bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6
Authors: Jackson Shaun W , Jacobs Holly , Arkatkar Tanvi , Dam Elizabeth M , Scharping Nicole , Kolhatkar Nikita , Hou Baidong , Buckner Jane H , Rawlings David J 
Published: January 2023

Abstract
Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although type 1 interferons (IFNs) are most frequently associated with lupus pathogenesis, type 2 interferon (IFN-γ) has also been shown to promote SLE. However, the respective impact of these cytokines in promoting B cell activation during humoral autoimmunity has not been addressed. Here, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for lupus development. In contrast, B cells functioning as antigen presenting cells initiate CD4+ T cell activation via B cell MHCII expression, resulting in prominent T cell IFN-γ production. Strikingly, B cell-intrinsic deletion of the IFN-γ receptor was sufficient to abrogate autoimmune GCs, class-switched autoantibodies and systemic autoimmunity. Mechanistically, although IFN-γ receptor signals increased B cell T-bet expression, B cell-intrinsic deletion of T-bet exerted an isolated impact on class-switch recombination to pathogenic IgG2c autoantibody subclasses without impacting GC development. Rather, in both murine and human B cells, IFN-γ synergized with BCR, TLR and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, BCL-6. Finally, IFN-γ driven BCL-6 expression in B cells was blocked using clinically-relevant Janus kinase inhibitors, ruxolitinib and tofacitinib. Our combined findings identify a novel B cell-intrinsic mechanism whereby interferon signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.
Follicular T helper cells and T helper 17 cells cooperate in promoting B-cell responses in neuro-inflammation
Authors: Quinn James L , Agasing Agnieshka , Ko Rose , Axtell Robert C. 
Published: January 2023

Abstract
Both T-cells and B-cells are implicated in the pathology of multiple sclerosis, but how these cells cooperate to drive disease activity is still unclear. Recent studies using experimental autoimmune encephalomyelitis (EAE) demonstrated that the T helper 17 (TH17) pathway is correlated with increased numbers of ectopic B-cell follicles in the CNS. As follicular T helper (TFH) cells are mediators of B-cell response, our hypothesis was that TH17 cells and TFH cells cooperate to drive pathogenic B-cell responses in the CNS and contribute to the severity of EAE. Therefore, the main objective of this project was to examine the role of TFHs in EAE induced by the transfer of myelin-specific TH17s (TH17 EAE).
At the peak of TH17 EAE, we saw 5.6–18.6% of CD4 cells in the CNS were CXCR5+PD1+ TFHs. Furthermore, the number of TFHs in the CNS was strongly correlated with the number of infiltrating B-cells and disease severity. We next transferred TH17s from congenic CD45.1 mice into CD45.2 recipient mice to determine whether the TFH cells were donor or recipient derived. We observed that the TFHs were CD45.2 recipient-derived whereas IL-17+ cells were CD45.1 donor-derived. We next assessed whether myelin-specific TFHs transferred into recipient mice were capable of migrating to the CNS and causing EAE. We found that TFHs transferred alone failed to traffic to the CNS. However, when TFHs were co-transferred with TH17s into recipient mice, we found increased numbers of TFHs in the CNS compared to the CNS of mice transferred with only TH17s.
These results show that TH17s migrate to the CNS to initiate neuro-inflammation in EAE and mediate of a second wave of CNS-infiltrating TFHs that facilitate a B-cell response in the CNS and contributes to disease severity.
Bim is a candidate gene in the regulation of merocytic dendritic cell proportion
Authors: Audiger Cindy , Chabot-Roy Geneviève , Lesage Sylvie 
Published: January 2023

