Immunological Hallmarks of Inflammatory Status in Vaso-Occlusive Crisis of Sickle Cell Anemia Patients

Abstract

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the β-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC (n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1β, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients.

Are IL-1 family cytokines important in management of sickle cell disease in Sub-Saharan Africa patients?

“…How much these values compare to cytokine levels of healthy subjects is currently unknown (study ongoing), although from previously published data steady state SCD patients seem to have increased levels of IL-6, IL-8 and IL-18 (which in normal subjects are ≤ 10 pg/ml for IL-6 and IL-8, and around 200 pg/ml for IL-18), suggesting a partially upregulated inflammatory level in steady state SCD. Variability of conditions in different geographical settings and differences in detection assays makes impossible any quantitative comparison with data from other studies ( 23 ).…”

Levels of inflammatory markers are differentially expressed in sickle cell anemia and sickle cell trait

“…TNF‐α showed a behavior similar to that of IL‐6 in the Hb‐AS group, in that it was lower than in the Hb‐SS group and comparable to the Hb‐AA group. The lower levels of the pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α in Hb‐AS individuals when compared to Hb‐SS individuals, in addition to the similarity of their levels to those of Hb‐AA individuals, indicate the absence of an intermediate inflammatory profile in individuals with SCT [8, 12].…”

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

“…vaso‐occlusive crisis, steady state, etc.) and alloimmunization status have profound effects on circulating cytokines and interferons 67,68 . It is also possible that the cytokine and/or interferon response required for enhanced alloimmunization occurs locally (e.g.…”

“…and alloimmunization status have profound effects on circulating cytokines and interferons. 67,68 It is also possible that the cytokine and/or interferon response required for enhanced alloimmunization occurs locally (e.g. in secondary lymphoid organ) following clearance of mitochondria-positive RBCs; thus, plasma cytokine and interferon levels may not reflect immune activation in compartments associated with RBC clearance and subsequent initiation of alloantibody production.…”