B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors and, each critical to B-cell differentiation and fate. All- retinoic acid (ATRA) increased expression, restored the-to- ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated and, but not (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.
Conclusions: Peripherally inserted central catheters (PICCs) are associated with a higher risk of venous thromboembolism (VTE) but not a higher risk of pulmonary embolism (PE) than central venous catheters (CVCs). VTE risk is greatest in those who are critically ill or with cancer. Summary: Use of PICC lines has increased dramatically secondary to many associated therapeutic applications and increasing availability of nurseled PICC teams for PICC insertion. PICCs are known to be associated with venous thrombosis. However, their relative risk compared with other forms of CVCs is unknown. Understanding this risk may be important to assessing costs and patient safety questions. The authors therefore performed a systematic review and meta-analysis to quantitate PICC risks for VTE compared with other forms of CVCs. They also sought to determine the frequency of PICC-related VTE in specific patient populations. The study was conducted by searching databases that included MEDLINE, EMBASE, BIOSIS, Cochrane Central Register of Controlled Trials, Conference Papers Index, and Scopus. Studies were also identified through hand searches of bibliographies as well as Internet searches. In addition, the authors contacted study authors to obtain unpublished data. Any human study published in full text, abstract, or poster form was eligible. All studies were of adult patients at least 18 years of age with PICC lines. The Newcastle-Ottawa risk of bias scale was used to assess study bias. The pooled frequency of VTE was calculated for patients receiving PICCs in studies without a comparison group. In studies that compared PICCs with other CVCs, odds ratios (ORs) for VTE were calculated using a random-effects metaanalysis model. The authors identified 533 citations. Of these, 64 studies, 52 without and 12 with a comparison group, met eligibility criteria. There were 29,503 patients analyzed in the 64 studies. In the noncomparison studies, weighted frequency of PICC-related VTE was highest in patients who were critically ill (13.91%; 95% confidence interval [CI], 7.68%-20.14%) and among those with cancer (6.67%; 95% CI, 4.69%-8.64%). In the studies comparing the risk of VTE related to PICCs compared with CVCs, PICCs were associated with an increased risk of VTE (OR, 2.55; 95% CI, 1.54-4.23; P < .0001). There were no PEs associated with PICCs. Using the baseline PICC-VTE rate of 2.7% and a pooled OR of 2.55, the authors concluded the number needed to harm with PICCs compared with CVCs was 26 (95% CI, 13-71). Comment: The fact PICCs are associated with high rates of VTE, particularly in critically ill and cancer patients, is not surprising. It is also not particularly surprising that PICCs are associated with a higher rate of VTE than CVCs. It is intriguing that PICCs in this large study of >29,000 patients were not associated with a single known case of PE. One wonders, therefore, whether PICC-associated deep venous thrombosis
Chronic graft versus host disease (cGVHD) patients have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major MHC-mismatched model with cGVHD-like manifestations we first examined B-lymphopenic mMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B cell number. Mice that later developed cGVHD, had significantly increased numbers of recipient fibroblastic reticular cells (FRCs) with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD since BAFF transcript in CD4+ T cells from diseased mice and patients was increased. Chronic GVHD manifestations in mice associated with high BAFF/B cell ratios and persistence of B Cell Receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR-responsiveness to surrogate antigen and NOTCH ligand. BAFF-Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR-activation or when alloantigen was present in vivo. Using T-cell depleted (BM only) BAFF-Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells and alloantibody production. We demonstrate that pathological production of BAFF promotes an altered B-cell compartment and augments BCR-responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in cGVHD patients.
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