Abstract
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.
Highlights
Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene (HBB), resulting in the production of hemoglobin S (HbS)
The frequencies of IFN-γ+-producing and IL17+-producing CD4+T cells in stimulated Bone marrow mononuclear cells (BM-Mononuclear Cell (MNC)) were significantly higher in SCD with osteonecrosis (SCD/ON) patients than controls patients with osteonecrosis not related to SCD
We demonstrated that polyclonal stimulation of Bone marrow (BM)-MNC induced an increased frequency of CD4+IFN-γ+ and CD4+IL-17+ in SCD BM compared to non-SCD BM patients
Summary
Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene (HBB), resulting in the production of hemoglobin S (HbS). The abnormal hemoglobin polymerizes upon deoxygenation and produces deformed red blood cells (RBCs). This primary pathophysiological alteration has many downstream effects including the production of several inflammatory molecules and responses that lead to hemolysis and vasoocclusion of microvessels [1]. Tissue hypoxia, and cytokine production perpetuate the chronic inflammatory state with a pivotal role in the vaso-occlusive crisis (VOC) and painful episodes, the major cause of hospitalization in SCD patients [2]. In addition to driving the vaso-occlusive processes, inflammatory responses are associated with numerous complications of the disease including osteonecrosis [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
