phagocytosis were comparatively assessed by flow cytometry in peripheral blood specimens and monocyte-derived macrophage (MDM) preparations from healthy blood donors (HBD) and consecutive SS, SLE and rheumatoid arthritis (RA) patients. Cross-admixture ApoCell-phagocytosis experiments were also performed using phagocytes from HBD or patients, and apoptotic cells pretreated with whole sera or purified serum IgG derived from patients or HBD.

Results: Compared to HBD, approximately half of SS and SLE patients studied (but not RA) manifested significantly reduced ApoCell-phagocytosis (p<0.001) and MB-phagocytosis (p<0.003) by blood-borne phagocytes that correlated inversely with disease activity (p≤0.004). In cross-admixture assays, healthy monocytes showed significantly reduced ApoCell-phagocytosis when fed with apoptotic cells that were pretreated with sera or purified serum IgG preparations from SS and SLE patients (p<0.0001, compared to those from HBD or RA). Such aberrant effect of the SS and SLE sera and IgG preparations correlated linearly with their content of IgG antibodies against apoptotic cells (p≤0.0001). Phagocytic dysfunction maybe also present in certain SS and SLE patients, as supported by deficient capacity of MDM for ApoCell-phagocytosis and MB-phagocytosis under patients' serum-free conditions.

Conclusion: Similarly to SLE, efferocytosis is frequently impaired in SS and is primarily due to the presence of inhibitory IgG anti-ApoCell antibodies and secondarily to phagocytes' dysfunction.

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The peripheral blood (PB) monocytes and monocyte-derived macrophages (MDM) of SS and SLE patients manifest significantly impaired ApoCell-phagocytosis.The aberrant uptake of apoptotic cells by blood-borne phagocytes largely resides in the patients' sera. A. Significantly decreased ApoCell-phagocytosis by PB monocytes in SS and SLE patients, but not in RA. B–C. The ApoCell-phagocytosis index values observed in SS and SLE patients correlated inversely with the disease activity indices of these diseases. D. Decreased ApoCell-phagocytosis by MDM in SS and SLE patients. E. Cross-admixture experiments illustrating the significantly reduced capacity of sera from SS and SLE patients to support ApoCell-phagocytosis by normal peripheral blood (PB) monocytes, in contrast to sera from HBD and from RA patients. In panels A, C and D the horizontal lines indicate the median levels in each group, whereas the numbers in boxes indicate the percentages of individuals with decreased ApoCell-phagocytosis, as defined by the presence of ApoCell-PhI values that were two standard deviations below the corresponding mean of HBD. Statistically significant comparisons of patient groups to HBD are shown. In panel B, the mean ApoCell-PhI values of SS-derived MDM were marginally different compared to MDM (p = 0.06).
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pone-0112100-g001: The peripheral blood (PB) monocytes and monocyte-derived macrophages (MDM) of SS and SLE patients manifest significantly impaired ApoCell-phagocytosis.The aberrant uptake of apoptotic cells by blood-borne phagocytes largely resides in the patients' sera. A. Significantly decreased ApoCell-phagocytosis by PB monocytes in SS and SLE patients, but not in RA. B–C. The ApoCell-phagocytosis index values observed in SS and SLE patients correlated inversely with the disease activity indices of these diseases. D. Decreased ApoCell-phagocytosis by MDM in SS and SLE patients. E. Cross-admixture experiments illustrating the significantly reduced capacity of sera from SS and SLE patients to support ApoCell-phagocytosis by normal peripheral blood (PB) monocytes, in contrast to sera from HBD and from RA patients. In panels A, C and D the horizontal lines indicate the median levels in each group, whereas the numbers in boxes indicate the percentages of individuals with decreased ApoCell-phagocytosis, as defined by the presence of ApoCell-PhI values that were two standard deviations below the corresponding mean of HBD. Statistically significant comparisons of patient groups to HBD are shown. In panel B, the mean ApoCell-PhI values of SS-derived MDM were marginally different compared to MDM (p = 0.06).

Mentions: The study of ApoCell-phagocytosis had yielded similar results between RA patients and HBD, but significantly decreased ApoCell-PhI values in both SS and SLE patient groups, compared to HBD (p = 0.0002 and p<0.0001, respectively) and to RA patients (p = 0.0009 and p = 0.0004, respectively) (Figure 1A). Conversely, ApoCell-PhI values were not statistically different between SS and SLE patients. Decreased ApoCell-phagocytosis was observed in approximately half of SS and SLE patients, compared to none of RA patients studied (Figure 1A).


Impaired clearance of early apoptotic cells mediated by inhibitory IgG antibodies in patients with primary Sjögren's syndrome.

