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Inflammatory Markers of the Systemic Capillary Leak Syndrome (Clarkson Disease).

Xie Z, Chan E, Yin Y, Ghosh CC, Wisch L, Nelson C, Young M, Parikh SM, Druey KM - J Clin Cell Immunol (2014)

Bottom Line: We analyzed serum cytokines in a cohort of 35 patients with an established diagnosis of SCLS and characterized the effects of SCLS sera on endothelial cell function.Several cytokines were elevated in acute SCLS sera compared to baseline or sera from healthy controls, including CXCL10, CCL2, IL-1β, IL-6, IL-8, IL-12 and TNFα.The majority of acute sera failed to activate endothelial cells as assessed by surface adhesion marker expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, MD, USA.

ABSTRACT

Objectives: The Systemic Capillary Leak Syndrome (SCLS) is a rare and potentially fatal disorder resembling systemic anaphylaxis that is characterized by transient episodes of hypotensive shock and peripheral edema. The pathogenesis of SCLS is unknown, and triggers for attacks are apparent only in a minority of patients. We introduce a clinical algorithm for the diagnosis of SCLS, and we investigated potential serum biomarkers of acute SCLS episodes.

Methods: We analyzed serum cytokines in a cohort of 35 patients with an established diagnosis of SCLS and characterized the effects of SCLS sera on endothelial cell function. We investigated the cellular source(s) of CXCL10, a chemokine that was significantly elevated in both basal and acute SCLS sera, by flow cytometry.

Results: Several cytokines were elevated in acute SCLS sera compared to baseline or sera from healthy controls, including CXCL10, CCL2, IL-1β, IL-6, IL-8, IL-12 and TNFα. The majority of acute sera failed to activate endothelial cells as assessed by surface adhesion marker expression. Monocytes appear to be the major source of serum CXCL10, and the percentage of CXLC10+ monocytes in response to IFNγ stimulation was increased in SCLS subjects compared to controls.

Conclusions: The presence of proinflammatory cytokines in acute SCLS sera suggests that inflammation or infection may have a role in triggering episodes. The enhanced capacity of monocytes from SCLS patients to produce CXCL10 suggests a new therapeutic avenue for SCLS.

No MeSH data available.


Related in: MedlinePlus

Endothelial surface activation marker expression induced by SCLS sera. HUVECs were incubated with 10% (vol/vol) test sera for 4 hours (A–B) or 24 hours (C) at 37°C. (A) Surface expression of E-selectin, VCAM-1 and ICAM-1 was evaluated by flow cytometry. The dotted lines represent adhesion molecule expression induced by TNFα (1.25 ng/ml). (B) Paired comparisons of E-selectin, VCAM-1 and ICAM-1 expression induced by basal and episodic sera from each individual subject. (C) CXCL10 in HUVEC culture supernatants was measured by ELISA.
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Figure 3: Endothelial surface activation marker expression induced by SCLS sera. HUVECs were incubated with 10% (vol/vol) test sera for 4 hours (A–B) or 24 hours (C) at 37°C. (A) Surface expression of E-selectin, VCAM-1 and ICAM-1 was evaluated by flow cytometry. The dotted lines represent adhesion molecule expression induced by TNFα (1.25 ng/ml). (B) Paired comparisons of E-selectin, VCAM-1 and ICAM-1 expression induced by basal and episodic sera from each individual subject. (C) CXCL10 in HUVEC culture supernatants was measured by ELISA.

Mentions: Skin biopsies of SCLS patients have revealed the presence of perivascular leukocytic inflammation during acute episodes in some cases [11]. Proinflammatory cytokines including TNFα and IL-8 have been shown to increase adhesion molecule surface expression on endothelial cells, which in turn promotes leukocyte rolling, migration and extravasation [12]. To determine whether factors in SCLS sera could evoke endothelial barrier dysregulation by inducing leukocyte adhesion, we incubated HUVECs with acute and baseline sera from SCLS subjects or healthy donors and analyzed surface expression of E-selectin, VCAM-1 and ICAM-1 by flow cytometry. Unexpectedly, among the SCLS sera tested (20 baseline and 13 acute) only Pt. 3’s episodic serum induced upregulation of these adhesion molecules in HUVECs (Figure 3A–B). Surface expression of these markers induced by Pt. 3’s episodic sera was comparable to that evoked by TNFα (Figure 3A, dotted line) [13], a well-known endothelial activator that served as positive control for these experiments. The concentration of TNFα in Pt. 3’ episodic serum (top square dot in Figure 2G) is comparable to that used in control experiments, 20-fold higher than that found in most of other SCLS sera (Figure 2G). These results and the unresponsiveness of HUVECs to acute SCLS serum samples containing low levels of TNFα suggest that TNFα is probably the cytokine that mediated endothelial adhesion/activation marker upregulation in Pt. 3’s episodic sera. Since endothelial cells have the capacity to produce CXCL10 in response to inflammatory stimuli [14], we examined whether they produced CXCL10 following treatment with SCLS sera. We incubated HUVECs with acute or baseline sera from healthy controls or subjects with SCLS for 24 hours and measured CXCL10 in culture supernatants. TNFα plus IFNγ served as a positive control, as described in previous work [14,15]. None of the SCLS sera tested elicited CXCL10 secretion from HUVECs (Figure 3C). Taking together, these results suggested that in classic SCLS, endothelium is probably not the major source of CXCL10.


