Concepts and Hypotheses

Shenkar, Robert; Shi, Changbin; Check, Irene J.; Lipton, Howard L.

doi:10.1227/01.neu.0000298897.38979.07

Cited by 42 publications

(21 citation statements)

References 56 publications

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“…[22, 27, 28] Consistent with this view, we found that plasma cells were present mainly in specimens that had hemosiderin deposition. However, we cannot draw any conclusion regarding adaptive immune responses to the presence of iron from our small descriptive study.…”

Section: Discussionsupporting

confidence: 84%

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Guo¹,

Tihan²,

Kim³

et al. 2014

Neuroimmunol Neuroinflammation

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Aim To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of microhemorrhage). Methods Sections of unruptured, previously untreated bAVM specimens (n=19) were stained immunohistochemically for T-lymphocytes (CD3+), B-lymphocytes (CD20+), plasma cells (CD138+) and macrophages (CD68+). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control. Results Both T lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence interval =20–67%). The samples with iron deposition tended to have more macrophages than those without (666±313 vs 478±174 cells/mm2; P=0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T lymphocyte load and iron deposition (P=0.88). No macrophages and lymphocytes were detected in STA controls. Conclusions T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.

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Section: Discussionsupporting

confidence: 84%

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Guo¹,

Tihan²,

Kim³

et al. 2014

Neuroimmunol Neuroinflammation

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“…Shenkar et al reported that immunoglobulin heavy and light chain genes were upregulated with up to 20-fold change in human CCM lesions in comparison to brain AVM and normal superficial temporal arteries [4, 11]. Interestingly, we found that 3 common variants in the immunoglobulin heavy locus ( IGH ) and 5 common variants in the immunoglobulin lambda light chain locus ( IGL ) were associated with either ICH or total lesions.…”

Section: Discussionmentioning

confidence: 58%

“…Our candidate gene list includes: 1) Inflammatory cytokines, as polymorphisms in notably IL1A, IL1B, IL1RN and TNF genes have been previously reported associated with phenotypes of brain vascular diseases, including brain arteriovenous malformations or intracranial aneurysms [12–17, 20]; 2) Transforming growth factor-β (TGF-β) and related genes that inhibit TGF-β signaling, reducing the number and size of lesions and vessel leakage in CCM1-deficient mice [10]; 3) Genes that encode proteins expressed or secreted by inflammatory or immune cells (T cells, B cells, monocytes and macrophages) and other related genes coding for proteins involved in immune cell development (i.e., CD14, IFNG, IL5, IL6R, IL8, IL18, IL18R1, IL12A, IL12B, IL2, IL17A, IL23A, NFKB1, MIF and MSR1) as inflammatory or immune cells are present in human CCM lesions [4, 6, 11]; 4) Toll-like receptors genes (TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 and TLR10) as well as COX-2 and Selenoprotein genes as encoded proteins have been reported to be essential in the pathogenesis of cerebral ischemia and the pathologic progression of the disease [21–26]; 5) Immunoglobulins and other related genes with altered expression in human CCM lesions (CD247, CD3G, CD68, CD200, GUSP11, HLA-DRB1, IGH, IGJ, IGL, LOC390714, MS4A1 and SDC1) [4, 11]. These genes were classified into the following biological sub-pathways [27, 28]: (a) cytokine signaling; (b) eicosanoid signaling; (c) extracellular pattern recognition; (d) NFKB signaling; (e) selenoproteins; and (f) immune response (see online Suppl.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have implicated dysregulated inflammatory and immune responses in vascular malformation pathogenesis, including CCM [4–7]. Inflammatory and immune cells such as monocytes, macrophages, B and T cells, are present in human CCM lesions, particularly in response to acute bleeding [6–8], as well as in mouse models of CCM [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…Inflammatory and immune cells such as monocytes, macrophages, B and T cells, are present in human CCM lesions, particularly in response to acute bleeding [6–8], as well as in mouse models of CCM [9, 10]. Further, gene expression arrays have revealed a number of immunoglobulin genes and markers of immune cells with altered expression in human CCM tissue [4, 11]. Common functional polymorphisms in inflammatory cytokine genes have been associated with ICH in other brain vascular diseases, including arteriovenous malformations (AVM) [12–16] and intracranial aneurysms [17].…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in Inflammatory and Immune Response Genes Associated with Cerebral Cavernous Malformation Type 1 Severity

Choquet¹,

Pawlikowska²,

Nelson³

et al. 2014

Cerebrovasc Dis

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Background: Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count. Methods: Hispanic CCM1 patients (n = 188) harboring the founder Q455X ‘common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways. Results: At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean w standard deviation (SD) of 60.1 w 115.0 (range 0-713) for total lesions and 4.9 w 8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE = 0.31), 0.81 (SE = 0.17), and 0.48 (SE = 0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p ≤ 0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p = 0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count. Conclusions: These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sam...

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Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm

Kim

Weinsheimer

et al. 2011

Acta Neurochirurgica Supplementum

122

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Brain arteriovenous malformations (AVMs) are a rare but important cause of intracranial hemorrhage (ICH) in young adults. In this paper, we review both human and animal studies of brain AVM, focusing on the: (1) natural history of AVM hemorrhage; (2) genetic and expression studies of AVM susceptibility and hemorrhage; and (3) strategies for development of a brain AVM model in adult mice. These data target various mechanisms which must act in concert to regulate normal angiogenic response to injury. Based on the various lines of evidence reviewed in this paper, we propose a “response-to-injury” model of brain AVM pathogenesis.

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Concepts and Hypotheses

Cited by 42 publications

References 56 publications

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Polymorphisms in Inflammatory and Immune Response Genes Associated with Cerebral Cavernous Malformation Type 1 Severity

Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm

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