Search NASA⌕ Search

SEARCH · Search NASA

Results for “immunization”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,063 records · Page 59
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Frequencies and expression levels of programmed death ligand 1 (PD-L1) in circulating tumor RNA (ctRNA) in various cancer types

Highlights: • Blood were collected from gastric, colorectal, lung, breast, prostate cancer patients. • PD-L1 expression was detected in the plasma at varying frequencies. • No PD-L1 mRNA was detected in cancer-free individuals. • PD-L1 mRNA can be detected and quantitated in ctRNA of cancer patients. Precision medicine and prediction of therapeutic response requires monitoring potential biomarkers before and after treatment. Liquid biopsies provide noninvasive prognostic markers such as circulating tumor DNA and RNA. Circulating tumor RNA (ctRNA) in blood is also used to identify mutations in genes of interest, but additionally, provides information about relative expression levels of important genes. In this study, we analyzed PD-L1 expression in ctRNA isolated from various cancer types. Tumors inhibit antitumor response by modulating the immune checkpoint proteins programmed death ligand 1 (PD-L1) and its cognate receptor PD1. The expression of these genes has been implicated in evasion of immune response and resistance to targeted therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

YY1 promotes IL-6 expression in LPS-stimulated BV2 microglial cells by interacting with p65 to promote transcriptional activation of IL-6

Neuroinflammation plays a critical role in the process of neurodegenerative disorders, during which microglia, the principal resident immune cells in the central nervous system, are activated and produce proinflammatory mediators. Yin-Yang 1 (YY1), a multi-functional transcription factor, is widely expressed in cells of the immune system and participate in various cellular processes. However, whether YY1 is involved in the process of neuroinflammation is still unknown. In the present study, we found that YY1 was progressively up-regulated in BV2 microglial cells stimulated with lipopolysaccharide (LPS), which was dependent on the transactivation function of nuclear factor kappa B (NF-κB). Furthermore, YY1 knockdown notably inhibited LPS-induced the activation of NF-κB signaling and interleukin-6 (IL-6) expression in BV-2 cells, but not mitogen-activated protein kinase (MAPK) signaling. Moreover, YY1 strengthened p65 binding to IL-6 promoter by interacting with p65 but decreased H3K27ac modification on IL-6 promoter, eventually increasing IL-6 transcription. Taken together, these results for the first time uncover the regulatory mechanism of YY1 on IL-6 expression during neuroinflammation responses and provide new lights into neuroinflammation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

PDGF family function and prognostic value in tumor biology

Highlights: • Large scale transcriptomic data analysis reveals tumor-specific roles of PDGF signaling. • Functional gene sets associated with PDGF expression are conserved between PDGF family members. • PDGF related gene signatures have increased prognostic value over each single gene. The development and progression of a tumor depends on the close interaction of malignant cells and the supportive and suppressive tumor microenvironment. Paracrine signaling enables tumor cells to shape the surrounding tissue in order to decrease recognition by the immune system, attract blood vessels to fuel growth, change metabolic programs, and induce wound healing programs. In this study, we investigate the role of the platelet-derived growth factor (PDGF) family members PDGFA, PDGFB, PDGFC and PDGFD and their cognate tyrosine kinase receptors PDGFRA and PDGFRB, using publicly available data from The Cancer Genome Atlas and the Human Protein Atlas. Large scale analysis of expression correlation in RNA sequencing data from 7616 samples derived from 16 tumor types, revealed conserved functional programs in PDGF signaling in the majority of solid tumor types. Besides the well-known effects of PDGF signaling in mesenchymal cells, our analyses revealed a potential role of PDGF signaling in the composition of the immune microenvironment. We furthermore derived gene signatures with increased prognostic value for each PDGF family member. This study emphasizes the potential to impinge on specific paracrine signaling events to interfere with the crosstalk between malignant cells and their microenvironment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identification of antibodies against extracellular matrix proteins in human osteoarthritis

Highlights: • Autoantibodies against the TSP-4, COMP and CLEC3A are present in serum of osteoarthritis (OA) patients. • The detection of autoantibodies against TSP-4, COMP and CLEC3A may support the clinical diagnosis of OA. • OA with autoantibodies against cartilage extracellular matrix proteins defines a new OA subgroup. • Patients with high concentrations of autoantibodies may benefit from an immune suppressive therapy. We investigated the presence of autoantibodies against the extracellular matrix proteins thrombospondin-4 (TSP-4), cartilage oligomeric matrix protein (COMP), C-type lectin domain family 3 member A (CLEC3A), collagen II, collagen VI, matrilin-3, and fibrillin-2 in the serum of osteoarthritis (OA) patients. We compared those results with the presence of such antibodies in rheumatoid arthritis (RA) patients and in healthy donors (HD). Our study examines whether antibodies against extracellular proteins can be used as potential biomarkers to support the clinical diagnosis of OA. 10 OA, 10 RA patients and 10 HD were enrolled in this explorative cross-sectional study. SDS-PAGE and immunoblot were used to investigate the presence of antibodies against extracellular matrix proteins. The serum of 5/10 OA patients but 0/10 HD exhibited TSP-4 IgG isotype antibodies (P = 0.033). The serum of 8/10 OA patients but only 1/10 HD exhibited IgG isotype antibodies against TSP-4 or COMP (P = 0.005). The serum of 9/10 OA patients but only 1/10 HD exhibited IgG isotype antibodies against TSP-4, COMP or CLEC3A (P = 0.005). We found strong evidence for the presence of IgG isotype autoantibodies against the cartilage extracellular matrix proteins TSP-4, COMP and CLEC3A in OA. The detection of IgG isotype autoantibodies against TSP-4, COMP and CLEC3A may support the clinical diagnosis of OA. OA with autoantibodies against cartilage extracellular matrix proteins defines a new OA subgroup suggesting that patients with high concentrations of autoantibodies may benefit from an immune suppressive therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells

Peripheral blood mononuclear cells (PBMCs) contain multipotent progenitor cell populations and possess the potential to differentiate into various types of immune cells under both physiological and pathological conditions. Ferroptosis is a type of oxidative stress-associated cell death that is mainly mediated by lipid peroxidation. However, the function of ferroptosis in cell differentiation remains unknown. Here, we showed that the ferroptosis inducer erastin did not cause cell death in human PBMCs. In contrast, erastin-induced lipid peroxidation promoted human PBMC proliferation and differentiation into B cells and natural killer cells through inhibition of bone morphogenetic protein family expression. These findings uncover a new immune modulation function of erastin in promoting PBMC proliferation and differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Anti-survivin single-domain antibodies derived from an artificial library including three synthetic random regions by in vitro selection using cDNA display

Highlights: • Single-domain antibodies can be selected with an artificial DNA library synthesized chemically. • cDNA display method is useful for in vitro selection from a large single-domain antibodies library (e.g. 1013). • A Brevibacillus protein expression system is suitable for synthesis of functional single-domain antibodies. Single-domain antibodies (variable domain of the heavy chain of a heavy chain antibody; VHH) are promising reagents for therapeutics and diagnostics because of their stability, cost-effective production and material workability as a small antibody. Currently, general acquisition of a VHH using immunization of camelids is inconvenient from the standpoint of animal protection, cost and the process is time-consuming. Thus, a straightforward and efficient method for screening VHHs against a target molecule is required. In this study, we examined whether in vitro selection of a VHH against a target protein could be performed by a cDNA display method with an artificial VHH library that had the three complementarity-determining regions (CDRs) randomized by chemical synthesis. The results revealed that a particular VHH against survivin, which is a member of the inhibitor of apoptosis family, was selected with affinity in the range of 10{sup −7} to 10{sup −8} M. The in vitro selection of a VHH using cDNA display with an artificial synthesized library without animal immunization was shown to be effective for rapid and inexpensive screening of VHHs against a target protein.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ERα is a negative regulator of PD-L1 gene transcription in breast cancer

Highlights: • PD-L1 mRNA level is much lower in ERα-positive breast cancer cell lines. • E2 treatment inhibits PD-L1 gene transcription in ERα-positive MCF7 cells. • Ectopic expression of ERα down-regulates PD-L1 gene expression in ERα-negative MDA-MB-231 cells. • ERα expression is negatively correlated with PD-L1 expression in ERα-positive breast cancer. The programmed death-ligand 1 (PD-L1) expression by tumors results in potent antitumor immune suppression through binding to programmed death-1 (PD-1) on T cells and subsequent inhibition of T cells activity. Although recent pathological studies have shown that PD-L1 is actively expressed in certain ERα-negative breast cancer, little is known about whether ER signaling regulates PD-L1 gene expression. Here, we investigated the relationship between ERα and PD-L1 in breast cancer. Analysis of Comprehensive Cell Line Encyclopedia (CCLE) data showed that the average mRNA level of PD-L1 in ERα-positive breast cancer cell lines was significantly lower than that in ERα-negative breast cancer cell lines. E2 treatment inhibited PD-L1 mRNA expression in hormone-depleted ERα-positive MCF7 cells. Moreover, ectopic expression of ERα in triple-negative MDA-MB-231 cells reduced PD-L1 mRNA and protein expression. Consistently, analysis of The Cancer Genome Atlas (TCGA) data revealed an inverse correlation between ERα and PD-L1 expression in ERα-positive breast cancer. Taken together, our results identify ERα as a negative regulator of PD-L1 gene transcription in breast cancer cells, suggesting that ERα loss-of-function may facilitate the immune evasion of breast cancer cells via up-regulation of PD-L1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

ODC1 inhibits the inflammatory response and ROS-induced apoptosis in macrophages

Highlights: • ODC1 is up-regulated by LPS, BCG and CCl4 stimulation. • ODC1 inhibits inflammatory responses in macrophages. • ODC1 mediates NF-κB and MAPK activation. • ODC1 inhibits ROS-induced macrophage apoptosis. Macrophage activation plays a critical role in the innate immune response. Ornithine decarboxylase (ODC1) metabolizes l-ornithine to polyamines and is the rate-limiting enzyme involved in the metabolism of polyamines, which are reportedly involved in cell differentiation, proliferation, and migration. However, the function of ODC1 in immune cells and especially in macrophages, as well as its underlying molecular mechanism, remains unclear. This study revealed the potential ODC1 function and mechanism associated with the lipopolysaccharide (LPS)-, Bacillus Calmette–Guerin (BCG)-, or carbon tetrachloride (CCl{sub 4})-induced inflammatory response in macrophages. We found significant upregulation of ODC1 in macrophages following LPS simulation and ODC1-specific suppression of proinflammatory cytokine secretion from macrophages upon stimulation with LPS, BCG and CCl{sub 4}, respectively, suggesting a role as a common control element of the inflammatory response. Western blotting for nuclear factor-κB and mitogen-activated protein kinases revealed significant inhibition of phosphorylation of multiple transcription factors following ODC1 overexpression in macrophages. Moreover, ODC1 inhibited reactive oxygen species-induced and caspase-dependent apoptosis highlighted by decreased caspase-3 and -9 expression following ODC1 upregulation. These findings indicated that ODC1 was involved in attenuating the inflammatory response upon stimulation of macrophages, making it a potential therapeutic target for inflammatory diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Depleting the carboxy-terminus of human Wnt5a attenuates collagen-induced arthritis in DBA/1 mice

Highlights: • phWnt5a-NL recombinant results in decreased severity of CII-induced arthritis. • phWnt5a-NL recombinant suppresses synovitis and osteoclastogenesis. • phWnt5a-NL recombinant induces the production of Treg cells. • phWnt5a-NL recombinant interrupts the Wnt5a-Ror2 signalling pathway. Wnt5a signalling plays pathological roles in synovial inflammation and bone destruction. In the present study, we designed four human Wnt5a-based DNA recombinants and detected their effects on immunogenicity and anti-rheumatism in a collagen-induced arthritis (CIA) model. Histomorphometry and micro-CT scanning showed that the phWnt5a-NL was superior to other recombinants because it resulted in decreased severity of arthritis, histopathological scores of synovial inflammation and bone erosion in CIA mice. In addition, ELISA and TRAP staining showed that the phWnt5a-NL-immunized CIA mice had reductions in the serum concentrations of the rheumatoid-associated cytokines IL-1β and RANKL and in osteoclastogenesis. Furthermore, flow cytometry showed that the phWnt5a-NL treatment increased the percentage of Treg cells. Finally, western blotting analysis showed that the phWnt5a-NL-immunization interrupted β-catenin and JNK expression in osteoclast precursors derived from the CIA mice. The results suggest that depleting the carboxy-terminus in hWnt5a-based DNA recombinants may be beneficial for the treatment of chronic inflammatory disorders involving bone resorption.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Helicobacter pylori flagellin: TLR5 evasion and fusion-based conversion into a TLR5 agonist