Manoussakis MN, Fragoulis GE, Vakrakou AG, Moutsopoulos HM - PLoS ONE (2014)

The peripheral blood (PB) monocytes and monocyte-derived macrophages (MDM) of SS and SLE patients manifest significantly impaired ApoCell-phagocytosis.The aberrant uptake of apoptotic cells by blood-borne phagocytes largely resides in the patients' sera. A. Significantly decreased ApoCell-phagocytosis by PB monocytes in SS and SLE patients, but not in RA. B–C. The ApoCell-phagocytosis index values observed in SS and SLE patients correlated inversely with the disease activity indices of these diseases. D. Decreased ApoCell-phagocytosis by MDM in SS and SLE patients. E. Cross-admixture experiments illustrating the significantly reduced capacity of sera from SS and SLE patients to support ApoCell-phagocytosis by normal peripheral blood (PB) monocytes, in contrast to sera from HBD and from RA patients. In panels A, C and D the horizontal lines indicate the median levels in each group, whereas the numbers in boxes indicate the percentages of individuals with decreased ApoCell-phagocytosis, as defined by the presence of ApoCell-PhI values that were two standard deviations below the corresponding mean of HBD. Statistically significant comparisons of patient groups to HBD are shown. In panel B, the mean ApoCell-PhI values of SS-derived MDM were marginally different compared to MDM (p = 0.06).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4232361&req=5

pone-0112100-g001: The peripheral blood (PB) monocytes and monocyte-derived macrophages (MDM) of SS and SLE patients manifest significantly impaired ApoCell-phagocytosis.The aberrant uptake of apoptotic cells by blood-borne phagocytes largely resides in the patients' sera. A. Significantly decreased ApoCell-phagocytosis by PB monocytes in SS and SLE patients, but not in RA. B–C. The ApoCell-phagocytosis index values observed in SS and SLE patients correlated inversely with the disease activity indices of these diseases. D. Decreased ApoCell-phagocytosis by MDM in SS and SLE patients. E. Cross-admixture experiments illustrating the significantly reduced capacity of sera from SS and SLE patients to support ApoCell-phagocytosis by normal peripheral blood (PB) monocytes, in contrast to sera from HBD and from RA patients. In panels A, C and D the horizontal lines indicate the median levels in each group, whereas the numbers in boxes indicate the percentages of individuals with decreased ApoCell-phagocytosis, as defined by the presence of ApoCell-PhI values that were two standard deviations below the corresponding mean of HBD. Statistically significant comparisons of patient groups to HBD are shown. In panel B, the mean ApoCell-PhI values of SS-derived MDM were marginally different compared to MDM (p = 0.06).
Mentions: The study of ApoCell-phagocytosis had yielded similar results between RA patients and HBD, but significantly decreased ApoCell-PhI values in both SS and SLE patient groups, compared to HBD (p = 0.0002 and p<0.0001, respectively) and to RA patients (p = 0.0009 and p = 0.0004, respectively) (Figure 1A). Conversely, ApoCell-PhI values were not statistically different between SS and SLE patients. Decreased ApoCell-phagocytosis was observed in approximately half of SS and SLE patients, compared to none of RA patients studied (Figure 1A).

Bottom Line: Compared to HBD, approximately half of SS and SLE patients studied (but not RA) manifested significantly reduced ApoCell-phagocytosis (p<0.001) and MB-phagocytosis (p<0.003) by blood-borne phagocytes that correlated inversely with disease activity (p≤0.004).In cross-admixture assays, healthy monocytes showed significantly reduced ApoCell-phagocytosis when fed with apoptotic cells that were pretreated with sera or purified serum IgG preparations from SS and SLE patients (p<0.0001, compared to those from HBD or RA).Such aberrant effect of the SS and SLE sera and IgG preparations correlated linearly with their content of IgG antibodies against apoptotic cells (p≤0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece; Hellenic Pasteur Institute, Athens, Greece.

ABSTRACT

Objectives: Deficient efferocytosis (i.e. phagocytic clearance of apoptotic cells) has been frequently reported in systemic lupus erythematosus (SLE). Todate, patients with primary Sjögren's syndrome (SS) have not been assessed for phagocytosis of apoptotic cells (ApoCell-phagocytosis) and of particulate targets (microbeads, MB-phagocytosis).

Design: ApoCell-phagocytosis and MB-phagocytosis were comparatively assessed by flow cytometry in peripheral blood specimens and monocyte-derived macrophage (MDM) preparations from healthy blood donors (HBD) and consecutive SS, SLE and rheumatoid arthritis (RA) patients. Cross-admixture ApoCell-phagocytosis experiments were also performed using phagocytes from HBD or patients, and apoptotic cells pretreated with whole sera or purified serum IgG derived from patients or HBD.

Results: Compared to HBD, approximately half of SS and SLE patients studied (but not RA) manifested significantly reduced ApoCell-phagocytosis (p<0.001) and MB-phagocytosis (p<0.003) by blood-borne phagocytes that correlated inversely with disease activity (p≤0.004). In cross-admixture assays, healthy monocytes showed significantly reduced ApoCell-phagocytosis when fed with apoptotic cells that were pretreated with sera or purified serum IgG preparations from SS and SLE patients (p<0.0001, compared to those from HBD or RA). Such aberrant effect of the SS and SLE sera and IgG preparations correlated linearly with their content of IgG antibodies against apoptotic cells (p≤0.0001). Phagocytic dysfunction maybe also present in certain SS and SLE patients, as supported by deficient capacity of MDM for ApoCell-phagocytosis and MB-phagocytosis under patients' serum-free conditions.

Conclusion: Similarly to SLE, efferocytosis is frequently impaired in SS and is primarily due to the presence of inhibitory IgG anti-ApoCell antibodies and secondarily to phagocytes' dysfunction.

Show MeSH
Related in: MedlinePlus