Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development.

B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell-activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.

B Lymphocyte-Derived CCL7 Augments Neutrophil and Monocyte Recruitment, Exacerbating Acute Kidney Injury.

Acute kidney injury (AKI) is a serious condition affecting one fifth of hospital inpatients. B lymphocytes have immunological functions beyond Ab production and may produce cytokines and chemokines that modulate inflammation. In this study, we investigated leukocyte responses in a mouse model of AKI and observed an increase in circulating and kidney B cells, particularly a B220low subset, following AKI. We found that B cells produce the chemokine CCL7, with the potential to facilitate neutrophil and monocyte recruitment to the injured kidney. Siglec-G-deficient mice, which have increased numbers of B220low innate B cells and a lower B cell activation threshold, had increased Ccl7 transcripts, increased neutrophil and monocyte numbers in the kidney, and more severe AKI. CCL7 blockade in mice reduced myeloid cell infiltration into the kidney and ameliorated AKI. In two independent cohorts of human patients with AKI, we observed significantly higher CCL7 transcripts compared with controls, and in a third cohort, we observed an increase in urinary CCL7 levels in AKI, supporting the clinical importance of this pathway. Together, our data suggest that B cells contribute to early sterile inflammation in AKI via the production of leukocyte-recruiting chemokines.

Novel immunotherapeutic strategies to target alloantibody-producing B and plasma cells in transplantation.

PURPOSE OF REVIEW: There is an unmet need for immunotherapeutic agents that target humoral alloimmunity in solid organ transplantation. This includes sensitized patients with preformed donor-specific human leucocyte antigen antibodies and patients who develop de-novo donor-specific antibodies, both of which are associated with acute and chronic antibody-mediated rejection and allograft loss. RECENT FINDINGS: In this review, we discuss recent progress in the generation of B-cell and plasma cell-targeted therapeutics, with an emphasis on novel agents. To deplete or inhibit B cells, B-cell-specific mAbs have been developed, including CD20, CD22, CD19 and bi-specific antibodies that target two B-cell antigens. In addition, inhibition of B-cell-activating cytokines, such as B cell-activating factor, may also reduce allo-B-cell activation. Plasma cells remain a difficult therapeutic target, but inhibition of germinal centre responses via costimulatory blockade or IL21 neutralization, induction of plasma cell apoptosis using proteasome inhibitors or disruption of the plasma cell niche are potential avenues being explored. SUMMARY: The ultimate aim of these animal and human studies is to develop agents that efficiently target humoral effectors, whilst sparing B and plasma cells with a regulatory capacity to promote long-term allograft survival, but we remain some distance away from this goal.

A case report: radiological findings in an unusual case of calciphylaxis 16 years after renal transplantation.

Calciphylaxis is a serious and potentially life-threatening disorder characterized by medial calcification of arterioles leading to subcutaneous ischemia and skin necrosis. It is most commonly seen in patients with end-stage renal disease or shortly after renal transplantation. We report an unusual case of calciphylaxis occurring 16 years after renal transplantation in a 48-year-old female with a failing graft, along with histological and striking radiological findings.

Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells.

Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.

Biting for attention: a case of dental discomfort manifesting in behavioural problems.

There is a dearth of literature describing behaviour that expresses discomfort caused by poor dentition in patients with dementia. In this paper, we report on a patient whose behaviour only abstrusely pointed to his teeth as the source of discomfort. Although changes to his medication over a 2-year period had little effect, eventual extraction of his caries brought about an almost immediate resolution of all antisocial behaviour. Clinicians must be mindful that poor dental care is easily meliorated but remains endemic in patients suffering from dementia.

Arteriovenous fistula failure: is there a role for accessory draining vein embolization?

PURPOSE: Arterio-venous fistulae (AVFs) are accepted as the best form of haemodialysis vascular access (VA) but are plagued by high primary failure. Accessory drainage veins (ADVs) may account for up to 40% of these failures. Furthermore, they may also lead to low flow in 'mature' AVFs. METHODS: We analysed the results of 42 patients who underwent endovascular coiling of ADVs at our centre over a 4-year period. RESULTS: Indications were failure to mature in 34%, low flow or cannulation difficulty in 56% and thrombosis in 10% of cases. 95% procedures involved a combination of angioplasty and coiling with only 5% patients having coiling of ADV alone. Forearm AVFs constituted the majority of the cases as opposed to upper arm AVFs (74% vs. 26% respectively). Primary patency at 3, 6, 12, 18 and 24 months was 90%, 87%, 76%, 70% and 55% respectively. Successful dialysis was achieved in 10 of the 14 fistulae that had hitherto failed to mature. Coil migration was observed in 1 patient, which led to fistula occlusion. CONCLUSION: Coil embolisation of ADVs is an effective treatment option for dysfunctional fistulae that can be performed at the same time as angioplasty.

Idiopathic or iatrogenic membranous glomerulonephritis? A case of spironolactone-induced membranous glomerulonephritis.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults in the UK. In most cases, the aetiology remains unknown, although recent data suggested a clear mechanism of pathogenesis. In approximately a quarter of cases, however, a presumed cause is found, such as systemic lupus nephritis, malignancy, hepatitis B and various drugs. Here, we present a patient who developed MN soon after commencing spironolactone and whose condition persisted for the duration of exposure to the drug only to resolve with cessation of the drug. No cases of spironolactone-induced MN have been reported in the literature previously.

Update and critical appraisal of sevelamer in the management of chronic renal failure.

Sevelamer (Renagel and Renvela), is an orally administered weakly basic anion exchange resin that binds dietary phosphate in the gastrointestinal tract, and is approved for use in the US, Europe and many other countries for the treatment of hyperphosphatemia in adult patients on hemodialysis or peritoneal dialysis. Clinical evidence shows that sevelamer is at least as effective as calcium-based oral phosphate binders in controlling serum phosphate, but with a lower incidence of hypercalcemia. Whilst sevelamer hydrochloride is associated with mild acidosis, sevelamer carbonate does not have this drawback. Use of sevelamer and avoidance of calcium-based binders may slow the progression of vascular calcification in hemodialysis patients, and it also reduces serum low-density lipoprotein-cholesterol levels. There was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis of the large (n >2100), 3-year DCOR trial. In the smaller (n = 109) nonblind RIND trial in patients new to hemodialysis, data suggest there may be an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment but the evidence on the efficacy of sevelamer in reducing mortality and hospitalization is not strong. The balance of evidence, however, does not strongly support the use of sevelamer over the much less costly calcium-based binders except in patients at risk of hypercalcemic episodes. Further research into cardiovascular and all-cause mortality over a longer time period would be needed to settle this issue, and the relative survival benefits and cost effectiveness of all phosphate binder therapies remains to be fully determined. Despite the relative paucity of data available, sevelamer has established itself as the most widely used binder in the United States and the most widely used noncalcium-based binder worldwide. However, affordability is a major issue for most health economies and in the light of recent economic events is likely to become more prominent.