Annette von Drygalski

Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis.

Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell-dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid-binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell-mediated immune responses.

Anemia After Bariatric Surgery: More Than Just Iron Deficiency

Bariatric surgery for morbid obesity is rapidly gaining popularity. Restrictive and/or malabsorptive surgical interventions result in dramatic weight loss with significantly decreased obesity-related morbidity and mortality. Anemia, which may affect as many as two-thirds of these patients, is of concern and generally thought to be caused by iron deficiency. Although iron deficiency in this population may be frequent given pouch hypoacidity, defunctionalized small bowel, and red meat intolerance, it may not account for all anemias seen. First, there is increasing evidence that obesity creates a state of chronic inflammation. Both iron deficiency anemia and anemia of chronic inflammation present with low serum iron levels. Most studies reporting anemia after bariatric surgery lack serum ferritin determinations so that the relative contribution of inflammation to anemia cannot be assessed. Second, a significant number of anemias after bariatric surgery remain unexplained and may be attributable to less frequently seen micronutrient deficiencies such as copper, fatsoluble vitamins A and E, or an imbalance in zinc intake. Third, although deficiencies of folate and vitamin B(12) are infrequent, study observation periods may be too short to detect anemia attributable to vitamin B(12) deficiency because vitamin B(12) storage depletion takes many years. This review is intended to increase awareness of the mechanisms of anemia above and beyond iron deficiency in the bariatric patient and provide healthcare providers with tools for a more thoughtful approach to anemia in this patient population.

Anemia after bariatric surgery cannot be explained by iron deficiency alone: results of a large cohort study.

BACKGROUND We sought to identify the frequency and mechanisms of anemia after bariatric surgery in a bariatric surgery program at the Medical College of Wisconsin, (Milwaukee, WI). Anemia after bariatric surgery has often been attributed to iron deficiency, although an inflammatory component might be present, making the anemia after surgery mechanistically complex. METHODS The body mass index and hemoglobin (Hb), vitamin B(12), folate, iron, and ferritin levels were extracted from the records of 1125 patients for ≤4 years after Roux-en-Y gastric bypass. Anemia was defined using the World Health Organization criteria. RESULTS The mean body mass index, Hb, and ferritin decreased after surgery. The body mass index decreased from 50.1 kg/m(2) (95% confidence interval [CI] 49.6-50.6) at baseline to 33.0 kg/m(2) (95% CI 32.3-33.6) at 12 months and remained unchanged thereafter. The Hb level decreased from 13.4 g/dL (95% CI 13.3-13.5) to 12.8 (95% CI 12.6-13.1) and ferritin from 87.5 ng/mL (95% CI 75.2-99.7) to 55.4 (95% CI 42.9-68.0) at 24-48 months, and serum iron increased from 68.4 μg/dL (95% CI 66.8-70.0) to 82.8 (95% CI 76.4-88.7); all P values were <.01. Anemia was present in 12% (95% CI 10-14%) of patients at baseline and had increased to 23% (95% CI 16-30%) at 24-48 months. The changes in ferritin, Hb, and the percentage of patients with anemia were most pronounced in premenopausal women. Vitamin B(12) and folate levels were unaffected. CONCLUSION The baseline incidence of anemia was greater than expected and increased significantly after surgery. The percentage of those with anemia and low ferritin was most significant in premenopausal women; however, the overall iron bioavailability improved significantly with pronounced weight loss, suggesting a reduction in inflammation. These findings indicate that anemia after bariatric surgery cannot be explained on the basis of iron availability and suggest that other mechanisms, currently undefined, contribute to the development of anemia in these patients.

Anemia in Cystic Fibrosis: Incidence, Mechanisms, and Association With Pulmonary Function and Vitamin Deficiency

BACKGROUND Anemia is associated with increased morbidity and mortality in many chronic diseases. Little is known about anemia in cystic fibrosis (CF). Because the majority of patients with CF die of lung disease, the objective of this study was to identify the frequency, severity, and mechanisms of anemia in CF and to determine if there was an association between anemia and poor lung function in these patients. Vitamin deficiency was used to assess the association of malabsorption and anemia. METHODS Charts of 218 CF patients (ages >1 month to 61 years) were reviewed. Information extracted included medical history, complete blood counts, iron studies, pulmonary function tests, vitamin levels, serum creatinine levels, and medications. RESULTS As patients aged, anemia increased from 12% in those < 16 to 58.3% > or = age 40. Anemic patients had poorer lung function than nonanemic patients. Mean forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were 51.6% (SEM +/- 10.3) and 69.7% (SEM +/- 9.3) in anemic and 82.5% (SEM +/- 9.2) and 95% (SEM +/- 8.3) in nonanemic patients, respectively (P < .001). Of vitamin-deficient patients, 90% were anemic whereas only 59.5% of nonvitamin-deficient patients were anemic (P = .02). Complete iron studies were only available in 17 of 48 anemic patients and 11 were diagnosed with iron deficiency. CONCLUSIONS Anemia in CF is associated with poor lung function and vitamin deficiency. Although anemia was often incompletely evaluated, iron deficiency was common. Recognition and complete evaluation of anemia might be important for continued improvement of care in CF.