Abstract
In contrast to conventional dendritic cells (cDC), when merocytic DC (mcDC) present antigens (Ag) derived from apoptotic bodies, T cell anergy is reversed rather than induced. Although helpful to tumour clearance, reversing T cell anergy is detrimental in autoimmunity. Interestingly, mcDC are present in higher proportion in type 1 diabetes (T1D)-prone NOD mice than in B6 mice. Recently, we found that the Idd13 T1D locus is linked to the control of mcDC number. Indeed, NOD.B6-Idd13 congenic mice are resistant to T1D and have the same low number of mcDC as the parental B6 mice. Thus, we hypothesize that defining the genetic factor implicated in the regulation of mcDC number could help maintain self-tolerance and prevent T1D onset. Within the Idd13 locus, both B2m and Bim are likely candidate genes. By exploiting both B2m−/−and Bim−/−mice, we show that B2m does not affect mcDC number while mcDC were significantly increased in Bim−/−mice. Competitive hematopoietic chimera validate Bim as an intrinsic factor implicated in the regulation of mcDC proportion. In line with a role for Bim in regulating mcDC number, we demonstrate that the caspase activity and Bcl2 expression is not differentially expressed between the different mouse model, suggesting that Bim is implicated in mcDC proportion regulation via a caspase-independent pathway.
Together, these data demonstrate that Bim, encoded within the Idd13 locus on the chromosome 2 modulates the number of mcDC. Identifying factors that facilitate apoptosis of mcDC may help prevent autoimmunity. Still, whether restoring Bim expression in NOD mice would prevent T1D remains to be addressed.
BCAP promotes TLR-induced IFNα in plasmacytoid DC
Authors: Chu Talyn , Hamerman Jessica 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) severity is correlated with elevated serum levels of type I interferons (IFN), specifically IFNα. pDC are important in the pathogenesis and etiology of SLE due to their ability to produce large amounts of IFNα. TLR-induced INFα production in pDC occurs upon RNA or DNA recognition by TLR7 or 9 respectively. Two events are necessary to induce IFNα by pDC: 1) the binding of ligand to TLR7 or TLR9 within the early endosome, and 2) the phosphorylation and nuclear translocation of the transcription factor IRF7. TLR7 and TLR9-induced IRF7 translocation to the nucleus and subsequent IFN production by pDC is dependent on phosphatidylinositol-3 kinase (PI3K), but how PI3K regulates this process remains undefined. The PI3K pathway is important for many cellular processes, but it is unknown how PI3K activation is induced by TLR signaling in pDC. Our lab showed that the cytosolic signaling adapter B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation in macrophages, resulting in inhibition of TLR-induced inflammatory cytokines. In contrast, here we show BCAP promotes TLR7 and TLR9-induced type I IFN production in pDC. We found that BCAP was required for optimal TLR9 and TLR7-induced IFNα production in pDC grown from BM in vitro in presence of Flt3L or sorted directly ex vivo, while inflammatory cytokine levels were less affected. Strikingly, BCAP−/− mice produced much less serum IFNα early after injection of TLR9 agonist than WT mice, consistent with a pDC IFNα defect. BCAP−/−pDC have reduced AKT phosphorylation when stimulated with TLR agonists, showing BCAP activates PI3K downstream of TLR in pDC. Overall, we show a novel role for BCAP in regulating IFNα production in pDC.
A critical link between Lyn-mediated suppression of the TLR-MyD88-IRF5 pathway and the development of SLE-like disease
Authors: Ban Tatsuma , Sato Go , Nishiyama Akira , Akiyama Ai , Takasuna Marie , Umehara Marina , Suzuki Shinsuke , Ichino Motohide , Matsunaga Satoko , Kimura Ayuko , Kimura Yayoi , Yanai Hideyuki , Miyashita Sadakazu , Kuromitsu Junro , Tsukahara Kappei , Yoshimatsu Kentaro , Endo Itaru , Yamamoto Tadashi , Hirano Hisashi , Ryo Akihide , Taniguchi Tadatsugu , Tamura Tomohiko 
Published: January 2023

Abstract
The transcription factor interferon regulatory factor 5 (IRF5) is critical for innate immune responses downstream of Toll-like receptors (TLRs). IRF5 is also linked to the pathogenesis of systemic lupus erythematosus (SLE) in humans and mice. However, it remains elusive whether and how IRF5 activity can be negatively regulated. The Src family kinase Lyn is also implicated in human SLE, and Lyn−/− mice develop an SLE-like disease. Here we show that Lyn selectively inhibits IRF5 activity, while it does not affect the NF-κB pathway. Lyn physically interacted with IRF5, thereby suppressing the phosphorylation and ubiquitination of IRF5, post-translational modifications important for IRF5 activation. Interestingly, the kinase activity of Lyn was dispensable for the suppression of IRF5 activity. IRF5 was hyper-activated in TLR7/9-stimulated Lyn−/− bone marrow-derived dendritic cells (BMDCs), and these cells hyper-produced IRF5-dependent cytokines especially type-I interferons (IFNs). IRF5 was constitutively activated (phosphorylated and translocated into the nucleus) in splenic DCs isolated from Lyn−/− mice. Importantly, even monoallelic ablation of the Irf5 gene was sufficient to alleviate the hyper-production of type-I IFNs in TLR7/9-stimulated Lyn−/− BMDCs, and to ameliorate the development of SLE-like symptoms, such as autoantibody production and autoimmune glomerulonephritis, in Lyn−/− mice. Our results identify Lyn as a critical suppressor of the TLR-MyD88-IRF5 pathway, and implicate that the selective control of IRF5 activity may contribute to better therapeutics for SLE.
The role of TWEAK and Fn14 in ultraviolet light-induced cutaneous lupus
Authors: Doerner Jessica L , Chalmers Samantha A. , Friedman Adam , Putterman Chaim 
Published: January 2023

