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Journal of Autoimmunity

Hsi-Ju Wei, Ashish Gupta, Wei-Ming Kao, Omar Almudallal, John J Letterio, Tej K Pareek
Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-β and suppression of TNFα, IFN-γ, and IL-12 levels in Nrf2+/+ but not Nrf2-/- DCs...
July 16, 2018: Journal of Autoimmunity
Brittany L Hartwell, Chad J Pickens, Martin Leon, Laura Northrup, Matthew A Christopher, J Daniel Griffin, Francisco Martinez-Becerra, Cory Berkland
Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen-specific targeting through the B cell receptor (BCR)...
July 12, 2018: Journal of Autoimmunity
Qianwen Li, Haijing Wu, Wei Liao, Ming Zhao, Vera Chan, Linfeng Li, Min Zheng, Genhui Chen, Jianzhong Zhang, Chak-Sing Lau, Qianjin Lu
Lupus erythematosus (LE) is an autoimmune disease with a broad clinical spectrum ranging from cutaneous lesions to severe systemic manifestations. The pathogenesis of the disease and the immunological mechanisms for the heterogeneities in lupus remain unclear. The LE-specific cutaneous manifestations are generally divided into three categories: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Clinically, lupus patients with skin lesions can be divided into two subsets based on the organs involved: cutaneous LE, such as DLE and SCLE, which appears only as a skin manifestation, and systemic lupus erythematosus (SLE), e...
July 11, 2018: Journal of Autoimmunity
Elke Gülden, Chen Chao, Ningwen Tai, James A Pearson, Jian Peng, Monika Majewska-Szczepanik, Zhiguang Zhou, F Susan Wong, Li Wen
The incidence of type 1 diabetes (T1D) is determined by both genetic and environmental factors. In recent years, the gut microbiota have been identified to be an important environmental factor that could modify diabetes susceptibility. We have previously shown that Myeloid differentiation primary response gene 88 (MyD88), a major adaptor protein downstream of most innate immune Toll-like receptor (TLR) signaling, is important for mediating diabetes susceptibility in the non-obese diabetic (NOD) mouse model of human T1D...
June 27, 2018: Journal of Autoimmunity
Tobias Alexander, Dominique Farge, Manuela Badoglio, James O Lindsay, Paolo A Muraro, John A Snowden
With accumulating evidence and improved outcomes along with recognition that modern biological therapies are not universally effective, require chronic administration and have high acquisition costs, hematopoietic stem cell transplantation (HSCT) has become an emerging direction for cell therapy in autoimmune diseases (ADs). The goal of this therapy is to induce medication-free remissions by resetting the immune system into a naïve and self-tolerant state through eradication of the autoreactive immunologic memory and profound re-configuration of the immune system induced by the transplant procedure...
June 19, 2018: Journal of Autoimmunity
Mahira Zaheer, Changjun Wang, Fang Bian, Zhiyuan Yu, Humberto Hernandez, Rodrigo G de Souza, Ken T Simmons, Deborah Schady, Alton G Swennes, Stephen C Pflugfelder, Robert A Britton, Cintia S de Paiva
CD25 knock-out (CD25KO) mice spontaneously develop Sjögren Syndrome (SS)-like inflammation. We investigated the role of commensal bacteria by comparing CD25KO mice housed in conventional or germ-free conditions. Germ-free CD25KO mice have greater corneal barrier dysfunction, lower goblet cell density, increased total lymphocytic infiltration score, increased expression of IFN-γ, IL-12 and higher a frequency of CD4+ IFN-γ+ cells than conventional mice. CD4+ T cells isolated from female germ-free CD25KO mice adoptively transferred to naive immunodeficient RAG1KO recipients caused more severe Sjögren-like disease than CD4+ T cells transferred from conventional CD25KO mice...
June 20, 2018: Journal of Autoimmunity
Johannes Nowatzky, Olivier Manches, Shaukat Ali Khan, Emmanuelle Godefroy, Nina Bhardwaj
OBJECTIVE: Apoptotic cell receptors contribute to the induction of tolerance by modulating dendritic cell function following the uptake of apoptotic cells or microparticles. Dendritic cells that have bound or ingested apoptotic cells produce only low amounts of pro-inflammatory cytokines and fail to prime effector T cell responses. Specifically, ligation of the apoptotic cell receptor CR3 (CD11 b/CD18) on human monocyte-derived dendritic cells (moDC) down-modates proinflammatory cytokine secretion, but the consequences for human Th17 cell homeostasis and effector responses remain unknown...
