Speak, A. | Search bioRxiv

bioRxiv2019

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation. Specifically, high-throughput phenotyping of 530 knockout mouse lines identified 140 monogenic \"hits\" (>25%), most of which had never hitherto been implicated in immunology. Furthermore, they were conspicuously enriched in genes for which humans show poor tolerance to loss-of-function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with one another and with specific physiologic traits. By limiting the freedom of individual immune parameters, such linkages impose genetically regulated \"immunological structures\", whose integrity was found to be associated with immunocompetence. Hence, our findings provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.

immunology↗

bioRxiv2018

EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease.

The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91phox-p22phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. We now show that the function of EROS is conserved in human cells and describe a case of CGD secondary to a homozygous EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of EROS in human immunity and describes a novel cause of CGD.\n\nClinical ImplicationsChronic granulomatous disease is caused by an inability to make reactive oxygen species via the phagocyte NADPH oxidase. Mutations in C17ORF62/EROS, which controls gp91phox- p22phox abundance, are a novel cause of chronic granulomatous disease.\n\nKey MessagesO_LIThe murine gene, Eros, is known to regulate abundance of gp91phox-p22phox heterodimer and Eros deficient mice are susceptible to infection\nC_LIO_LIWe show that the function of EROS is conserved in human cells and that a homozygous mutation in EROS causes chronic granulomatous disease\nC_LI

immunology↗