Abstract
Cutaneous lupus erythematosus (CLE) is a common disease manifestation in SLE patients. Ultraviolet-B irradiation (UVB) is well-known trigger of CLE; many lupus patients are photosensitive, and develop skin lesions following sun exposure.
TWEAK, a TNF superfamily member, is a soluble cytokine that binds a sole signaling receptor, Fn14. TWEAK/Fn14 interactions are important in key biologic processes, including angiogenesis, cell death and inflammation, and are often upregulated during tissue injury. We found that MRL-lpr/lpr (MRL/lpr) lupus-prone mice deficient for the Fn14 receptor (Fn14KO) had markedly attenuated skin lesions following UVB irradiation, as compared to Fn14WT mice. Histologically, MRL/lpr Fn14WT mice had more keratinocyte apoptosis, degeneration of the basement membrane, and dermal inflammation. Further evaluation showed decreased infiltration of IBA-1+ macrophages, CD3+ T cells, and NGAL+ cells (neutrophils) in the skin of MRL/lpr Fn14KO mice. Depletion of macrophages in MRL/lpr mice using the CSF1R/fms kinase inhibitor GW2580 attenuated irradiation-induced tissue injury, confirming a pathogenic role for these Fn14-expressing cells in UVB-induced lesions. Several key chemokines (including MCP-1, MIP-1α, MIP-1β) were decreased following macrophage depletion and also differentially expressed between Fn14KO and WT mice, suggesting regulation through TWEAK/Fn14 signaling. Finally, both in vitro and in vivo, Fn14 was upregulated on dead and dying cells following irradiation, which can locally sensitize cells to the effects of TWEAK. Our data reveals important contributors to the pathogenesis of UVB-induced cutaneous lesions, and suggests a novel role for TWEAK/Fn14 signaling in skin disease.
MerTK mediates T cell tolerance in the pancreatic islets during type 1 diabetes
Authors: Friedman Rachel Sharon , Tracy Dayna , Lindsay Robin S 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that results from destruction of the beta cells in the pancreatic islets. Curiously, infiltrated islets can continue to contain beta cells for years following disease onset, suggesting a tolerance checkpoint following islet infiltration. While T cells are required for T1D progression, other immune cell populations also infiltrate the islets, including CD11c+ antigen presenting cells (APCs). We depleted CD11c+ cells to determine their role in maintaining T cell tolerance in the islets. CD11c depletion resulted in increased CD8 T cell motility arrest and effector function. MerTK+ APCs have been associated with T cell tolerance induction following apoptotic cell uptake. We identified MerTK expression on a subset of islet-infiltrating CD11c+ APCs. To test if MerTK mediates T cell tolerance in the islets, we treated pre-diabetic non-obese diabetic (NOD) and non-autoimmune C57BL/6 mice with a MerTK/Flt3 inhibitor. Blood glucose remained normal in C57BL/6 mice. However, in 50% of NOD mice with pre-existing islet infiltration, MerTK/Flt3 inhibition resulted in extremely rapid diabetes onset. The rapid disease onset occurred prior to Flt3-dependent population shifts in the islets, suggesting a MerTK rather than Flt3 mediated effect. Within 24 hours of MerTK inhibition, islet-antigen specific CD4 and CD8 T cells arrested motility in the islets, and CD8 T cell activation increased in the islets. Thus, inhibition of MerTK signaling resulted in a break in T cell tolerance and rapid islet destruction. These results suggest that CD11c+ APCs are involved in a MerTK-dependent tolerance checkpoint during T1D, which maintains T cell tolerance in the islets following islet infiltration.
A20-deficient microglia and CD8 T cells in the brain
Authors: Mohebiany Alma N , Waisman Ari 
Published: January 2023

