Background/Purpose:

Toll-like receptors (TLR) are a major class of pathogen detectors in the cell that can trigger the innate defense and lead to activation of immunocompetent cells. Endosomal TLR have been recently associated to the pathogenesis of SLE and to the production of autoantibodies. In this study we have explored associations between TLR and disease phenotypes, which could help us understand pathogenesis and find biomarkers in specific subgroups of patients.

Methods:

Thirty four patients diagnosed with lupus and 12 matched healthy controls were recruited. Patients had stable treatment during the last 4 weeks prior to recruitment. Cumulative features, and serologic markers were registered. Selena-SLEDAI and BILAG scales were employed to measure disease activity. The distribution of peripheral blood mononuclear cells (PBMC) subpopulations and their expression of TLR2, TLR4, TLR3, TLR7, and TLR9 were analyzed in patients and controls with flow cytometry. Statistics were carried out with Spearman’s correlation and Mann Whitney tests for independent samples, setting significance at 95%. The relationship between dual variables was assessed with contingency tables and Fisher’s exact test, setting significance at 99%.

Results:

The appearance of TLR3, TLR7, and TLR9 in lymphoplasmocytoid (CD19lp) cells was higher in SLE than in healthy controls. The presence of TLR3 in CD19 cells (n = 9) was associated to active disease (p 0.006), hypocomplementemia ( p 0.002), and SLEDAI and BILAG scores (p 0.018, p 0.012). SLEDAI scores were also higher in patients with TLR9 expression in CD19 cells (n= 14, p 0.044). The percentage of CD19lp cells expressing TLR3, and TLR9 increased with SLEDAI scores (rho 0.401, p 0.021; and rho 0.403, p 0.02,respectively), but not with other activity measures.

Subgroups of patients with TLR2 expression in CD3+ cells (n = 5) or in CD19+ cells (n = 6) displayed higher activity as reflected by SLEDAI (p 0.05, p 0.015) and BILAG (p 0.005, p 0.004) scores. Patients with TLR4 in CD3+ cells (n = 5) or in CD19+ cells (n = 6), showed higher SLEDAI scores (p 0.05, p 0.045), while presence of TLR4 in CD19+ and in monocytes (n = 5) were associated to higher BILAG scores (p 0.004, p 0.005). Serological markers of activity were also found more frequently in patients showing expression of TLR2 or TLR4 in PBMC. Furthermore, the appearance of TLR2 or TLR4 in CD19+ cells, CD3+ cells or monocytes was associated with renal disease and with major organ involvement. Interestingly, patients with positive past history for bacterial or viral infections more often showed TLR2 and TLR4 in CD3 and CD19+ cells, and TLR4 in monocytes (CI 99%).

Conclusion:

Endosomal TLR were found significantly enhanced in patients with lupus compared to controls, and TLR3 and TLR9 expression by CDlp cells could be used as a biomarker of disease activity. However, the induction of TLR2 and TLR4 in different PBMC subsets identified a subgroup of patients with high activity, whom frequently displayed major organ involvement. Our data suggest that there could be a subgroup of patients with lupus, in whom exposure to germs could sensitize immunocompetent cells, and facilitate their activation during flares.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/both-endosomal-and-surface-toll-like-receptors-can-act-as-biomarkers-in-lupus/