June 13, 2018: Journal of Autoimmunity
Yuxuan Zhen, Iris J Lee, Fred D Finkelman, Wen-Hai Shao
Glomerulonephritis (GN) is a typical lesion in autoantibody and immune complex disorders, including SLE. Because the Gas6/Axl pathway has been implicated in the pathogenesis of many types of GN, targeting this pathway might ameliorate GN. Consequently, we have studied the efficacy and mechanism of R428, a potent selective Axl inhibitor, in the prevention of experimental anti-GBM nephritis. Axl upregulation was investigated with Sp1/3 siRNA in the SV40-transformed mesangial cells. For Axl inhibition, a daily dose of R428 (125 mg/kg) or vehicle was administered orally...
June 9, 2018: Journal of Autoimmunity
R S Hardy, C Fenton, A P Croft, A J Naylor, R Begum, G Desanti, C D Buckley, G Lavery, M S Cooper, K Raza
OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11β-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11β-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11β-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis...
June 8, 2018: Journal of Autoimmunity
Susana Brun, Nicolas Schall, Srinivasa Reddy Bonam, Kévin Bigaut, Ayikoe-Guy Mensah-Nyagan, Jérôme de Sèze, Sylviane Muller
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves evolving with diffuse sensory and motor symptoms. Although it is claimed that in neurodegenerative pathologies, a common feature is the failure of proteolytic systems to adequately eliminate aggregated or misfolded proteins, it has not been addressed whether autophagy, a central "clearance" system delivering damaged intracellular components to lysosomes, is affected in CIDP. The focus of the present investigation was therefore to determine if some defects exist in autophagy processes in this setting and if they can be corrected or minimized using an appropriate treatment targeting this survival pathway...
June 5, 2018: Journal of Autoimmunity
Lisa Rizzetto, Francesca Fava, Kieran M Tuohy, Carlo Selmi
Unresolved low grade systemic inflammation represents the underlying pathological mechanism driving immune and metabolic pathways involved in autoimmune diseases (AID). Mechanistic studies in animal models of AID and observational studies in patients have found alterations in gut microbiota communities and their metabolites, suggesting a microbial contribution to the onset or progression of AID. The gut microbiota and its metabolites have been shown to influence immune functions and immune homeostasis both within the gut and systematically...
May 31, 2018: Journal of Autoimmunity
Evangelos Theodorou, Adrianos Nezos, Eleni Antypa, Dimitrios Ioakeimidis, Michael Koutsilieris, Maria Tektonidou, Haralampos M Moutsopoulos, Clio P Mavragani
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with an increased atherosclerotic risk compared to healthy population, partially explained by traditional cardiovascular (CV) risk factors. Recent data suggest B-cell activating factor (BAFF) as an important contributor in the pathogenesis of both SLE and atherosclerosis. The aim of the current study is to explore whether serum BAFF levels along with variants of the BAFF gene increase lupus related atherosclerotic risk...
May 30, 2018: Journal of Autoimmunity
Yong Chan Kim, Ai-Hong Zhang, Jeongheon Yoon, William E Culp, Jason R Lees, Kai W Wucherpfennig, David W Scott
Expanded polyclonal T regulatory cells (Tregs) offer great promise for the treatment of immune-mediated diseases. Inhibition by Tregs is under the control of the T-cell receptor (TCR). Therefore, we created Tregs with defined antigen specificity, using a recombinant T-cell receptor isolated from a myelin-basic protein specific T-cell clone of a multiple sclerosis (MS) patient (Ob2F3). We expressed this TCR using a retroviral expression vector in human Tregs from peripheral blood. We observed that transduced Tregs were activated in vitro in response to myelin basic protein (MBP) peptide on DR15 antigen-presenting cells (APC) and upregulated Treg markers, Foxp3, LAP and Helios...
May 29, 2018: Journal of Autoimmunity
Jennifer Pieper, Anatoly Dubnovitsky, Christina Gerstner, Eddie A James, Mary Rieck, Genadiy Kozhukh, Karolina Tandre, Sara Pellegrino, John A Gebe, Lars Rönnblom, Tatyana Sandalova, William W Kwok, Lars Klareskog, Jane H Buckner, Adnane Achour, Vivianne Malmström
ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within α-enolase326-340 in the context of HLA-DRB1*04:01 and assessed the corresponding CD4+ T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated α-enolase326-340 peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of α-enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry...