Abstract
Tumor necrosis factor alpha induced protein 3 (TNFAIP3), also known as A20, is a key negative regulator of the canonical NFkB pathway, and acts at various levels of the signaling cascade downstream of receptor stimulation, thereby regulating the pro-inflammatory response. As such, its absence leads to the development of spontaneous inflammation; indeed, a number of SNPs in the A20 gene have been associated with various autoimmune diseases. Cell-specific deletion of A20 in mice can also lead to the development of spontaneous disease. Mice lacking A20 in their astrocytes have stronger disease in a model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Furthermore, A20ko mice demonstrate spontaneous neuroinflammation, attributed to A20 deletion in either endothelial cells or microglia, the resident immune cells of the brain and spinal cord. We chose to examine the role of microglial A20 expression in the context of neuroinflammation by crossing A20fl/fl to CX3CR1-CreERT2 mice. The resulting A20fl/flCX3CR1-CreERT2 (A20Δmg) mice were injected with tamoxifen to induce A20 deletion. Without A20, microglia spontaneously upregulate a number of NFkB target genes and have an activated morphology accompanied by an increase in GFAP+ astrocytes in the cortex. Surprisingly, we found significantly more T cells (mainly CD8) infiltrate the brain and spinal cords of naïve A20Δmg mice relative to controls, after A20 deletion. Furthermore, upon EAE induction, A20Δmgmice develop symptoms sooner than controls, and have stronger disease. Overall, the deletion of A20 in microglia leads to a spontaneous activation, which may enhance the susceptibility of these animals to developing neuroinflammation under specific condtions.
Aberrant expression of CD11b and CD11a underlies impaired neutrophil adhesion in glucose-6-phosphate transporter-deficient mice
Authors: Jun Hyun Sik , Kim Goo-Young , Kwon Joon Hyun , Chou Janice 
Published: January 2023

Abstract
Neutrophils play an essential role in defense against intruding microorganisms. They are produced in great number in the bone marrow and circulate in blood where they are found in a quiescent state. In response to inflammatory stimuli, neutrophils take different steps-rolling, adhesion, and transmigration-to migrate towards inflammation sites. In this study, we investigated the underlying mechanisms of impaired neutrophil adhesion in glycogen storage disease type Ib (GSD-Ib) which is caused by a deficiency of the glucose-6-phosphate transporter (G6PT). GSD-Ib is characterized not only by disrupted glucose homeostasis but also by neutropenia and neutrophil dysfunction. GSD-Ib mice were infused with a recombinant adeno-associated virus (rAAV) vector expressing human G6PT only in liver to increase their survival. Unlike control mice, GSD-Ib-rAAV mice manifested severe neutropenia in both blood and bone marrow and neutrophils of GSD-Ib-rAAV mice were defective in adhesion to tumor necrosis factor-a-treated epithelial cells and intercellular adhesion molecule 1 and fibrinogen. The β2-integrins including CD11a/CD18 and CD11b/CD18 are recognized as vital players in neutrophil recruitment. Consistent with impaired neutrophil adhesion, the expression of CD11a and CD11b were found to be decreased in neutrophils of GSD-Ib-rAAV mice, compared with that of control mice. Particularly neutrophils of GSD-Ib-rAAV mice showed increased proteolytic degradation of CD11b. Given the central role of β2-integrins in neutrophil adhesion, this alternation of CD11a and CD11b molecules and their effect on neutrophil adhesion probably define a molecular mechanism to neutrophil dysfunction manifested in GSD-Ib.
Lung IL-33 overexpression does not cause inflammation, but increases allergen sensitivity and disrupts lung morphogenesis
Authors: Drake Li Y , Squillace Diane , Iijima Koji , Kobayashi Takao , Kephart Gail , O’Brien Daniel , Kita Hirohito 
Published: January 2023

