No abstract

VEXAS syndrome (vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, autoinflammatory manifestations and somatic) is an autoinflammatory condition caused by somatically acquired UBA1 mutations. Heiblig et al report on an international retrospective analysis of 30 patients with VEXAS syndrome treated with different Janus kinase (JAK) inhibitors, finding encouraging evidence supporting the use of the JAK1/2 inhibitor ruxolitinib with clinical remissions and reductions in steroid use seen in the majority of patients.

Abstract-Aldosteronism eventuates in a proinflammatory/fibrogenic vascular phenotype of the heart and systemic organs.It remains uncertain whether peripheral blood mononuclear cells (PBMCs) are activated before tissue invasion by monocytes/macrophages and lymphocytes, as is the case for responsible pathogenic mechanisms. Uninephrectomized rats treated for 4 weeks with dietary 1% NaCl and aldosterone (ALDOST, 0.75 g/h) with or without spironolactone (Spi, 100 mg/kg per daily gavage) were compared with unoperated/untreated and uninephrectomized/salt-treated controls. Before intramural coronary vascular lesions appeared at week 4 of ALDOST, we found (1) a reduction of PBMC cytosolic free [Mg 2ϩ ] i , together with intracellular Mg 2ϩ and Ca 2ϩ loading, whereas plasma and cardiac tissue Mg 2ϩ were no different from controls; (2) increased H 2 O 2 production by monocytes and lymphocytes together with upregulated PBMC gene expression of oxidative stress-inducible tyrosine phosphatase and Mn 2ϩ -superoxide dismutase and the presence of 3-nitrotyrosine in CD4ϩ and ED-1-positive inflammatory cells that had invaded intramural coronary arteries; (3) B-cell activation, including transcription of immunoglobulins, intracellular adhesion molecule-1, and CC and CXC chemokines and their receptors; (4) expansion of B lymphocyte subset and myosin heavy chain class II-expressing lymphocytes; and (5) autoreactivity with gene expression for antibodies to acetylcholine receptors and a downregulation of RT-6.2, which is in keeping with cell activation and associated with autoimmunity. Spi cotreatment attenuated the rise in intracellular Ca 2ϩ , the appearance of oxidative/nitrosative stress in PBMCs and invading inflammatory cells, and alterations in PBMC transcriptome. Thus, aldosteronism is associated with an activation of circulating immune cells induced by iterations in PBMC divalent cations and transduced by oxidative/nitrosative stress. ALDO receptor antagonism modulates this neuroendocrine-immune interface. The full text of this article is available online at http://www.circresaha.org. (Circ Res. 2003;93:e124-e135.) Key Words: aldosterone Ⅲ peripheral blood mononuclear cells Ⅲ hydrogen peroxide production Ⅲ cytosolic free Mg 2ϩ and Ca 2ϩ Ⅲ transcriptome I rrespective of its etiologic origins, asymptomatic ventricular systolic dysfunction eventuates in an activation of the circulating renin-angiotensin-aldosterone system (RAAS), whose effector hormones contribute to the appearance of the congestive heart failure (CHF) syndrome. A chronic systemic illness ensues that features oxidative/nitrosative stress in such diverse tissues as skeletal muscle, peripheral blood mononuclear cells (PBMCs) (monocytes and lymphocytes), and heart 1-11 ; elevated circulating levels of proinflammatory cytokines and chemokines [12][13][14][15][16][17][18][19][20][21] ; and a wasting syndrome that eventuates in cachexia. 22 Pharmacological modulation of RAAS effector hormones has proven clinical benefits in patients with CHF. [23][24][25][26][27] A ro...

