Neutrophil characterization and chemokine modification in arthritic disorders

An optimal immune response requires the spatiotemporal coordination of leukocyte migration and activation. Neutrophils, as protagonists of the innate immune system, are usually the first leukocytes that arrive at the site of infection or tissue injury. They are best known as pathogen exterminators during acute inflammation. However, recent discoveries have uncovered complex functions for neutrophils as decision shaping cells during innate and adaptive immune responses. Consistently, neutrophils appear to play multifaceted roles also in infection-unrelated human diseases including autoinflammatory and autoimmune arthritic disorders. Neutrophils are provided with a broad armamentarium of defense mechanisms, implying that their migration and activation require tight regulation. Chemotactic cytokines or chemokines play a vital role in this process. These low molecular mass proteins function by interaction with specific G protein-coupled receptors and glycosaminoglycans (GAGs), with postranslational modifications fine-tuning their exact biological activity. During this doctoral research, we collected blood and/or synovial fluid samples from patients with juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA), pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), and familial Mediterranean fever (FMF). We studied the general effects of posttranslational modifications on the biological activity of the neutrophil-attracting chemokines CXCL5 and CXCL8, investigated the role of GAGs in regulating the activity of the CXCR3 ligands CXCL9, CXCL10, and CXCL11, and developed methodology that allows for differential detection of native and modified chemokines in human samples. Furthermore, we studied neutrophils in the circulation and in inflamed joints from patients with arthritic disorders.

Jaar van publicatie:2021

Toegankelijkheid:Closed