Iron Metabolism in Man

Iron metabolism in man is a highly regulated process designed to provide iron for erythropoiesis, mitochondrial energy production, electron transport, and cell proliferation. The mechanisms of iron handling also protect cells from the deleterious effects of free iron, which can produce oxidative damage of membranes, proteins, and lipids. Over the past decade, several important molecules involved in iron homeostasis have been discovered, and their function has expanded our understanding of iron trafficking under normal and pathological conditions. Physiologic iron metabolism is strongly influenced by inflammation, which clinically leads to anemia. Although hepcidin, a small circulating peptide produced by the liver, has been found to be the key regulator of iron trafficking, molecular pathways of iron sensing that control iron metabolism and hepcidin production are still incompletely understood. With this review, we provide an overview of the current understanding of iron metabolism, the recently discovered regulators of iron trafficking, and a focus on the effects of inflammation on the process.

Prevalence and Risk Factors for Hypertension in Hemophilia

Hypertension (HTN) is a major risk factor for intracranial hemorrhage. We, therefore, investigated the prevalence, treatment, and control of HTN in adult patients with hemophilia (PWH). PWH≥18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for HTN and risk factors. Results were compared with the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of HTN compared with NHANES. Overall, the prevalence of HTN was 49.1% in PWH compared with 31.7% in NHANES. At ages 18 to 44, 45 to 64, 65 to 74, and ≥75 years, the prevalence of HTN for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared with 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared with 47.7% in NHANES (all P<0.05). Age, body mass index, diabetes mellitus, and renal function were independently associated with HTN. Among patients with moderate or severe hemophilia there was a trend (≈1.5-fold) for higher odds of having HTN compared with patients with mild hemophilia. On the basis of these results, new care models for adult PWH and further studies for the causes of HTN in hemophilia are recommended.

Organ-Specific Protection Against Lipopolysaccharide-Induced Vascular Leak Is Dependent on the Endothelial Protein C Receptor

Objective—To study the role of the endothelial protein C receptor (EPCR) in the modulation of susceptibility to inflammation-induced vascular leak in vivo. Approach and Results—Genetically modified mice with low, <10% EPCR expression (EPCRlow) and control mice were challenged with lipopolysaccharides in a mouse model of endotoxemia. Infrared fluorescence and quantification of albumin-bound Evans Blue in tissues and intravascular plasma volumes were used to assess plasma extravasation. Pair-wise analysis of EPCRlow and control mice matched for sex, age, and weight allowed determination of EPCR-dependent vascular leak. Kidney, lung, and brain were the organs with highest discriminative increased Evans Blue accumulation in EPCRlow versus control mice in response to lipopolysaccharides. Histology of kidney and lung confirmed the EPCR-specific pathology. In addition to severe kidney injury in response to lipopolysaccharides, EPCRlow and anti-EPCR–treated wild-type mice suffered from enhanced albuminuria and profound renal hemorrhage versus controls. Intravascular volume loss at the same extent of weight loss in EPCRlow mice compared with control mice provided proof that plasma leak was the predominant cause of Evans Blue tissue accumulation. Conclusions—This study demonstrates an important protective role for EPCR in vivo against vascular leakage during inflammation and suggests that EPCR-dependent vascular protection is organ-specific.

Vascular remodeling underlies rebleeding in hemophilic arthropathy.

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII‐deficient mouse. We found soft‐tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft‐tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII‐deficient mice involved pronounced remodeling with expression of α‐Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α‐SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease. Am. J. Hematol. 90:1027–1035, 2015.

Advances and challenges in hemophilic arthropathy.

Hemophilic arthropathy is a form of joint disease that develops secondary to joint bleeding and presents with synovial hypertrophy, cartilage and bony destruction. The arthropathy can develop despite clotting factor replacement and is especially disabling in the aging population. Pathobiological tissue changes are triggered by release of hemoglobin and iron deposition in the joint, but the sequence of events and the molecular mechanisms resulting in joint deterioration are incompletely understood. Treatment options other than clotting factor replacement are limited. Improvements in the treatment of hemophilia necessitate a better understanding of the processes that lead to this disabling condition and better diagnostic tools. Towards that end, studies of the molecular mechanisms leading to the arthropathy, as well as the development of sensitive imaging techniques and biomarkers are needed. These will pave the way to identify the cause of acute pain such as joint bleeding or synovitis, detect early, potentially reversible structural changes, and predict progression of disease. This review describes current imaging techniques and the development of high resolution musculoskeletal ultrasound with power Doppler to afford point-of-care diagnosis and management, the potential utility of diagnostic biomarkers, and summarizes our current knowledge of the pathobiology of hemophilic arthropathy.

Ironing out fatigue

Women who are not anemic but who suffer from fatigue may benefit from iron supplementation. In this issue of Blood, Krayenbühl et al provide strong evidence that women complaining of fatigue who were not anemic but who had reduced or absent iron stores were symptomatically improved after receiving parenteral iron. Given the numbers of women who are iron deficient, the findings could find broad application, but work needs to be done to refine the approach to this common problem.