Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD

Lys/STELLA: H Lyman Alpha Spectrograph for the Interstellar Probe

International audienceThe Interstellar Probe project gives an unprecedented opportunity to study the hydrogen atom distribution from the interstellar medium to the inner heliosphere. The solar H Lyman alpha emission (121.6nm) is the brightest line in the UV range. Solar Lyman alpha photons are backscattered by hydrogen atoms in the interplanetary medium producing the interplanetary glow that extends far beyond the heliopause into the interstellar medium. A Lyman alpha spectrograph will measure the LISM H number density giving the first direct measurement of this quantity just outside of the heliospheric interface. This value is one of the critical parameters defining the size and behavior of the heliospheric interace. With a high resolution spectrograph, it will be possible to differentiate between the Lyman alpha galactic emission derived from the UVS-Voyager data and the LISM H Lyman alpha emission from the line of sight velocity of the atoms. Because of resonant charge exchange between the hydrogen atoms and the protons, the H atom distribution is strongly affected when the neutrals cross the heliospheric interface region. H atoms created after charge exchange keep the velocity distribution of the protons that they were created from. Therefore, the backscattered Lyman alpha line profile will change as the interstellar probe crosses through the inner heliosheath to the outer heliosheath and then moves into the LISM, providing a test on the proton distribution in the heliosphere regions crossed by the interstellar probe. Here, we will present an instrumental design that will allow for this study bringing new information on the heliospheric interface and the very local interstellar medium

Lys/STELLA: H Lyman Alpha Spectrograph for the Interstellar Probe

International audienceThe Interstellar Probe project gives an unprecedented opportunity to study the hydrogen atom distribution from the interstellar medium to the inner heliosphere. The solar H Lyman alpha emission (121.6nm) is the brightest line in the UV range. Solar Lyman alpha photons are backscattered by hydrogen atoms in the interplanetary medium producing the interplanetary glow that extends far beyond the heliopause into the interstellar medium. A Lyman alpha spectrograph will measure the LISM H number density giving the first direct measurement of this quantity just outside of the heliospheric interface. This value is one of the critical parameters defining the size and behavior of the heliospheric interace. With a high resolution spectrograph, it will be possible to differentiate between the Lyman alpha galactic emission derived from the UVS-Voyager data and the LISM H Lyman alpha emission from the line of sight velocity of the atoms. Because of resonant charge exchange between the hydrogen atoms and the protons, the H atom distribution is strongly affected when the neutrals cross the heliospheric interface region. H atoms created after charge exchange keep the velocity distribution of the protons that they were created from. Therefore, the backscattered Lyman alpha line profile will change as the interstellar probe crosses through the inner heliosheath to the outer heliosheath and then moves into the LISM, providing a test on the proton distribution in the heliosphere regions crossed by the interstellar probe. Here, we will present an instrumental design that will allow for this study bringing new information on the heliospheric interface and the very local interstellar medium

Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease.

BACKGROUND & AIMS: The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy. METHODS: We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy. RESULTS: IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors. CONCLUSIONS: A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease

Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease

Contains fulltext : 215586.pdf (publisher's version ) (Open Access)Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vgamma4(+)/Vdelta1(+) intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vgamma4(+)/Vdelta1(+) IELs was accompanied by the expansion of gluten-sensitive, interferon-gamma-producing Vdelta1(+) IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vgamma4(+)/Vdelta1(+) subset among TCRgammadelta(+) IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRgammadelta(+) IEL compartment in CeD. VIDEO ABSTRACT

Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease

Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD