Grant no. 23984234
Immuno-metabolic disease
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. We considered that immunometabolic factors might affect iNKT cell function. To this end, in a study supervised by Dr. H. Schipper, we investigated iNKT cell phenotype and function in a cohort of adolescents with chronic disease and immunometabolic abnormalities. We analyzed blood iNKT cells of adolescents with cystic fibrosis (CF, n = 24), corrected coarctation of the aorta (CoA, n = 25), juvenile idiopathic arthritis (JIA, n = 20), obesity (OB, n = 20), and corrected atrial septal defect (ASD, n = 25) as controls. Our results support that circulating immuno-metabolic factors including lipoproteins may be involved in Th1 skewing of the iNKT cell cytokine response in immunometabolic disease (Ververs FA et al., Sci Rep. 2021).
Immunodeficiency
Combined immunodeficiencies (CID) include combined defects of lymphoid cell development and function. We identified a heterozygous c.184G>A (pE62K) variant in the RAC2 gene in a family with three CID affected members (a 1-year old, his father and grandfather). RAC2 is part of the small Rho GTPase superfamily and is involved in ROS production through NADPH activation and f-actin remodeling, and is activated upon GTP binding. We modeled the patient RAC2-RacGAP1 complex, measured GTP binding to RAC2 and assessed neutrophil function. We cultured neutrophils in 3D fibrin matrices and found that migratory speed was reduced by 50% and when cultured with GFP-expressing S. aureus we found reduced bacterial killing. Altogether, our data support that the RAC2-E62K variant leads to more GTP-bound, active RAC2 by hampered GAP binding, contributing to immune cell dysfunction (Smits B et al., Clin Immunol. 2020).
Chronic Inflammation
Plasmacytoid dendritic cells (pDCs) are a rare immune cell type that links innate with adaptive immunity and are specialised in the production of type I interferon (IFN). In autoimmune diseases characterised by a type I IFN signature, including juvenile idiopathic arthritis, SLE and primary Sjögren’s syndrome, pDCs are implicated in the pathophysiology. A remaining question has been how type I IFN secretion by pDCs is regulated. Among the leucocytes in peripheral blood, expression of secretory carrier membrane protein 5 (SCAMP5) is highly selective for pDCs. To further study the role of SCAMP5 in type I IFN secretion, we focused on the cellular distribution of SCAMP5 in human pDCs freshly isolated from peripheral blood (Pouw JN et al., Lupus Sci Med. 2022).
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