Upregulation and atypical expression of the CD1 molecules on monocytes in sickle cell disease

Abstract

Human CD1 group I molecules CD1a, b, and c are expressed on antigen-presenting cells, notably dendritic cells, and implicated in glycolipids presentation to T lymphocytes. Expression of CD1 on monocytes is a hallmark of their activation. Because monocyte activation has been reported during steady state disease in sickle cell anemia (SCA) patients, we have analyzed CD1 expression on monocytes from 45 SCA patients originating from Africa and 27 healthy control subjects. CD1 expression was detected on monocytes in the majority of SCA patients (75%), whereas it was not observed in the vast majority of the control group (70.4%). CD1b and CD1c were highly expressed in Sβ thalassemia patients and CD1a expression was predominant in SDPunjab patients. This expression of the CD1 molecules is correlated with an increased expression of the major histocompatibility complex class II invariant chain (CD74). Finally, we have observed that the majority of SCA patients (68%) express only two or one CD1 isoforms. This study demonstrates the particular phenotype of SCA monocytes intermediate between normal resting and activated monocytes, a phenotype that could have consequences on regulation of the infection outcome.

Introduction

Sickle cell anemia (SCA), the first recognized prototype monogenic disorder [1], is characterized by a striking variability of the clinical presentation ranging from an early-onset life-threatening disease to a milder condition compatible with an almost normal life course. The unpredictability of the major complications (i.e., hemolytic anemia, painful vaso-occlusive crises, and severe infections) is a characteristic feature and a major determinant of the clinical outcome. Among them, severe infections remain the most poorly understood complication in term of pathophysiologic mechanism [2].

For this reason, and to pursue our previous studies [3, 4] contributing to a better comprehension of these infectious events, we have investigated, particularly, the role of the immune system in the defense against infections in SCA patients. The immune system has developed at least three types of molecules able to present antigen to T cells. Two of them, class I and class II molecules, are encoded by the major histocompatibility complex (MHC), and the third one is encoded by the CD1 complex localized outside the MHC. These molecules present, respectively, peptidic and glycolipidic antigens and thus mediate distinct but complementary mechanisms of defense against infections.

The CD1 molecules are a family of cell-surface glycoproteins encoded by five genes located on chromosome 1 in man [5]. They are distant relatives of the MHC class I and class II molecules, but unlike MHC proteins, have a limited polymorphism [6]. Expression of CD1 molecules were first identified on cortical thymocytes; however, they are also expressed on antigen-presenting dendritic cells, activated monocytes, and B cells. This pattern of expression, which resembles that of the MHC class II molecules, as well as their structural similarity and DNA sequence homology with MHC class I molecules, has led to the suggestion that the CD1 molecules could participate to antigen presentation. In fact, the CD1 molecules have a entirely new role in antigen presentation to T cells by their ability to present mycobacterial lipidic or glycolipidic antigens [7, 8, 9, 10]. The first mycobacterial lipidic antigens identified, such as mycolic acid and lipoarabinomannan, recognized by CD1-restricted T cells, are also the target of a powerful innate mechanism of recognition. These innate mechanisms are responsible of multiple effects, such as the induction of costimulatory molecules and cytokines necessary during the adaptive response. As suggested by Park and Bendelac, this relation between innate mechanism and adaptive cellular responses places CD1 at the interface between innate and adaptative immunity [11].

Monocytes activation status has been recently demonstrated in SCA in steady state [12]. Because the expression of CD1 group I molecules on monocytes is a hallmark of their activation, we have explored, in this study, their expression at the surface of monocytes from SCA patient. The results obtained demonstrate a significant CD1 expression and an atypical CD1 phenotype on monocytes from the majority of SCA patients.