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T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?

Wilde B, Thewissen M, Damoiseaux J, van Paassen P, Witzke O, Tervaert JW - Arthritis Res. Ther. (2010)

Bottom Line: Circulating effector T-cell populations are expanded and are in a persistent state of activation.Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response.Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Division of Clinical and Experimental Immunology, University Hospital Maastricht, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht The Netherlands. benjamin.wilde@immuno.unimaas.nl.

ABSTRACT
Anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T cells are also involved in disease pathogenesis. This review stresses the hallmarks of T cell-mediated pathology in AAV and highlights the characteristics of lesional and circulating T cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T cells are present in granulomas, vasculitic lesions, and nephritis. Lesional T cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response. Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV.

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Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis [87]. We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.
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Figure 1: Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis [87]. We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.

Mentions: Two major subsets of T cells are thought to dominate the adaptive T-cell immune response: regulatory T cells (Tregs) and CD4+ effector T cells (Teffs). Tregs limit and regulate the immune response, whereas Teffs are 'executors' controlled by Tregs. If this control is not regulated properly, excessive immune responses and loss of self-tolerance will follow (Figure 1). According to this concept, Treg and Teff subsets are the focus of research in AAV. Indeed, numerous reports have confirmed an expanded circulating CD4+CD25+ T-cell population in AAV [4,11-13]. This T-cell subset usually contains activated Teffs as well as Tregs [14] (Table 1).


T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?

Wilde B, Thewissen M, Damoiseaux J, van Paassen P, Witzke O, Tervaert JW - Arthritis Res. Ther. (2010)

Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis [87]. We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2875650&req=5

Figure 1: Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis [87]. We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.
Mentions: Two major subsets of T cells are thought to dominate the adaptive T-cell immune response: regulatory T cells (Tregs) and CD4+ effector T cells (Teffs). Tregs limit and regulate the immune response, whereas Teffs are 'executors' controlled by Tregs. If this control is not regulated properly, excessive immune responses and loss of self-tolerance will follow (Figure 1). According to this concept, Treg and Teff subsets are the focus of research in AAV. Indeed, numerous reports have confirmed an expanded circulating CD4+CD25+ T-cell population in AAV [4,11-13]. This T-cell subset usually contains activated Teffs as well as Tregs [14] (Table 1).

Bottom Line: Circulating effector T-cell populations are expanded and are in a persistent state of activation.Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response.Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine, Division of Clinical and Experimental Immunology, University Hospital Maastricht, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht The Netherlands. benjamin.wilde@immuno.unimaas.nl.

ABSTRACT
Anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T cells are also involved in disease pathogenesis. This review stresses the hallmarks of T cell-mediated pathology in AAV and highlights the characteristics of lesional and circulating T cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T cells are present in granulomas, vasculitic lesions, and nephritis. Lesional T cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response. Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV.

Show MeSH
Related in: MedlinePlus