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Background Recent evidences have suggested the involvement of toll-like receptor (TLR)-4 in the pathogenesis of cerebral cavernous malformations (CCM). Elevated frequency of TLR + T-cells has been associated with neurological inflammatory disorders. As T-cells and B-cells are found in CCM lesions, the objective of the present study was to evaluate the cytokine profile of T-cells expressing TLR2 and TLR4, as well as B-cell subsets, in asymptomatic (CCM Asympt ) and symptomatic (CCM Sympt ) patients. Methods For our study, the cytokine profile from TLR2 +  and TLR4 +  T-cell and B-cell subsets in CCM Asympt  and CCM Sympt  patients was investigated using flow cytometry and ELISA. T-cells were stimulated in vitro with anti-CD3/anti-CD28 beads or TLR2 (Pam3C) and TLR4 (LPS) ligands. Results CCM Symptc  patients presented a higher frequency of TLR4 + (CD4 +  and CD8 + ) T-cells and greater density of TLR4 expression on these cells. With regard to the cytokine profile, the percentage of TLR2 +  and TLR4 +  Th17 cells was higher in CCM Sympt  patients. In addition, an elevated proportion of TLR4 +  Tc-1 cells, as well as Tc-17 and Th17.1 cells expressing TLR2 and TLR4, was observed in the symptomatic patients. By contrast, the percentage of TLR4 +  IL-10 + CD4 +  T cells was higher in the CCM Asympt  group. Both Pam3C and LPS were more able to elevate the frequency of IL-6 + CD4 + T cells and Th17.1 cells in CCM Sympt  cell cultures. Furthermore, in comparison with asymptomatic patients, purified T-cells from the CCM Sympt  group released higher levels of Th17-related cytokines in response to Pam3C and, mainly, LPS, as well as after activation via TCR/CD28. Concerning the B-cell subsets, a higher frequency of memory and memory activated B-cells was observed in CCM Sympt  patients. Conclusions Our findings reveal an increase in circulating Th17/Tc-17 cell subsets expressing functional TLR2 and, mainly, TLR4 molecules, associated with an increase in memory B-cell subsets in CCM patients with clinical activity of the disease.

journal of neuroinflammation

Elevated proportion of TLR2- and TLR4-expressing Th17-like cells and activated memory B cells was associated with clinical activity of cerebral cavernous malformations