Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis

Falk Weih,Rolf Gräbner,Andreas J R Habenicht,Michael Beer,Desheng Hu

doi:10.3389/fphys.2012.00226

Falk Weih, Rolf Gräbner + Show 3 more

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https://doi.org/10.3389/fphys.2012.00226

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Journal: Frontiers in Physiology	Publication Date: Jan 1, 2012
Citations: 76	License type: cc-by

Affiliation: Universitätsklinikum Erlangen

Abstract

Tertiary lymphoid organs (TLOs) emerge in tissues in response to non-resolving inflammation such as chronic infection, graft rejection, and autoimmune disease. We identified artery TLOs (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE−/− mice. ATLOs are structured into T cell areas harboring conventional dendritic cells and monocyte-derived DCs; B cell follicles containing follicular dendritic cells within activated germinal centers; and peripheral niches of plasma cells. ATLOs also show extensive neoangiogenesis, aberrant lymphangiogenesis, and high endothelial venule (HEV) neogenesis. Newly formed conduit networks connect the external lamina of the artery with HEVs in T cell areas. ATLOs recruit and generate lymphocyte subsets with opposing activities including activated CD4+ and CD8+ effector T cells, natural and induced CD4+ T regulatory (nTregs; iTregs) cells as well as B-1 and B-2 cells at different stages of differentiation. These data indicate that ATLOs organize dichotomic innate and adaptive immune responses in atherosclerosis. In this review we discuss the novel concept that dichotomic immune responses toward atherosclerosis-specific antigens are carried out by ATLOs in the adventitia of the arterial wall and that malfunction of the tolerogenic arm of ATLO immunity triggers transition from silent autoimmune reactivity to clinically overt disease.

Highlights

We identified artery Tertiary lymphoid organs (TLOs) (ATLOs) in the adventitia adjacent to atherosclerotic plaques of aged hyperlipidemic ApoE −/− mice
ATLOs are structured into T cell areas harboring conventional dendritic cells and monocyte-derived DCs; B cell follicles containing follicular dendritic cells within activated germinal centers; and peripheral niches of plasma cells
Immune complexes with unprocessed antigen can gain access to TLOs where they bind to FDCs within germinal centers (GCs) at higher concentrations compared to FDCs in the more distant secondary lymphoid organs (SLOs) (Kratz et al, 1996; Mackay and Browning, 1998; Stott et al, 1998; Kim et al, 1999; Luther et al, 2000; Weyand et al, 2001; Itano and Jenkins, 2003; Kosco-Vilbois, 2003; Moyron-Quiroz et al, 2004; Allen et al, 2007; Lee et al, 2007; Timmer et al, 2007; Lund and Randall, 2010; Sweet et al, 2011)

Summary

Introduction

TLOs ARISE IN CHRONIC NON-RESOLVING INFLAMMATION OF PERIPHERAL TISSUES The immune system aims at identification and destruction of foreign antigens while preserving self (Shlomchik et al, 2001; Cyster, 2003; Drayton et al, 2003, 2006; Gommerman and Browning, 2003; Cupedo et al, 2004; Browning et al, 2005; Aloisi and PujolBorrell, 2006; Browning, 2006; Goodnow, 2007; Carragher et al, 2008; Shlomchik, 2008, 2009). There is evidence from human autoimmune diseases indicating that TLOs mount specific T and B cell immune responses toward self-antigens (Fütterer et al, 1998; Kim et al, 1999; Ettinger et al, 2001; Gommerman and Browning, 2003; Cupedo et al, 2004; Browning, 2006; Lee et al, 2006), major issues of their formation and functional impact on disease progression remain to be explored: (i) How do innate immune cells, i.e., activated monocytes/macrophages, neutrophils, mast cells, DCs, and lymphoid tissue inducer cells prompt adaptive immune responses within the target tissue (Tellides et al, 2000; Lopez-Diego and Weiner, 2008)?

Results

Conclusion