ϩ intake) elevations in circulating aldosterone (ALDO), termed aldosteronism, are associated with remodeling of intramural arteries of the right and left heart. Lesions appear at week 4 of treatment with ALDO and 1% dietary NaCl in uninephrectomized rats (ALDOST) and include invading monocytes, macrophages and lymphocytes with intracellular evidence of oxidative and nitrosative stress, myofibroblasts, and perivascular fibrosis. In this study, we tested the hypothesis that an immunostimulatory state with activated circulating peripheral blood mononuclear cells (PBMCs) precedes this proinflammatory and profibrogenic cardiac phenotype and is initiated by reduction in the cytosolic free Mg 2ϩ concentration ([Mg 2ϩ ]i). At 1 and 4 wk of ALDOST (preclinical and clinical stages, respectively), we monitored serum Mg 2ϩ , PBMC [Mg 2ϩ ]i and cytosolic free [Ca 2ϩ ] (via fluorimetry), and expressed genes (via microchip array) as well as markers of oxidative and nitrosative stress in plasma [␣ 1 -antiproteinase activity (␣ 1 -AP)] and cardiac tissue (immunohistochemical detection of gp91 phox subunit of NADPH oxidase and 3-nitrotyrosine). Age-and gender-matched unoperated and untreated (UO) rats and uninephrectomized salt-treated (UN) rats served as controls. Serum [Mg 2ϩ ] was unchanged by ALDOST. In contrast with UO and UN, [Mg 2ϩ ]i and plasma ␣1-AP were each reduced (P Ͻ 0.05) at weeks 1 and 4. The decline in PBMC [Mg 2ϩ ]i was accompanied by Ca 2ϩ loading. Differential (twofold and higher) expression (up-and downregulation) in PBMC transcriptomes was present at week 1 and progressed at week 4. Involved were genes for the ␣ 1-isoform of Na ϩ -K ϩ -ATPase, the ATPdependent Ca 2ϩ pump, antioxidant reserves, inducible nitric oxide synthase, and PBMC activation with autoimmune responses. Expression of 3-nitrotyrosine and activation of gp91 phox were seen in inflammatory cells that invaded intramural arteries. Thus early in aldosteronism (preclinical stage), an immunostimulatory state featuring activated circulating PBMCs with reduced ionized [Mg 2ϩ ]i and oxidative and nitrosative stress precedes and may even predispose to coronary vascular lesions that first appear at week 4. peripheral blood mononuclear cells; ionized magnesium; oxidative and nitrosative stress; transcriptome; pathology IN BOTH HUMANS AND RATS and whether derived from endogenous or exogenous sources, chronic inappropriate (relative to dietary Na ϩ intake) elevations in circulating aldosterone (ALDO) are associated with structural remodeling of intramural arteries of the right and left heart and systemic organs (9,14,15,27,39,45,52,53,63,66,75). Coronary vascular lesions in uninephrectomized rats first appear at 4 wk of ALDO-andsalt treatment (ALDOST) and involve progressively more vascular sites with continued treatment (64). Lesions consist of circulating monocytes, macrophages and lymphocytes that have invaded the perivascular space; fibroblastlike cells or myofibroblasts that express fibrillar type I and III collagens; and ultimately a pe...

Objective. To identify and validate, using computer-driven methods, patterns of arterial disease in Takayasu arteritis (TAK) and giant cell arteritis (GCA). Methods. Patients with TAK or GCA were studied from the Diagnostic and Classification Criteria for Vasculitis (DCVAS) cohort and a combined North American cohort. Case inclusion required evidence of large-vessel involvement, defined as stenosis, occlusion, or aneurysm by angiography/ultrasonography, or increased 18 F-fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) in at least 1 of 11 specified arterial territories. K-means cluster analysis identified groups of patients based on the pattern of arterial involvement. Cluster groups were identified in the DCVAS cohort and independently validated in the North American cohort. Results. A total of 1,068 patients were included (DCVAS cohort: TAK = 461, GCA = 217; North American cohort: TAK = 225, GCA = 165). Six distinct clusters of patients were identified in DCVAS and validated in the North American cohort. Patients with TAK were more likely to have disease in the abdominal vasculature, bilateral disease of the subclavian and carotid arteries, or focal disease limited to the left subclavian artery than GCA (P < 0.01). Patients with GCA were more likely to have diffuse disease, involvement of bilateral axillary/subclavian arteries, or minimal disease without a definable pattern than TAK (P < 0.01). Patients with TAK were more likely to have damage by angiography, and patients with GCA were more likely to have arterial FDG uptake by PET without associated vascular damage. Conclusion. Arterial patterns of disease highlight both shared and divergent vascular patterns between TAK and GCA and should be incorporated into classification criteria for large-vessel vasculitis.