May 28, 2018: Journal of Autoimmunity
Qinlan Wang, Chunmei Wang, Nan Li, Xingguang Liu, Wenhui Ren, Qingqing Wang, Xuetao Cao
Structural maintenance of chromosome (Smc) protein complex (condensin) plays a central role in organizing and compacting chromosomes, which determines DNA-binding activity and gene expression; however, the role of condensin Smc in innate immunity and inflammation remains largely unknown. Through a high-throughput screening of the epigenetic modifiers, we identified Smc4, a core subunit of condensin, to potentially promote inflammatory innate immune response. Knockdown or deficiency of Smc4 inhibited TLR- or virus-triggered production of proinflammatory cytokines IL-6, TNF-α and IFN-β in macrophages...
May 24, 2018: Journal of Autoimmunity
Gregg E Dinse, Christine G Parks, Helen C S Meier, Caroll A Co, Edward K L Chan, Todd A Jusko, James Yeh, Frederick W Miller
BACKGROUND: Clinical reports link specific medications with the development of antinuclear antibodies (ANA), but population-based evidence is limited. OBJECTIVE: The present study investigated associations between prescription medication use and ANA in a representative sample of the adult noninstitutionalized US population, first focusing on medications previously related to ANA and then considering all medications reported in the National Health and Nutrition Examination Survey (NHANES)...
May 17, 2018: Journal of Autoimmunity
Ricard Cervera, Ignasi Rodríguez-Pintó, Gerard Espinosa
The catastrophic antiphospholipid syndrome (CAPS) is a life-threating variant of the antiphospholipid syndrome characterized by the development of multiple thrombosis in a short period of time, usually ending up in the failure of function of several vital organs. Most CAPS episodes are related to a prothrombotic situation or precipitating factor such as infections, surgical procedures or malignant diseases. In patients with CAPS, the development of multiple thrombosis leads to an important cytokine release that worsens the already critical patient's situation...
May 17, 2018: Journal of Autoimmunity
Edith Hintermann, Monika Bayer, Clara Benedetta Conti, Sina Fuchs, Michel Fausther, Patrick S Leung, Michel Aurrand-Lions, Richard Taubert, Josef M Pfeilschifter, Mireen Friedrich-Rust, Detlef Schuppan, Jonathan A Dranoff, M Eric Gershwin, Michael P Manns, Beat A Imhof, Urs Christen
Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively...
July 2018: Journal of Autoimmunity
Erika Cretney, Patrick Sk Leung, Stephanie Trezise, Dane M Newman, Lucille C Rankin, Charis E Teh, Tracy L Putoczki, Daniel Hd Gray, Gabrielle T Belz, Lisa A Mielke, Sheila Dias, Stephen L Nutt
Regulatory T (Treg ) cells maintain immunological tolerance in steady-state and after immune challenge. Activated Treg cells can undergo further differentiation into an effector state that highly express genes critical for Treg cell function, including ICOS, TIGIT and IL-10, although how this process is controlled is poorly understood. Effector Treg cells also specifically express the transcriptional regulator Blimp-1 whose expression overlaps with many of the canonical markers associated with effector Treg cells, although not all ICOS+ TIGIT+ Treg cells express Blimp-1 or IL-10...
July 2018: Journal of Autoimmunity
Amal Ghraieb, Aviad Keren, Alex Ginzburg, Yehuda Ullmann, Adam G Schrum, Ralf Paus, Amos Gilhar
Alopecia areata (AA) is understood to be a CD8+/NKG2D+ T cell-dependent autoimmune disease. Here, we demonstrate that human AA pathogenesis of is also affected by iNKT10 cells, an unconventional T cell subtype whose number is significantly increased in AA compared to healthy human skin. AA lesions can be rapidly induced in healthy human scalp skin xenotransplants on Beige-SCID mice by intradermal injections of autologous healthy-donor PBMCs pre-activated with IL-2. We show that in this in vivo model, the development of AA lesions is prevented by recognized the iNKT cell activator, α-galactosylceramide (α-GalCer), which stimulates iNKT cells to expand and produce IL-10...
July 2018: Journal of Autoimmunity
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