Inflammatory status in pediatric sickle cell disease: Unravelling the role of immune cell subsets

Abstract

Introduction: The mutation of the beta-globin gene that causes sickle cell disease (SCD) results in pleiotropic effects, such as hemolysis and vaso-occlusive crisis that can induce inflammatory mechanisms with deleterious consequences on the organism. Moreover, SCD patients display an increased susceptibility to infections. Few studies are currently available that evaluate a wide immunological profile in a pediatric population. This study proposes an evaluation of the immune profile in subjects with SCD in a pediatric population through a detailed analysis by flow cytometry.Methods and Materials: Peripheral blood samples from 53 pediatric patients with SCD (mean age 9.8 years, interquartile range 9 years) were obtained and then analyzed by flow cytometry, in order to evaluate changes in the immune populations compared to 40 healthy donors (mean age 7.3 years, interquartile range 9.5 years).Results: Our data showed an increase in neutrophils (with a reduction in the CD62L + subpopulation) and monocytes (with a decrease in HLA-DRlow monocytes) with normal values of lymphocytes in SCD patients. In the lymphocyte subpopulations analysis we observed lower values of CD4+ T cells (with higher number of memory and central memory T lymphocytes) with increased frequency of CD8+ T cells (with a predominant naive pattern). Moreover, we observed higher values of CD39+ Tregs and lower HLA-DR+ and CD39− T cells with an increased Th17, Th1-17 and Th2 response.Conclusion: We observed immunological alterations typical of an inflammatory status (increase in activated neutrophils and monocytes) associated with a peculiar Treg pattern (probably linked to a body attempt to minimize inflammation intrinsic to SCD). Furthermore, we highlighted a T helper pathway associated with inflammation in line with other studies. Our data showed that immunological markers may have an important role in the understanding the pathophysiology of SCD and in optimizing targeted therapeutic strategies for each patient.

Safety and efficacy study of CRISPR/Cas9 treatment of sickle cell disease in clinically relevant conditions highlights disease-specific response

“…The incidence of nearly every clinical manifestation of SCD correlates with high white blood cell count, indicating a role for leukocytes and inflammation in the pathophysiology of SCD. Leukocytosis is common in SCD patients and is manifested by elevation in monocyte and neutrophil counts [33][34][35] , accompanied by elevated levels of circulating inflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin (IL)-1, and IL-8 36 . The difficulty in obtaining high cell doses and a robust engraftment of LV-transduced HSPCs in SCD patients suggests that the unique inflammatory bone marrow (BM) environment associated with SCD may have a significant impact on HSPCs 37 .…”

Characterizing the Immature Immunophenotype of Sickle Cell Disease Monocytes

“…It has been widely reported that recurrent sickling creates a pro-inflammatory state, causing SCD to have an immune profile similar to a chronic inflammatory condition [ 6 , 7 ]. Importantly, innate immune cells (monocytes, neutrophils, basophils, eosinophils, natural killer (NK) cells, platelets, macrophages, and mast cells) have been implicated as drivers of inflammation in SCD [ 6 , 8 , 9 ].…”

HLA haplotype frequencies and diversity in patients with hemoglobinopathies

“…Structurally characterized either by a glutamic acid to valine amino acid change of the hemoglobin β chain or defective/inefficient synthesis of hemoglobin due to various point mutations, respectively, SCD and β-Thal have long been considered as prototypic monogenic disorders [1]. Further knowledge demonstrated the involvement of other pathways/processes such as immunological underpinnings of the evolution of the two disorders [4]. Until a few years ago, allogeneic hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA) identical siblings or alternative donors was the only available curative treatment; however, a variety of novel disease-modifying drugs, gene addition and gene editing strategies have been recently developed and are, now, the object of many ongoing clinical studies yielding variable results [2,5,6].…”

“…an important notion given the central role of inflammatory processes in the evolution of the two disorders [4,9,10].…”

“…Due to its dual implications, both in the development of disease‐related complications and in the successful matching of donor–recipient pairs in HCT settings, the HLA system and its genetic diversity constitute one of the best candidates deserving to be studied. Because of the extreme polymorphism of the HLA allelic pool, haplotype‐based analyses were developed especially as some of the so‐called HLA ancestral haplotypes are endowed by inflammatory properties [7, 8], an important notion given the central role of inflammatory processes in the evolution of the two disorders [4, 9, 10].…”