Inflammatory consequences of inherited disorders affecting neutrophil function

Abstract

Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.

<p>Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease</p>

“…Individuals with defects in NCF4 and CYBC1 typically have more residual superoxide production and present with more mild infections compared to those with defects in the 4 other known genetic causes of CGD. 26 Information regarding a patient's ROI and specific genetic variant can be beneficial in guiding clinical decision-making and providing individualized patient care. These values can often be derived directly from the sequence data.…”

Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection

“…Neutrophils migrate from the circulating blood to infected tissues in response to inflammatory stimuli, where they protect the host by phagocytosing, killing, and digesting bacterial and fungal pathogens Darrah and Andrade, 2012;Lee et al, 2003;Ley et al, 2018;Nauseef and Borregaard, 2014;Nicolas-Avila et al, 2017;Segal, 2005). Neutrophil function must be tightly controlled during infection and inflammation: excessive neutrophil accumulation or hyper-responsiveness can be detrimental (Baggiolini, 2001;Castanheira and Kubes, 2019;Davis et al, 2003;Wipke and Allen, 2001), while defects in neutrophil development, trafficking, or function can result in immunological and hematological disorders (Bunting et al, 2002;Burg and Pillinger, 2001;Dinauer, 2019;Fodil et al, 2016;Kruger et al, 2015;Witko-Sarsat et al, 2000).…”

Gene therapy for severe combined immunodeficiencies and beyond

“…This disease is caused by defective expression of the heavy glycoprotein (gp91 phox, encoded by CYBB ) in the NADPH oxidase complex. The latter is notably required to generate the oxygen radicals that kill bacteria and fungi engulfed in phagolysosomes (Dinauer, 2019). A lack of NADPH oxidase exposes the individual to a lifelong threat of recurrent severe infections and inflammation (Dinauer, 2019).…”

“…The latter is notably required to generate the oxygen radicals that kill bacteria and fungi engulfed in phagolysosomes (Dinauer, 2019). A lack of NADPH oxidase exposes the individual to a lifelong threat of recurrent severe infections and inflammation (Dinauer, 2019). Although allogeneic HSCT is effective (Güngör et al, 2014), morbidity and mortality rates were up to recently still high in cases with an HLA mismatch.…”