Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1β secretion in response to anti-MPO antibodies

O'Brien, Eóin C; Abdulahad, Wayel H.; Rutgers, Abraham; Huitema, Minke G.; O’Reilly, Vincent; Coughlan, Alice M; Harrington, Mark; Heeringa, Peter; Little, Mark A.; Hickey, Fionnuala B.

doi:10.1038/srep11888

Cited by 49 publications

(44 citation statements)

References 31 publications

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“…Similar to our results, lower amounts of CD14++ monocytes have been described in patients with multiple sclerosis (MS) [34] and juvenile idiopathic arthritis (JIA) with enthesitis [35]. Besides, a higher percentage of CD16+ intermediate and non-classical monocytes with a pro-inflammatory phenotype has been described in patients with MS [34], neuromyelitis optica [36], RA [18], SLE [37], ANCA-vasculitis [38], sarcoidosis [39], IgA nephropathy [40], JIA with enthesitis [35], type 1 diabetes mellitus [41], thromboembolism [42], atherosclerosis and stroke [43] which is according to our results. Also, we found that the absolute number of classical monocytes inversely correlated with the disease activity (MYOACT and MITAX), which is according with previous data in patients with RA, where there is a higher percentage of intermediate monocytes during disease activity and a higher proportion of classical monocytes during remission [44].…”

Section: Discussionsupporting

confidence: 89%

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

et al. 2020

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Background: Monocytes and toll-like receptors (TLR) have been found in the inflammatory infiltrate of muscle biopsies in patients with idiopathic inflammatory myopathies (IIM), suggesting an important role of these cells in the pathogenesis of myositis. The monocyte subsets, their TLR expression in peripheral blood and their relationship with the clinical characteristics of patients with IIM has not been addressed. Methods:We recruited 45 patients with IIM diagnosis and 15 age and sex-adjusted healthy controls. We assessed the disease activity and damage, performed a nailfold capillaroscopy and registered the cardio-pulmonary parameters from the medical charts. Monocyte subsets, their expression of TLR2 and TLR4 and the serum Th1/Th2/Th17 cytokines levels were evaluated by flow cytometry. We expressed quantitative variables as medians and interquartile ranges (IQR) or minimum and maximum (min-max). Differences between groups were assessed with Mann-Whitney U and the Kruskal-Wallis tests. Correlation between quantitative variables was assessed with Spearman Rho.Results: Twenty-nine patients were women (64.4%) and 32 (71.1%) had dermatomyositis. In comparison to healthy controls, patients with active IIM had a higher percentage of intermediate monocytes and lower amounts of classical monocytes. Patients with IIM had a higher expression of TLR4 in all their monocyte subsets, regardless of disease activity and prednisone treatment. Serum IL-6 correlated with the TLR2 expression in every monocyte subset and the expression of TLR2 in intermediate monocytes was higher among patients with dysphagia. Subjects with nailfold capillaroscopy abnormalities had a higher amount of TLR2+ classical and non-classical monocytes and those with interstitial lung disease (ILD) had a higher percentage of TLR4+ non-classical monocytes. The classical and intermediate monocytes from patients with anti Mi2 antibodies had a higher expression of TLR4. The percentage of intermediate monocytes and the expression of TLR4 in all monocyte subsets showed a good diagnostic capacity in patients with IIM. Conclusion:Patients with IIM have a differential pool of monocyte subsets with an enhanced expression of TLR2 and TLR4, which correlates with disease activity and distinctive clinical features including dysphagia, ILD, vasculopathy, and pro-inflammatory cytokines. These immunological features might be useful as a potential diagnostic tool as well as novel disease activity biomarkers in IIM.

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Section: Discussionsupporting

confidence: 89%

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

et al. 2020

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“…In comparison with age- and sex-matched controls, total monocyte count was elevated in asymptomatic NF1 patients. Examination of monocyte subpopulation frequency showed that some healthy persons with NF1 had a substantial increase in the frequency of a monocyte subpopulation (CD14 + CD16 + + ) associated with inflammatory conditions and oxidative stress [48–50] (Fig. 7A and B).…”

Section: Resultsmentioning

confidence: 99%

Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

Bessler

Hudson

Zhang

et al. 2016

Free Radical Biology and Medicine

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Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease. Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21Ras activity and phosphorylation of multiple downstream kinases, including Erk and Akt. Nf1 heterozygous (Nf1+/−) mice develop a robust neointima that mimics human disease. Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells alone are sufficient to reproduce the enhanced neointima observed in Nf1+/− mice. Though the molecular mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound mutant and lineage-restricted mice to demonstrate that Nf1+/− macrophages produce excessive ROS, which enhance Nf1+/− smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1+/− mice. Finally, mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing novels therapies and interventions.

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“…ANCAs also activate monocytes ex vivo, as monocytes express PR3 and MPO, albeit at lower levels than neutrophils. Compared with studies in neutrophils, the pathogenetic implications of any direct effects of ANCAs on monocytes is less certain 97,98 . Whether the 5-10% of patients with GPA or MPA who are ANCAhave a relevant autoantibody is unresolved.…”

Section: The Role Of Anca and Neutrophilsmentioning

confidence: 99%

ANCA-associated vasculitis

Kitching

Anders

Basu

et al. 2020

Nat Rev Dis Primers

622

507

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The anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitides (AAVs) are diseases characterized by inflammation of blood vessels, endothelial injury and tissue damage. The three types of small-vessel vasculitis, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA; previously known as Churg-Strauss syndrome), feature a loss of tolerance to neutrophil primary granule proteins, most often leukocyte proteinase 3 (PR3; also known as myeloblastin) or myeloperoxidase (MPO) (Table 1). The vessels involved in AAV are typically capillaries, arterioles and venules but small arteries and veins may also be affected. Autoimmunity is documented clinically by serum ANCAs to PR3 (PR3-ANCA) or MPO (MPO-ANCA), which are generally associated with the main syndromic AAV presentations (box 1). AAVs collectively represent one of several types of autoimmune vasculitis (Fig. 1). GPA and MPA can involve small blood vessels in any organ or tissue but commonly affect the upper and lower respiratory tract and the kidneys (box 2). Patients with AAV typically present with severe organ-threatening or life-threatening disease, although less severe presentations also occur. GPA is predominantly associated with PR3-ANCA and its clinical features typically include sinonasal disease, lower respiratory tract involvement with pulmonary haemorrhage and granulomatous inflammation, and glomerulonephritis. MPA is usually associated with MPO-ANCA and clinical features include more severe renal disease and some of the manifestations of GPA but without granulomatous inflammation. EGPA is characterized by asthma, eosinophilia and, in many (but not all) cases, vasculitis. EGPA is less common than GPA or MPA and, in some cases, is associated with ANCAs, mainly MPO-ANCA (Table 1). Although categorized as a form of AAV, EGPA has less overlap with the other AAVs than that between GPA and MPA with regard to its genetic, pathogenetic, and clinical features and its management and is typically considered a separate entity. Improvements in treatment and prognosis for patients with AAV have resulted from the translation of both preclinical and clinical research findings. Here, we provide an updated overview of the clinical and

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Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1β secretion in response to anti-MPO antibodies

Cited by 49 publications

References 31 publications

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

ANCA-associated vasculitis

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