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Stimulation of the co-inhibitory BTLA pathway protects against atherosclerosis by selectively reducing atherogenic B cells
B-and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which was identified as a marker for Th1 cells. However, nowadays it is known that BTLA is most abundantly expressed on B cells. Also, we showed earlier that BTLA was specifically expressed on atherogenic follicular B2 cells with low expression on other B cell subtypes. Since it has been shown that stimulating co-inhibitory pathways can greatly influence atherosclerosis, we aimed to induce BTLA signaling in diet-induced atherosclerosis.
For the initiaton study, LDLR-/- mice were fed a western type diet (WTD) for...
Show moreB-and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which was identified as a marker for Th1 cells. However, nowadays it is known that BTLA is most abundantly expressed on B cells. Also, we showed earlier that BTLA was specifically expressed on atherogenic follicular B2 cells with low expression on other B cell subtypes. Since it has been shown that stimulating co-inhibitory pathways can greatly influence atherosclerosis, we aimed to induce BTLA signaling in diet-induced atherosclerosis.
For the initiaton study, LDLR-/- mice were fed a western type diet (WTD) for 6 weeks and received twice a week i.p. injections with an agonistic BTLA antibody. Mice in the control groups either received PBS or an isotype control antibody. For the progression study, mice were first fed a WTD for 10 weeks after which they received the same treatment as in the initiation experiment.
Lesion development in mice receiving the agonistic BTLA antibody was significantly lower than in mice treated with PBS (PBS:2.6±0.8x105 μm2 vs. BTLA:1.5±0.8x105 μm2; p<0.05). A similar trend was observed in mice treated with the isotype control (Isotype: 2.4±0.9x105 μm2 vs. BTLA; p=0.07). This corresponded with a major decrease in circulating (PBS: 44.2±4.9%, Isotype: 50.6±5.8% vs. BTLA: 24.5±12.0%; p<0.0001) and splenic CD19+ B cells (PBS:29.1±4.2%, Isotype:30.8.±3.6% vs. BTLA:21.1±7.4%; p<0.01 and p<0.001). The antibody specifically targeted atherogenic follicular B2 cells (picture), while atheroprotective B cells (marginal zone, B1 and B10) were all increased compared to mice receiving PBS or the isotype antibody. Although the BTLA antibody did not reduce already established lesions, it signficantly increased the collagen content, indicating a more stable lesion phenotype.
In conclusion, stimulation of the BTLA pathway in experimental atherosclerosis in LDLR-/- mice reduces lesion development and increases stability of established lesions, presumably by specifically inhibiting atherogenic B cells, while leaving atheroprotective B cell subsets unaffected.
- All authors
- Douna, H.; Amersfoort, J.; Schaftenaar, F.H.; Puijvelde, G.H.M. van; Kuiper, J.; Foks, A.C.
- Date
- 2018-06-30
- Volume
- 32
- Pages
- 89 - 89