Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission

Abdulahad, Wayel H.; Stegeman, Coen A.; Geld, Ymke M. van der; Meer, Berber Doornbos-van der; Limburg, Pieter C.; Kallenberg, Cees G. M.

doi:10.1002/art.22692

Cited by 159 publications

(131 citation statements)

References 44 publications

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“…T cell responses are not suppressed by a population of antigenspecific Treg cells, unlike the effector T cells in Goodpasture's disease, a "one hit" autoimmune disease (15). Similar findings demonstrating ineffective Treg cell suppression have been obtained in patients with Wegener's granulomatosis (WG), in whom functional defects in Treg cells have been demonstrated during disease remission, despite augmented numbers of circulating CD4ϩCD25ϩ FoxP3-expressing Treg cells (27). However, unlike the Treg cells in WG patients, we found that the isolated Treg cells from MPO AAV patients were equally capable of suppressing nonspecific responses.…”

Section: Discussionmentioning

confidence: 61%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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Objective. T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO)antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness.Methods. MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed.Results. During disease remission, MPO-specific interferon-␥-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4؉CD25؉ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPOimmunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis.Conclusion. Our findings indicate that MPOspecific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.The antineutrophil cytoplasmic antibodyassociated vasculitides (AAV) are a group of relapsingremitting systemic diseases that result in considerable morbidity and mortality. Up to 25% of patients develop end-stage renal failure despite optimal immunosuppression. Understanding the immune mechanisms that regulate disease activity is critical for a more successful therapeutic approach to management of the disease. Recent work has highlighted the importance of both humoral and cellular effectors in disease pathogenesis. Pathogenic transplacental transfer of antimyeloperoxidase (anti-MPO) antibody to a neonate has been re-

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Section: Discussionmentioning

confidence: 61%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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“…Several studies have been performed on Tregs in vasculitis. In patients with Wegener's granulomatosis in remission an expanded proportion of regulatory T cells that are functionally defective was found [90]. In addition, in patients with active Churg-Strauss syndrome, regulatory T cells producing interleukin-10 are detected rarely compared with patients with chronic eosinophilic pneumonia and/or asthma [91].…”

Section: Cd28mentioning

confidence: 99%

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

Tervaert

2009

Clinical and Experimental Immunology

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SummaryPremature atherosclerosis has been observed during the course of different systemic inflammatory diseases such as rheumatoid arthritis and sytemic lupus erythematosus. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis. In giant cell arteritis (GCA), mortality because of ischaemic heart disease is not increased. In addition, intima media thickness (IMT) is lower in patients with GCA than in age-matched controls. In contrast, IMT is increased significantly in Takayasu arteritis, another form of large vessel vasculitis occurring in younger patients. In Takayasu arteritis and in Kawasaki disease, a form of medium-sized vessel vasculitis, accelerated atherosclerosis has been well documented. In small vessel vasculitis because of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis, cardiovascular diseases are a major cause of mortality. IMT measurements reveal conflicting results. During active disease these patients experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients have atherosclerotic development as in healthy subjects. Several risk factors, such as diabetes and hypertension, are present more often in patients with vasculitis compared with healthy controls. In addition, steroids may be pro-atherogenic. Most importantly, many patients have impaired renal function, persistent proteinuria and increased levels of C-reactive protein, well-known risk factors for acceleration of atherosclerosis. Enhanced oxidation processes, persistently activated T cells and reduced numbers of regulatory T cells are among the many pathophysiological factors that play a role during acceleration of atherogenesis. Finally, autoantibodies that may be relevant for acceleration of atherosclerosis are found frequently in elevated titres in patients with vasculitis. Because patients have an increased risk for cardiovascular events, vasculitis should be treated with as much care as possible. In addition, treatment should be considered with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-1 blockers, statins and acetylsalicyl acid. Finally, classical risk factors for cardiovascular disease should be monitored and treated as much as possible.

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“…While AAV is characterized (and defined) by autoantibody formation, cellular immunity is critical for the development of autoimmunity and renal injury (5)(6)(7). Furthermore, while antineutrophil cytoplasmic antibody (ANCA) characterizes (and defines) the disease, the vasculitis involving the glomerular capillary bed has little or no antibody deposited, but rather demonstrates infiltration of delayed-type hypersensitivity (DTH) effector cells and fibrin.…”

mentioning

confidence: 99%

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Summers¹,

Steinmetz²,

Gan³

et al. 2011

Arthritis & Rheumatism

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Objective. Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody-associated vasculitis (AAV); however, CD4؉ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll-like receptors (TLRs) a potential link between infection and autoimmunity. This study was undertaken to investigate the role of TLR ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO)-induced AAV.Methods. We analyzed autoimmune responses in wild-type mice immunized with MPO alone or coimmunized with MPO and a TLR-2 or TLR-9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis, was triggered by administering a subnephritogenic dose of nephrotoxic serum.Results. MPO alone induced low-titer antineutrophil cytoplasmic antibodies (ANCAs) without delayedtype hypersensitivity or CD4 cytokine responses. However, when MPO was given with either TLR ligand, cellular and humoral autoimmunity was enhanced, but with distinctly different CD4 subsets and IgG ANCA isotypes. TLR-2 ligand induced Th17 autoimmunity, with retinoic acid receptor-related orphan nuclear receptor ␥t-dependent interleukin-17A (IL-17A) production. TLR-9 ligand promoted Th1 autoimmunity, with enhanced production of interferon-␥ (IFN␥) and Th1-associated IgG subclasses. Glomerular vasculitis developed only after the administration of nephrotoxic serum in mice immunized with either TLR ligand and MPO. Glomerulonephritis directed by MPO and TLR-2 ligation was attenuated when IL-17A was neutralized, while glomerulonephritis induced by MPO and TLR-9 ligation was attenuated when IFN␥ was neutralized.Conclusion. Our findings indicate a pathogenic role of TLRs in initiating autoimmune AAV. TLR-2 induces Th17 CD4 cells while TLR-9 can also direct vasculitis, by directing Th1 autoimmunity.

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Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission

Cited by 159 publications

References 44 publications

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

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