Inflammatory Markers of the Systemic Capillary Leak Syndrome (Clarkson Disease).

Xie Z, Chan E, Yin Y, Ghosh CC, Wisch L, Nelson C, Young M, Parikh SM, Druey KM - J Clin Cell Immunol (2014)

Endothelial surface activation marker expression induced by SCLS sera. HUVECs were incubated with 10% (vol/vol) test sera for 4 hours (A–B) or 24 hours (C) at 37°C. (A) Surface expression of E-selectin, VCAM-1 and ICAM-1 was evaluated by flow cytometry. The dotted lines represent adhesion molecule expression induced by TNFα (1.25 ng/ml). (B) Paired comparisons of E-selectin, VCAM-1 and ICAM-1 expression induced by basal and episodic sera from each individual subject. (C) CXCL10 in HUVEC culture supernatants was measured by ELISA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232957&req=5

Figure 3: Endothelial surface activation marker expression induced by SCLS sera. HUVECs were incubated with 10% (vol/vol) test sera for 4 hours (A–B) or 24 hours (C) at 37°C. (A) Surface expression of E-selectin, VCAM-1 and ICAM-1 was evaluated by flow cytometry. The dotted lines represent adhesion molecule expression induced by TNFα (1.25 ng/ml). (B) Paired comparisons of E-selectin, VCAM-1 and ICAM-1 expression induced by basal and episodic sera from each individual subject. (C) CXCL10 in HUVEC culture supernatants was measured by ELISA.
Mentions: Skin biopsies of SCLS patients have revealed the presence of perivascular leukocytic inflammation during acute episodes in some cases [11]. Proinflammatory cytokines including TNFα and IL-8 have been shown to increase adhesion molecule surface expression on endothelial cells, which in turn promotes leukocyte rolling, migration and extravasation [12]. To determine whether factors in SCLS sera could evoke endothelial barrier dysregulation by inducing leukocyte adhesion, we incubated HUVECs with acute and baseline sera from SCLS subjects or healthy donors and analyzed surface expression of E-selectin, VCAM-1 and ICAM-1 by flow cytometry. Unexpectedly, among the SCLS sera tested (20 baseline and 13 acute) only Pt. 3’s episodic serum induced upregulation of these adhesion molecules in HUVECs (Figure 3A–B). Surface expression of these markers induced by Pt. 3’s episodic sera was comparable to that evoked by TNFα (Figure 3A, dotted line) [13], a well-known endothelial activator that served as positive control for these experiments. The concentration of TNFα in Pt. 3’ episodic serum (top square dot in Figure 2G) is comparable to that used in control experiments, 20-fold higher than that found in most of other SCLS sera (Figure 2G). These results and the unresponsiveness of HUVECs to acute SCLS serum samples containing low levels of TNFα suggest that TNFα is probably the cytokine that mediated endothelial adhesion/activation marker upregulation in Pt. 3’s episodic sera. Since endothelial cells have the capacity to produce CXCL10 in response to inflammatory stimuli [14], we examined whether they produced CXCL10 following treatment with SCLS sera. We incubated HUVECs with acute or baseline sera from healthy controls or subjects with SCLS for 24 hours and measured CXCL10 in culture supernatants. TNFα plus IFNγ served as a positive control, as described in previous work [14,15]. None of the SCLS sera tested elicited CXCL10 secretion from HUVECs (Figure 3C). Taking together, these results suggested that in classic SCLS, endothelium is probably not the major source of CXCL10.

Bottom Line: We analyzed serum cytokines in a cohort of 35 patients with an established diagnosis of SCLS and characterized the effects of SCLS sera on endothelial cell function.Several cytokines were elevated in acute SCLS sera compared to baseline or sera from healthy controls, including CXCL10, CCL2, IL-1β, IL-6, IL-8, IL-12 and TNFα.The majority of acute sera failed to activate endothelial cells as assessed by surface adhesion marker expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, MD, USA.

ABSTRACT

Objectives: The Systemic Capillary Leak Syndrome (SCLS) is a rare and potentially fatal disorder resembling systemic anaphylaxis that is characterized by transient episodes of hypotensive shock and peripheral edema. The pathogenesis of SCLS is unknown, and triggers for attacks are apparent only in a minority of patients. We introduce a clinical algorithm for the diagnosis of SCLS, and we investigated potential serum biomarkers of acute SCLS episodes.

Methods: We analyzed serum cytokines in a cohort of 35 patients with an established diagnosis of SCLS and characterized the effects of SCLS sera on endothelial cell function. We investigated the cellular source(s) of CXCL10, a chemokine that was significantly elevated in both basal and acute SCLS sera, by flow cytometry.

Results: Several cytokines were elevated in acute SCLS sera compared to baseline or sera from healthy controls, including CXCL10, CCL2, IL-1β, IL-6, IL-8, IL-12 and TNFα. The majority of acute sera failed to activate endothelial cells as assessed by surface adhesion marker expression. Monocytes appear to be the major source of serum CXCL10, and the percentage of CXLC10+ monocytes in response to IFNγ stimulation was increased in SCLS subjects compared to controls.

Conclusions: The presence of proinflammatory cytokines in acute SCLS sera suggests that inflammation or infection may have a role in triggering episodes. The enhanced capacity of monocytes from SCLS patients to produce CXCL10 suggests a new therapeutic avenue for SCLS.

No MeSH data available.


Related in: MedlinePlus