CITRYLL,  Innovation in Medicine

Science of NETosis and autoantigens

Neutrophils are the essential custodians of the innate immune system. As such they play a critical role in defending the host against invading microorganisms which are cleared by phagocytosis and production of bactericidal molecules by emptying the contents of the neutrophil granules, this neutrophil function is called degranulation.

Net image 1A relatively recent discovery is that neutrophils upon sterile or non-sterile stimuli can form extracellular traps characterised by the extrusion of granular proteins, that are attached to a meshwork of de-condensed chromatin and other nuclear components. These lattices have been called NETs and the process of NET formation has been designated NETosis.

The formation of Neutrophil Extracellular Traps or NETosis is a unique form of cell death that is morphologically distinct from necrosis, apoptosis and others.

NETs are pro-inflammatory as well as immuno-stimulatory, and neutrophils show increased activity in inflammatory conditions. And since its description the dysregulation of NET biology has been associated with a number of human diseases and as such has drawn a growing interest as a potential target for therapeutic intervention. Diseases where NET biology is contributing or even causal to the pathology include rheumatoid arthritis, vasculitis, sepsis, various lung conditions including pulmonary and cystic fibrosis, lupus, wound healing in diabetes, otitis media, Transfusion Related Acute Lung Injury (TRALI), and the list is growing.

The formation of NETs is dependant on a number of factors including myeloperoxidase (MPO), NADPH oxidase, elastase and PAD4. Neutrophils from chronic granulomatous disease (CGD) patients fail to make NETs. CGD is caused by mutations that disrupt the ability of the NADPH oxidase to generate superoxide, which dismutates to hydrogen peroxide, the substrate of MPO. Neutrophils from donors who are completely deficient in MPO do not form NETs, indicating that MPO is required for NET formation. In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation (Blood. 2011;117(3): 953-959).

In diseases like RA and SLE NETs are the sources of auto antigens. Citrullinated proteins in RA and DNA and nuclear proteins in SLE.