ena-STUDY-dfdong-12-12-2016-18:17:33:609-297
this work combines newly developed methods of host gene expression analysis in duodenal tissues with unique approaches to the identification of specific pathobiont bacteria in the duodenal microbiome to elucidate mechanisms of GI dysfunction in Common Variable Immunodeficiency (CVID).  As such it provides new insights into how the mucosal immune response controls gut function in general.
Common variable immunodeficiency (CVID), the most frequently occurring form ofsymptomatic immunodeficiency, is a heterogeneous disease that is most likely due to manydifferent genetic defects. In recent years, some of these have been described, but the vastmajority of patients with CVID are still without a defined genetic abnormality (ref).With the advent of early gamma globulin replacement therapy, CVID patients are relativelyfree from life-threatening infections and have a more prolonged survival (REF). The latter,however, has revealed that CVID can be associated with other problems not due tocommon infectious agents. One of these, CVID enteropathy is characterized by villousatrophy, malabsorption and diarrhea and occurs in up to 25% of CVID patients insymptomatic form and perhaps in a larger percentage in asymptomatic form (PMID:20551941; other ref). It is not clear why only a subset of patients with CVID developenteropathy since this manifestation of the disease has not been coupled to a particulargenetic defect or environmental exposure.The villous atrophy accompanying CVID enteropathy is histologically similar to that in celiacdisease and, as such, is characterized by lamina propria inflammation accompanied bypolymorphonuclear cell infiltration and increased numbers of intra-epithelial lymphocytes;however, the prominent plasma cell infiltration seen in celiac disease is not present (PMID:20551941). These studies also showed that intraepithelial lymphocytes (IELs) in CVIDenteropathy differed from those in celiac disease in regarding some natural killer cellmarkers and TCR?/? characteristic of those in celiac disease were generally not present inCVID. Further, studies of the immunologic features of this gastrointestinal syndromeconducted by Mannon et al. (PMID: 16952544) revealed that lamina propria cells wereproducing increased amounts of IL-12 and IFN-? but little if any IL-17.In previous studies we have shown using systems biology methodology that totalimmunoglobulin and IgA deficiency in mice or indeed CVID in humans is associated with aremarkable up-regulation of interferon-inducible genes accompanied by a down-regulationof GATA4-related metabolic genes in the gut epithelium (PMID: 22101768). Since thesechanges were not seen in germ-free mice it clearly implied that they were dependent onone or more organisms in the gut microbiota. These studies therefore suggested that thepathogenesis of CVID enteropathy may be related to the presence of an immune defect thatleads to the colonization with an organism that drives these multiple gene expressionchanges. In the present study, we have again applied a systems biology approach to addressthis possibility, in this case including human transcriptome and microbiome analyses ofduodenal tissues of patients and healthy controls. To our surprise, we found that CVIDenteropathy was strictly limited to those CVID patients with vanishing low gut tissue IgAlevels irrespective of accompanying gut IgG levels and serum IgA levels. We used this globalomics data for transkingdom network analysis (PMID: 25614621;) to identify candidatebacteria capable of inducing the interferons response causing the villous atrophy andmalabsorption. Lastly, also using gene expression network of CVID enteropathy we pinpointand later validated in vitro two immune genes that mediate inhibitory effect of interferonson lipid metabolism in epithelium.
Common variable immunodeficiency (CVID), the most frequently occurring form ofsymptomatic immunodeficiency, is a heterogeneous disease that is most likely due to manydifferent genetic defects. In recent years, some of these have been described, but the vastmajority of patients with CVID are still without a defined genetic abnormality (ref).With the advent of early gamma globulin replacement therapy, CVID patients are relativelyfree from life-threatening infections and have a more prolonged survival (REF). The latter,however, has revealed that CVID can be associated with other problems not due tocommon infectious agents. One of these, CVID enteropathy is characterized by villousatrophy, malabsorption and diarrhea and occurs in up to 25% of CVID patients insymptomatic form and perhaps in a larger percentage in asymptomatic form (PMID:20551941; other ref). It is not clear why only a subset of patients with CVID developenteropathy since this manifestation of the disease has not been coupled to a particulargenetic defect or environmental exposure.The villous atrophy accompanying CVID enteropathy is histologically similar to that in celiacdisease and, as such, is characterized by lamina propria inflammation accompanied bypolymorphonuclear cell infiltration and increased numbers of intra-epithelial lymphocytes;however, the prominent plasma cell infiltration seen in celiac disease is not present (PMID:20551941). These studies also showed that intraepithelial lymphocytes (IELs) in CVIDenteropathy differed from those in celiac disease in regarding some natural killer cellmarkers and TCR?/? characteristic of those in celiac disease were generally not present inCVID. Further, studies of the immunologic features of this gastrointestinal syndromeconducted by Mannon et al. (PMID: 16952544) revealed that lamina propria cells wereproducing increased amounts of IL-12 and IFN-? but little if any IL-17.In previous studies we have shown using systems biology methodology that totalimmunoglobulin and IgA deficiency in mice or indeed CVID in humans is associated with aremarkable up-regulation of interferon-inducible genes accompanied by a down-regulationof GATA4-related metabolic genes in the gut epithelium (PMID: 22101768). Since thesechanges were not seen in germ-free mice it clearly implied that they were dependent onone or more organisms in the gut microbiota. These studies therefore suggested that thepathogenesis of CVID enteropathy may be related to the presence of an immune defect thatleads to the colonization with an organism that drives these multiple gene expressionchanges. In the present study, we have again applied a systems biology approach to addressthis possibility, in this case including human transcriptome and microbiome analyses ofduodenal tissues of patients and healthy controls. To our surprise, we found that CVIDenteropathy was strictly limited to those CVID patients with vanishing low gut tissue IgAlevels irrespective of accompanying gut IgG levels and serum IgA levels. We used this globalomics data for transkingdom network analysis (PMID: 25614621;) to identify candidatebacteria capable of inducing the interferons response causing the villous atrophy andmalabsorption. Lastly, also using gene expression network of CVID enteropathy we pinpointand later validated in vitro two immune genes that mediate inhibitory effect of interferonson lipid metabolism in epithelium.