Background/Purpose: The transglutaminase Factor XIII (FXIII) stabilizes blood clots through crosslinking fibrin lysine and glutamine residues at the end of the complement cascade. Enzymatic activity and plasma levels of FXIII appear to be tightly controlled, as excess FXIII can lead to increased arterial plaque, yet low or absent FXIII leads to thrombosis due to fibrin instability. In addition, recent data suggest that tissue macrophages could be the main source of plasma FXIII. Anti-FXIII antibodies have been observed in SLE and correlate with brain hemorrhage, although other clinical correlations between plasma FXIII and SLE remain unexplored.

Methods: 120 SLE patients were recruited from a pre-existing longitudinal cohort developed to study atherosclerosis in SLE. Anti-dsDNA, C3 and C4 levels were analyzed in the clinical lab of our university hospital. Carotid ultrasound was performed to determine the presence or absence of subclinical atherosclerosis and intima-media thickness (IMT). The Technochrom FXIII kit (Diapharma, West Chester, OH) was utilized to determine plasma FXIII transglutaminase activity. Plasma monocyte subpopulations were identified by flow cytometry using anti-CD14 and –CD16 fluorescent antibodies (Biolegend).

Results: 66/120 SLE patients had high plasma FXIII transglutaminase activity (>143% of the mean of the standard curve). SLEDAI was significantly lower in the high FXIII activity group compared to patients with normal FXIII activity (2.08±3.9 versus 4.2±3.1, p=0.006). In addition, anti-dsDNA antibody levels were significantly lower in the high FXIII activity group (87.5±255.7 versus 274.7±323.8, p=0.041). Significantly higher levels of plasma C3 and C4 levels were also observed in the high FXIII activity group. Taken together, these results show that higher FXIII activity might be a biomarker for lower SLE disease activity.

In contrast, percentages of CD14⁺CD16^int and CD14⁺CD16^hi plasma monocytes (considered precursors to anti-inflammatory ‘M2” macrophages) were inversely proportional to FXIII activity (r=-0.54, p=0.008; r=-.064, p=0.005, respectively), although there was no correlation between classical plasma monocyte levels (CD14⁺CD16^–, ‘M1’ macrophage precursors) and FXIII enzymatic activity. In addition, IMT positively correlated with FXIII activity (r=0.40, p=0.01). No correlations between carotid plaque presence and FXIII activity were noted.

Conclusion: High plasma FXIII transglutaminase activity correlates with multiple measures of low disease activity in SLE patients. Conversely, high FXIII activity inversely correlated with low numbers of anti-inflammatory monocytes. Higher IMT was also observed in patients with high FXIII activity. Careful regulation of FXIII enzymatic activity, and, by extension, its crucial role in fibrin crosslinking and plaque stabilization, could be dysregulated in a subset of SLE patients at risk for accelerated atherosclerosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-plasma-factor-xiii-transglutaminase-activity-inversely-correlates-with-sle-disease-activity-yet-associates-with-higher-carotid-artery-imt-and-low-cd14cd16-monocyte-levels/