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The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T cell-independent (TI) and T cell-dependent (TD) antigens. Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I IFN (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of antigen administration. Consistent with the enhanced TI-2 immune responses in SCD mice, the frequencies of B-1b cells (B-1 cells in humans), a major cell type responding to TI-2 antigens, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti-red blood cell (RBC) autoantibodies were detected in both SCD mice and patients. Both the levels of TI-2 immune responses and anti-RBC autoantibodies were significantly reduced following IFNAR antibody blockades and in IFNAR-1 deficient SCD mice. Moreover, the alteration of B-1 cell subsets were reversed in IFNAR-1 deficient SCD mice, uncovering a critical role for IFN-I in the enhanced TI-2 immune responses and the increased production of anti-RBC autoantibodies by modulating the innate B-1 cell subsets in SCD. Overall, our study provides experimental evidence that the modulation of B-1 cells and IFN-I can regulate TI immune responses and the levels of anti-RBC autoantibodies in SCD., (Copyright © 2024 American Society of Hematology.)

Objective: Platelet transfusions for patients with intracerebral hemorrhage (ICH) on antiplatelet therapy (APT) remain controversial. Diverging past research and differences in platelet preparation warrant further investigation of this topic. In this study, the association between platelet transfusion and clinical outcomes of ICH is investigated in patients matched by ICH score, a validated predictor of mortality., Methods: A consecutive review of all patients from 2012 to 2015 with nontraumatic ICH was performed. Risk factors including demographics, medical comorbidities, APT use, and ICH score were reviewed. Standardized differences were used to assess baseline characteristics; logistic regression models were performed to determine whether platelet transfusions were associated with adverse outcomes, both before and after matching for ICH score., Results: A total of 538 patients with nontraumatic ICH were investigated. Of these, 168 were on APT; 71 were excluded. Thirty-nine patients (40%) received platelet transfusions and 58 (60%) did not. An overall mortality of 9.3% was measured, with 29.9% of patients enduring complications. In the unmatched cohort, patients who received platelet transfusions were more likely to deteriorate (odds ratio [OR], 4.7), undergo surgical intervention during their hospital stay (OR, 7.2), be discharged with a worse modified Rankin Scale score (OR, 3.6), or die (OR, 6.1). After matching by ICH score, platelet transfusion was not a significant predictor for any negative outcome., Conclusions: This is the first analysis of platelet transfusions in patients with ICH based on ICH score. For patients on APT, platelet transfusion is not associated with clinical outcomes in an ICH score-matched sample., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/ emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO.

Many facets of accommodation have been explored since this process was first observed in ABO-incompatible renal allografts over 17 years ago. Intriguing new pieces of the puzzle have emerged to be fitted into the picture in several places. For example, vascular endothelial cells can be stimulated to secrete substantial amounts of blood group A and B antigens linked to von Willebrand factor; the antibody response to A and B antigens stimulated by ABO-incompatible renal allografts can show epitope spreading; complement can inhibit inflammation through actions of some complement split products, particularly iC3b and C3a; endothelial cells can upregulate various cytoprotective mechanisms; and clinically, new protocols for achieving accommodation have been implemented with improved results.