Highlights: • Helicobacter flagellin (hFlg) evades TLR5 by modifying a TLR5-activation hot spot. • The hypervariable domains of hFlg were identified as the soluble part of hFlg. • hFlg was engineered to activate TLR5 through fusion with Bacillus flagellin. Helicobacter pylori is a flagellated bacterium of the Epsilonproteobacteria class that causes peptic ulcers. Flagellin is a primary structural protein that assembles into the flagellar filament. Flagellins from bacteria that belong to the Gammaproteobacteria and Firmicutes groups are detected by Toll-like receptor 5 (TLR5) in the host, triggering the innate immune response, and thus have been studied for the development of vaccines against diverse infections through fusion with protein antigens. However, H. pylori flagellin (hFlg) does not stimulate TLR5, allowing H. pylori to evade TLR5-mediated immune surveillance. The unresponsiveness of TLR5 to hFlg, along with the tendency of the hFlg protein to precipitate, limits the utility of hFlg for H. pylori vaccine development. Here, we report a soluble hFlg derivative protein that activates TLR5. We performed expression and purification screens with full-length and fragment hFlg proteins and identified the hypervariable domains as the soluble part of hFlg. The hypervariable domains of hFlg were engineered into a TLR5 agonist through fusion with the TLR5-activating Bacillus subtilis flagellin. Furthermore, based on comparative sequence and mutation analyses, we reveal that hFlg evolved to evade TLR5 detection by modifying residues that correspond to a TLR5-activation hot spot.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mesenchymal stem cells induced CD4+ T cell apoptosis in treatment of lupus mice

Highlights: • The apoptosis of peripheral blood CD4+ T cell was reduced in lupus-prone mice. • UC-MSCs ameliorated disease progression of lupus mice. • UC-MSCs promoted CD4+ T lymphocyte apoptosis of lupus mice in vivo and vitro. Umbilical cord-derived mesenchymal stem cell transplantation (UCMSCT) has been used to treat human autoimmune diseases like lupus for example, but little is known about its effect on cell apoptosis. Here we evaluated the efficacy of UCMSCT for lupus treatment and explored the mechanism by which mesenchymal stem cells (MSCs) modulate T cell apoptosis in lupus mice. 1 × 10{sup 6} human umbilical cord-derived mesenchymal stem cells (UC-MSCs) were injected into B6.MRL-Fas{sup lpr} (B6.lpr) mice via tail vein. 6 h, 24 h or 4 weeks later, the mice were sacrificed and the apoptosis of lymphocytes in peripheral blood and spleen were detected by flow cytometry. The immune cell subpopulations in spleen were also measured at 6 h and 24 h, respectively. The therapeutic effects were assessed after 4 weeks. The frequency of peripheral blood CD4+ T cell apoptosis was reduced in lupus-prone B6.lpr mice. UCMSCT alleviated the disease phenotypes in B6.lpr mice, decreased the ratio of Th1 as well as Th2 cells, and increased percentages of apoptotic CD4+ T cells in vivo and vitro. Collectively, our findings unravel that UCMSCT alleviate lupus disease and reverse immune imbalance possibly by promoting T cell apoptosis in B6.lpr mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Streptococcus gallolyticus conspires myeloid cells to promote tumorigenesis of inflammatory bowel disease

Highlights: • Streptococcus gallolyticus shows a distinctive enrichment at colonic mucosa in colitis-associated carcinoma. • Introduction of Streptococcus gallolyticus could aggravate the development of colitis-associated carcinoma. • CD11b{sup +} myeloid cells recruitment are initialed by Streptococcus gallolyticus to promote colitis-associated carcinoma progress. Metagenomic analyses indicate that streptococcus gallolyticus is enriched at carcinoma in colitis associated colorectal cancer compared with sporadic colorectal cancer. But the particular mechanism of streptococcus gallolyticus in Inflammatory Bowel Disease malignant progression remains undefined yet. We aim to explore the biological carcinogenesis efficacy of streptococcus gallolyticus and its potential mechanism in azoxymethane and dextran sodium sulphate-induced colitis associated colorectal cancer in mice. Oral pretreatment of streptococcus gallolyticus was adopted to evaluate its detrimental effect. The colorectums of experimental C57BL/6 mice were collected and examined for the degree of tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe streptococcus gallolyticus alterations in abundance. We found that streptococcus gallolyticus are enriched in colonic carcinoma compared to adenoma and healthy mice. Pretreatment of Streptococcus gallolyticus aggravated tumor formation, with more colonic obstruction, larger number and diameter of tumor node. Furthermore, Streptococcus gallolyticus selectively recruits tumor-infiltrating myeloid cells but not mast cells, including marrow-derived suppressor cells, tumor-associated macrophages and dendritic cells, which can inhibit competence of T cells. Moreover, several myeloid-cell-derived proinflammatory cytokines (IL-6, IL-1β, IL-8, CCL2, COX-2, TNF-α) were increased with the formation of carcinoma in IBD. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, Streptococcus gallolyticus generate an immune suppressive microenvironment that is conducive for neoplasia progression of Inflammatory Bowel Disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Lattice light-sheet microscopy allows for super-resolution imaging of receptors in leaf tissue

