Toll-Like Receptors 4 and 5 Induce Distinct Types of Vasculitis

Deng, Jiusheng; Ma-Krupa, Wei; Gewirtz, Andrew T.; Younge, Brian R.; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.1161/circresaha.108.185777

Cited by 118 publications

(106 citation statements)

References 25 publications

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“…The vasculopathy associated with SAMHD1 mutation in this study consistently targets certain organs while sparing others. Remarkable target tissue tropisms with distinctive vascular territories have been observed in several other inflammatory vasculopathies related to their vessel-specific Toll-like receptor (TLR) profile (18)(19)(20). We speculate that SAMHD1 may play an important role in cerebral vasculopathy, and further studies of the role of SAMHD1 in blood vessel integrity and homeostasis of the brain will be very significant not only for this condition, but for a group of diseases related to cerebral vasculopathies, such as moyamoya (21) and primary angiitis of the central nervous system (22).…”

Section: Discussionmentioning

confidence: 99%

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

Xin

Jones

Puffenberger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

101

113

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We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud’s phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411–2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.

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Section: Discussionmentioning

confidence: 99%

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

Xin

Jones

Puffenberger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

101

113

View full text Add to dashboard Cite

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“…Although this was the case for the neutrophil chemokine IL-8, the opposite was true for CCL20, which recruits subsets of DCs, B-, and T-cells to mucosal sites via interaction with CCR6 (reviewed 60 ). Since CCL20 recruits of distinct subsets of immune cells, 61,62 including memory T-regulatory cells and Th17 cells, 63 the downregulation of CCL20 by ATP could reflect a change in the type of inflammation and subsequent adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

The Stress signal extracellular ATP modulates antiflagellin immune responses in intestinal epithelial cells

Ivison¹,

Himmel²,

Mayer³

et al. 2011

Inflammatory Bowel Diseases

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“…They were able to show that depending on the original danger signal, vascular dendritic cells edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis. 23 The findings could implicate an external disease-initiating factor.…”

Section: Discussionmentioning

confidence: 98%