The roles of immune cells in Behçet's disease

Hu, Dan; Guan, Jian-Long

doi:10.1186/s42358-023-00328-w

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Sumário

Review • Adv. rheumatol. 63 • 2023 • https://doi.org/10.1186/s42358-023-00328-w copy

The roles of immune cells in Behçet's disease

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Behçet's disease (BD) is a systemic vasculitis that can affect multiple systems, including the skin, mucous membranes, joints, eyes, gastrointestinal and nervous. However, the pathogenesis of BD remains unclear, and it is believed that immune-inflammatory reactions play a crucial role in its development. Immune cells are a critical component of this process and contribute to the onset and progression of BD. By regulating the function of these immune cells, effective control over the occurrence and development of BD can be achieved, particularly with regards to monocyte activation and aggregation, macrophage differentiation and polarization, as well as T cell subset differentiation. This review provides a brief overview of immune cells and their role in regulating BD progression, which may serve as a theoretical foundation for preventing and treating this disease.

Keywords
Behçet's disease; Immune cells; Macrophages; Monocytes; Neutrophils; NK cells; T cells

Cells	Cytokines	biological relevance and functional impact	References
Monocytes	TNF-a	Classical monocytes in patients with BD can promote TNF-a production and promote Th1 differentiation.	[¹⁰10 Li C, Liu J, Yu X, et al. Aberrant monocyte subsets in patients with Behçet's disease. Clin Immunol. 2021;225:108683.]
	sCD14	sCD14 increased the adhesion of normal neutrophils to the monolayer of endothelial cells.	[¹²12 Sahin S, Lawrence R, Direskeneli H, et al. Monocyte activity in Behçet's disease. Br J Rheumatol. 1996;35(5):424–9.]
	TLR2	Monocytes may produce neutrophil-stimulated proinflammatory factors through TLR2 that play a role in BD.	[¹⁴14 Neves FS, Carrasco S, Goldenstein-Schainberg C, et al. Neutrophil hyper-chemotaxis in Behçet's disease: a possible role for monocytes orchestrating bacterial-induced innate immune responses. Clin Rheumatol. 2009;28(12):1403–10.]
	VEGF, MCP-1	VEGF and MCP-1 levels were significantly elevated in BD patients with thrombosis, which promoted the aggregation and adhesion of monocytes.	[²³23 Bozoglu E, Dinc A, Erdem H, et al. Vascular endothelial growth factor and monocyte chemoattractant protein-1 in Behçet's patients with venous thrombosis. Clin Exp Rheumatol. 2005;23(4 Suppl 38):42–S48.]
	FcγRIIb, FcγRIII	Low expression of FcγRIIb and high expression of FcγRIII in monocytes of BD patients may lead to overactivation of BD monocytes.	[²⁶26 Huang L, Yu X, Li L, et al. Aberrant FcγRIIb and FcγRIII expression on monocytes from patients with Behçet's disease. Clin Immunol. 2020;219:108549.]
	CXCL10	Post-transcriptional dysregulation of CXCL10 mRNA may lead to an aggravation of BD characteristic inflammatory response.	[²⁸28 Ambrose N, Khan E, Ravindran R, et al. The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway. Clin Exp Immunol. 2015;181(3):427–33.]
	P2×7r	P2×7r activation significantly increases IL-1β release from LPS-stimulated BD monocytes, and TNF-α can up-regulate the expression and function of P2×7r in monocytes.	[³⁰30 Castrichini M, Lazzerini PE, Gamberucci A, et al. The purinergic P2×7 receptor is expressed on monocytes in Behçet's disease and is modulated by TNF-α. Eur J Immunol. 2014;44(1):227–38.]
	UA	Uric acid (UA) can significantly increase the activity levels of NO, IL-1β and caspase-1 in peripheral blood monocytes of BD patients, aggravating the development of BD.	[³¹31 Chekaoui A, Belguendouz H, Lahmar K, et al. Uric acid increases IL-1β secretion and Caspase-1 activation in PBMCs of Behçet's disease patients: the in vitro immunomodulatory effect of xanthine oxidase inhibitor Allopurinol. Int Immunopharmacol. 2020;80:106119.]
Macrophages	IL-10, CCR1	BD-associated CCR1 and IL10 loci can promote polarization of M1 macrophages.	[³⁵35 Hirahara L, Takase-Minegishi K, Kirino Y, et al. The roles of Monocytes and Macrophages in Behçet's Disease with Focus on M1 and M2 polarization. Front Immunol. 2022;13:852297., ⁴³43 Nakano H, Kirino Y, Takeno M, et al. GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet's disease. Arthritis Res Ther. 2018;20(1):124.]
T cells	IL-17	Th17 cells can recruit neutrophils to the inflammatory site and mediate the hyperreactivity of BD neutrophils by secreting cytokines such as IL-17.	[⁸³83 Direskeneli H, Fujita H, Akdis CA. Regulation of TH17 and regulatory T cells in patients with Behçet disease. J Allergy Clin Immunol. 2011;128(3):665–6.]
	IL-2	Treg cells were significantly increased after IL-2 treatment, alleviating the progression of the disease.	[⁸⁷87 Liu X, Li W, Liu X, et al. Low-dose IL-2 effectively restored decreased regulatory T cells in patients with Behçet's disease. Clin Exp Rheumatol. 2021;39(4):746–52.]
	IL-21	IL-21 induced the increase of Th17 cells and the decrease of regulatory Tregs in peripheral blood of BD patients.	[⁹⁰90 Geri G, Terrier B, Rosenzwajg M, et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J Allergy Clin Immunol. 2011;128(3):655–64.]
	INF-α	The activity of NK cells in peripheral blood of patients with active BD was significantly enhanced after the addition of INF-α.	[⁵⁹59 Kaneko F, Takahashi Y, Muramatsu R, et al. Natural killer cell numbers and function in peripheral lymphoid cells in Behcet's disease. Br J Dermatol. 1985;113(3):313–8.]
NK cells	IL-17	The levels of IL-17 of CD56^dim NK cell subset in BD may play a role in neutrophilic infiltration.	[⁶¹61 Gelmez MY, Cinar S, Cetin EA, et al. Inflammatory status might direct ILC and NK cells to IL-17 expressing ILC3 and NK subsets in Behcet's disease. Immunol Lett. 2021;235:1–8.]
Neutrophils	sCD40L	BD patients release higher levels of sCD40L, which promotes neutrophil adhesion and migration. It can also stimulate a burst of neutrophil oxidation	[⁵⁰50 Jin R, Yu S, Song Z, et al. Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst. PLoS ONE. 2013;8(6):e64631., ⁵¹51 Fernández Bello I, Álvarez MT, López-Longo FJ, et al. Platelet soluble CD40L and matrix metalloproteinase 9 activity are proinflammatory mediators in Behçet disease patients. Thromb Haemost. 2012;107(1):88–98., ⁵⁴54 Perazzio SF, Soeiro-Pereira PV, Dos Santos VC, et al. Soluble CD40L is associated with increased oxidative burst and neutrophil extracellular trap release in Behçet's disease. Arthritis Res Ther. 2017;19(1):235.]

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[1] *Correspondence: Jian-Long Guan jianlong_guan@126.com