Plant leaf tissues are difficult to image via fluorescent microscopy, largely due to the presence of chlorophyll and other pigments that provide large background fluorescence. An advantage of Lattice Light-Sheet microscopy is its use of Bessel beams that illuminate a thin focal region of interest for microscopy, allowing for the excitation of fluorescent molecules within this region without surrounding chlorophyll-like objects outside of the region of interest. Here, we apply STORM Super-resolution techniques to observe Receptor-Like Kinases in Arabidopsis thaliana leaf cells. By applying this technique with the Lattice Light-Sheet, we can localize immune response proteins in sub-100 nm length scales and reconstruct three-dimensional locations of proteins within individual leaf cells. Using this technique, we observed the effect of the elicitors ATP and flg22, where we observed a significant degree of internalization of cognate receptors P2K1 and FLS2. We were also able to similarly observe differences in colocalization due to stimulation with these elicitors, where we observe proteins on the membrane becoming less colocalized as a result of stimulation, suggesting an immune response mechanism involving receptors internalizing via pathways distinct to the receptor. Further, these data show the Lattice Light-Sheet’s capabilities for imaging tissue with problematic background fluorescence that otherwise makes super-resolution fluorescence microscopy difficult.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Antibodies to a Conserved Influenza Head Interface Epitope Protect by an IgG Subtype-Dependent Mechanism

Vaccines to generate durable humoral immunity against antigenically evolving pathogens such as the influenza virus must elicit antibodies that recognize conserved epitopes. Analysis of single memory B cells from immunized human donors has led us to characterize a previously unrecognized epitope of influenza hemagglutinin (HA) that is immunogenic in humans and conserved among influenza subtypes. Structures show that an unrelated antibody from a participant in an experimental infection protocol recognized the epitope as well. IgGs specific for this antigenic determinant do not block viral infection in vitro, but passive administration to mice affords robust IgG subtype-dependent protection against influenza infection. The epitope, occluded in the pre-fusion form of HA, is at the contact surface between HA head domains; reversible molecular “breathing” of the HA trimer can expose the interface to antibody and B cells. Lastly, antigens that present this broadly immunogenic HA epitope may be good candidates for inclusion in “universal” flu vaccines.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Formin nanoclustering-mediated actin assembly during plant flagellin and DSF signaling

Plants respond to bacterial infection acutely with actin remodeling during plant immune responses. The mechanisms by which bacterial virulence factors (VFs) modulate plant actin polymerization remain enigmatic. Here, we show that plant-type-I formin serves as the molecular sensor for actin remodeling in response to two bacterial VFs: Xanthomonas campestris pv. campestris (Xcc) diffusible signal factor (DSF), and pathogen-associated molecular pattern (PAMP) flagellin in pattern-triggered immunity (PTI). Both VFs regulate actin assembly by tuning the clustering and nucleation activity of formin on the plasma membrane (PM) at the nano-sized scale. By being integrated within the cell-wall-PM-actin cytoskeleton (CW-PM-AC) continuum, the dynamic behavior and function of formins are highly dependent on each scaffold layer’s composition within the CW-PM-AC continuum during both DSF and PTI signaling. Our results reveal a central mechanism for rapid actin remodeling during plant-bacteria interactions, in which bacterial signaling molecules fine tune plant formin nanoclustering in a host mechanical-structure-dependent manner.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the “RBD-up” position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont

Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii , may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

60 APPLIED LIFE SCIENCES↗