Common Autoantibody among Takayasu Arteritis and Ulcerative Colitis: A Possible Pathophysiology That Includes Gut-Vessel Connection in Vascular Inflammation

Abstract

Takayasu arteritis (TAK) is a type of large-vessel vasculitis that predominantly affects young females. The precise pathomechanism of TAK is still under investigation. In TAK, the vasa vasorum is considered to be the initial inflammatory site. Disruption of the vasa vasorum induces the entry of inflammatory cells into the vascular wall of large vessels between the media and adventitia, and infiltrated cells damage the vascular components, eventually leading to stenosis or dilatation of the affected arteries. In addition, T cells are considered key players in TAK, and myeloid cells function as effector cells. Although the roles of B cells in TAK are poorly understood, recent evidence supports their contribution to the pathogenicity of TAK. Particularly, two autoantibodies have been identified in TAK through investigation of anti-endothelial cell antibodies, and they could be involved in the maintenance of vascular inflammation. Furthermore, one of the autoantibodies, anti-endothelial protein C receptor, was shown to be present in ulcerative colitis (UC), which is genetically and clinically associated with TAK. Similar autoantibodies in inflammatory diseases with different target organs indicate a common underlying pathophysiology of these diseases, which could be characterized by the aberrant activation of B cells. This review discusses recent understanding of the pathomechanisms of TAK and UC, with a focus on the involvement of B cells and autoantibodies. The close association of UC with TAK further suggests a common etiology, and the importance of the intestinal microbiota, including dysbiosis, is also becoming known in TAK. Investigation of such common factors among TAK and UC would improve understanding of the interplay between gut and vascular inflammation, which is a new concept for developing vascular inflammation through the gut-vessel connection.

Keywords: B-cell; Takayasu arteritis; autoantibody; endothelial protein C receptor; ulcerative colitis.

Figure 1.

Suggested pathophysiology in Takayasu arteritis Inflammation begins around the vasa vasorum, and the involvement of heat-shock protein 65 and MHC Class I chain-related A has been suggested. Although the first inflammatory process is unproven, cytotoxic activity by CD8+ T cells, γδ T cells, and natural killer cells, or the activation of dendritic cells (DC) and subsequent recruitment of immune cells by chemokines, seems to be the initial step. The recent discovery of anti-EPCR autoantibodies (Ab) and anti-SR-BI Ab suggests their roles in endothelial cell (EC) activation. Furthermore, anti-EC Ab (AECA) induces cytotoxicity, cytokine production, apoptosis, and mTOR pathway activation in EC. Subsequently, the recruited immune cells are activated. The activation of Th1 cells together with IL-12 and IL-18 secreted from DC releases tumor necrosis factor α and interferon γ, which activate macrophages, giant cells, and EC. The differentiation of Th17 cells is induced by IL-23, which is secreted by DC and macrophages. Anti-EPCR antibodies also promote Th17 cell differentiation, and Th17 cells promote neutrophil recruitment. Monocytes differentiate into macrophages and perform multiple effector functions. One of their functions is to promote inflammation by secreting chemokines, cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). They also produce matrix metalloproteinase (MMP), which damages vascular components, and vascular endothelial growth factor (VEGF), which promotes neovascularization and subsequent inflammatory cell recruitment. Monocytes form granulomas together with neutrophils and T cells, and multinucleated giant cells are formed. Such inflammation disrupts the elastic lamellae, which contributes to artery dilatation. Giant cells and macrophages also produce growth factors, including platelet-derived growth factors and fibroblast growth factor-2 (FGF2), which trigger the migration of vascular smooth muscle cells into the intima, promote intimal proliferation of myofibroblasts, and produce matrix proteins, both of which contribute to artery stenosis. Tertiary lymphoid organs (TLOs) are formed in the adventitia, consisting of B cells, follicular dendritic cells (FDC), and high endothelial venules (HEV). Follicular helper T cells (Tfh) promote the maturation of B cells, and inflammation results in fibrous thickening and scarring of the adventitia. Ab, autoantibody; AECA, anti-endothelial cell antibody; DC, dendritic cell; EC, endothelial cell; EPCR, endothelial protein C receptor; FDC, follicular dendritic cells; HEV, high endothelial venule; IL, interleukin; IFN-γ, interferon γ; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; RNI, reactive nitrogen intermediates; ROS, reactive oxygen species; SR-BI, scavenger receptor class B type 1; T, T cells; Tfh, follicular helper T cells; TLO, tertiary lymphoid organ; TNFα, tumor necrosis factor α; VEGF, vascular endothelial growth factor.

Figure 2.

Comparison between Takayasu arteritis and ulcerative colitis: a possible role of gut-vessel connection in vascular inflammation Takayasu arteritis and ulcerative colitis sometimes coexist and share genetic risks and comorbidities. Although different antibodies appear, anti-EPCR autoantibodies are present in both diseases, and B-cell dysregulation is increasingly known. Dysbiosis is a critical pathogenesis in ulcerative colitis and is related to the dysregulation of intestinal immunity and, subsequently, B cells. Dysbiosis is also present in Takayasu arteritis, and such common features of ulcerative colitis suggest a relationship between dysbiosis and immune dysregulation in Takayasu arteritis. Ab, antibody; ANCA, anti-neutrophil cytoplasmic antibody; EPCR, endothelial protein C receptor; HLA, human leukocyte antigen; PR3, proteinase 3.