Functional evaluation of neutrophils in CD40L-DEFICIENCY patients

Abstract

Patients with X-Linked Hyper IgM Syndrome (X-HIGM), a rare immunodeficiency caused by the deficiency of the CD40 ligand molecule (CD40L), are highly susceptible to infections by several classes of microorganisms, and opportunistic infections caused by fungi represent a significant cause of morbidity and mortality, even in patients undergoing treatment with the current drug protocols. Recent studies point to changes in important effector responses in X-HIGM patients' phagocytes, such as lower production of reactive oxygen species, dysregulation in NETs generation and deficient fungicidal activity, even though the persistence of infections cannot be justified by only these mechanisms, because some of them have been shown to be only partially reduced. The CD40-CD40L interaction play a key role in several immune processes and its absence in the bone marrow results in dysregulation of the granulopoiesis process, as demonstrated by neutropenia and incomplete neutrophil maturation in X-HIGM patients. Defects in neutrophil maturation can lead to dysregulation in various mechanisms that precede activation and action at the infectious site, such as survival rate, receptor expression and migration capacity, thereby compromising any subsequent immune response. Preliminary X-HIGM patients' neutrophil assays confirmed the presence of immature peripheral neutrophils and a strong reduction in migration, indicating the presence of defects not yet elucidated. Based on these observations, we propose to investigate the functional profile presented by neutrophils of patients with CD40L deficiency prior to their effector role at the infectious site - such as viability and subpopulation profile; mechanisms involved in the recruitment to the infectious site, such as adhesion capacity, migration, chemotaxis and degranulation; and finally, fungal recognition immediately preceding the effector response against microorganisms. In addition, we will investigate whether the in vitro interferon-gamma (IFN-³) treatment, known to boost phagocyte activity, has the potential to improve these cells' response. The elucidation of the immunopathological mechanisms involved in the susceptibility of X-HIGM patients' to infections will allow a better understanding of the function of CD40-CD40L interaction in the bone marrow and in the immune response. In addition, advances in knowledge associated with the study of the effect of IFN-³ treatment can substantiate the development of new therapeutic strategies aimed at improving the quality of life of patients affected by this syndrome. (AU)