The Red Blood Cell—Inflammation Vicious Circle in Sickle Cell Disease

Ribeiro

Mediators of Inflammation

et al. 2020

Recent evidence suggests that abnormalities involving CD4+T lymphocytes are associated with the pathophysiology of osteonecrosis (ON); however, few studies have addressed the CD4+T cells in ON related to sickle cell disease (SCD/ON). In addition, T cells producing multiple cytokines simultaneously are often present in the inflammatory milieu and may be implicated in the immune response observed in SCD/ON. In the present study, we aimed to characterize the functional status of CD4+T cells in SCD by simultaneously determining the frequency of IFN-γ+, IL-4+, and IL-17+ CD4+T in cell cultures under exogenous stimuli. Peripheral blood mononuclear cells (PB-MNCs) from 9 steady-state SCD patients, 15 SCD/ON patients, and 19 healthy controls had functional status of CD4+T cells analyzed. Bone marrow mononuclear cells (BM-MNCs) from 24 SCD/ON patients (SCD BM) and 18 patients with ON not related to SCD (non-SCD BM) were also analyzed. We found that PB-MNC of SCD patients with or without ON presented significantly reduced TCD4+, TCD8+, and TCD4+ naïve cell frequencies and increased frequency of circulating CD4+T cells able to simultaneously produce IFN-γ+/IL4+ and IL-17+/IL4+ compared to healthy controls. Conversely, the polyclonal stimulation of BM-MNC induced an increased frequency of CD4+IFN-γ+ and CD4+IL-17+ in SCD BM compared to non-SCD BM. The increased proportion of CD4+ T cells able to produce a broad spectrum of proinflammatory cytokines after a strong stimulus indicates that the immune system in SCD/ON patients presents an expressive pool of partially differentiated cells ready to take on effector function. It is possible that this increased subpopulation may extend to inflammatory sites of target organs and may contribute to the maintenance of inflammation and the pathophysiology of osteonecrosis in sickle cell disease.

Section: Introductionmentioning

confidence: 99%

CD4⁺ T Cell Profile and Activation Response in Sickle Cell Disease Patients with Osteonecrosis

Ribeiro

Mediators of Inflammation

et al. 2020

“…Heme oxygenase activity causes resolution of inflammation. We and others previously demonstrated that HO-activity is pivotal for reducing heme-induced vascular adhesion molecule expression and leukocyte extravasation, whereas inhibition of HO-activity further increases adhesion molecules and leukocyte influx [ 14 , 28 , 30 , 57 , 58 , 59 ].…”

Section: Protective Mechanisms Against Free Hemementioning

confidence: 99%

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections

et al. 2020

SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel “proof of concept” studies in the context of COVID-19.

“…Nader et al . ( 97 ) and others ( 98 , 99 ) have reviewed the existing literature on microparticles and SCD. Generated primarily from RBCs and platelets, the number of microparticles is significantly higher in people with SCD compared with healthy controls, and these numbers increase further with increasing degrees of hemolysis and with vaso-occlusion.…”

Section: Characteristic Of Cell Subsets As Related To Alloimmunizatiomentioning

confidence: 99%

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Hendrickson¹

2020

Ann Blood

The high prevalence of red blood cell (RBC) alloantibodies in people with sickle cell disease (SCD) cannot be debated. Why people with SCD are so likely to form RBC alloantibodies, however, remains poorly understood. Over the past decade, a better understanding of non-ABO blood group antigen variants has emerged; RH genetic diversity and the role this diversity plays in RBC alloimmunization is discussed elsewhere. Outside of antigen variants, the immune systems of people with SCD are known to be different than those of people without SCD. Some of these differences are due to effects of free heme, whereas others are impacted by hyposplenism. Descriptive studies of differences in white blood cell (WBC) subsets, platelet counts and function, and complement activation between people with SCD and race-matched controls exist. Studies comparing the immune systems of alloimmunized people with SCD to non-alloimmunized people with SCD to race-matched controls without SCD have uncovered differences in T-cell subsets, monocytes, Fcγ receptor polymorphisms, and responses to free heme. Studies in murine models have documented the role that recipient inflammation plays in RBC alloantibody formation, with human studies reporting a similar association. Murine studies have also reported the importance of type 1 interferon (IFNα/β), known to play a pivotal role in autoimmunity, in RBC alloantibody formation. The goal of this manuscript is to review existing data on factors influencing RBC alloantibody induction in people with SCD with a focus on inflammation and other immune system considerations, from the bench to the bedside.