Abstract
IL-33 is an IL-1 cytokine family member that promotes inflammatory responses via activation of many immune cell types. IL-33 is expressed in epithelial barrier tissues such as lung epithelium under both resting and inflammatory conditions. Secreted IL-33 plays an important role in type 2 innate immunity and adaptive immune responses. To characterize the roles of IL-33 in tissue and immune homeostasis in lung epithelium, we generated a novel transgenic mouse in which IL-33 was overexpressed only in lung epithelial cells driven by the tetracycline-sensitive Club cell secretory protein (CCSP) promoter. When IL-33 expression was induced in adult mice, overexpression of IL-33 protein approximately 3-fold above normal levels produced no pathological or immunological changes in the lungs. However, these animals developed significant increases in innate type 2 immune responses when exposed to natural or model allergens. When IL-33 expression was induced in pre- and post-natal mice, these mice had increased mortality, which was accompanied by lung hemorrhage and lung lobe malformation without detectable signs of inflammation and immune responses. Furthermore, IL-33 transgenic mice that survived to adulthood exhibited simplified and enlarged alveoli resembling bronchopulmonary dysplasia. Correspondingly, the epithelial cells from IL-33 transgenic mice displayed altered expression of genes involved in tissue and hematological system development. These data indicate dual effects of IL-33 overexpression depending on the developmental stage of the lungs, namely impairment of lung morphogenesis in the neonatal period and heightened sensitivity of innate type 2 immunity in adult mice.
High sensitivity multiplex cytokine panel used to identify unique signatures in serum associated with gallbladder cancer.
Authors: Corbel Amanda Faith , Kemp Troy J , Pinto Ligia A , Koshiol Jill 
Published: January 2023

Abstract
Gallstones (GS) and chronic inflammation are two of the strongest risk factors associated with gallbladder cancer (GBC). Since these conditions are frequently asymptomatic, GBC detection often occurs incidentally and when the cancer has reached a progressive stage. Gaining a better understanding of the mechanisms involved in the development and progression of GBC could help identify the subpopulation of gallstone patients that will go on to develop GBC. Therefore, we sought to measure 16 key inflammatory markers in serum samples with a high sensitivity bead-based multiplex cytokine assay of population-based controls (PBC), patients with gallstone(s) (GS), and patients with gallbladder cancer (GBC), from Shanghai, China. Wilcoxon’s rank sum test was used to compare median concentrations. We found 11 markers (IL-1β, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p70), IL-13, IL-17A, IL-21, and IL-23) that were significantly (p value &lt;0.01) elevated in GS compared to PBC; fold changes ranged from 1.3 to 1.7. We found 6 markers (MIP-1α, MIP-1β, IL-6, IL-7, IL-8, and IL-10) that were significantly elevated in GBC compared to GS; fold changes ranged from 1.2 to 3.6. Moreover, only 3 markers (IL-6, IL-7, and IL-10) were elevated in both comparison groups. The unique set of markers highlighted between the two comparison groups suggests that there is a transitional stage in the progression of disease leading up to GBC. Future studies are needed to further evaluate the common pathway or mechanism associated with these cytokine signatures. Futhermore, such studies should be replicated in bile to assess the local inflammatory response that develops in the gallbladder.
IL-22RA1 signaling regulates intestinal secretory cell development and protects against infectious colitis
Authors: Good Misty , Kumar Pawan , Parks Olivia , Ma Congrong , Horne William , Kolls Jay K 
Published: January 2023

Abstract
The gastrointestinal tract harbors a complex immune system to contend with both normal flora and invasive pathogens. Recently, interleukin (IL)-22 signaling has proven to play a critical role in maintaining the gut barrier, promoting epithelial healing and controlling inflammation from attaching and effacing pathogens. Specifically, IL-22 produced by Th17 cells and group 3 innate lymphoid cells (ILCs) is critical for host resistance to the attaching and effacing gut pathogen Citrobacter rodentium. However, the importance of intestinal epithelial IL-22Ra1 signaling in regulating secretory cell development and protecting against infectious colitis remains unknown. We hypothesize that intestinal IL-22 signaling plays an important role in mucosal host defense against infectious colitis by regulating the intestinal cell types that maintain the gut barrier. To test this hypothesis, we generated mice that selectively lack the receptor for IL-22, IL-22RA1, and discovered these mice have a striking phenotype of intestinal cell differentiation. We demonstrate that abrogation of intestinal IL-22 signaling led to a decreased number of goblet and paneth cells and decreased expression of the antimicrobial peptide Reg3g. Further, the IL-22RA1 intestinal specific knock-out mice were more susceptible to C. rodentium colitis than WT mice as demonstrated by increased weight loss that correlated with increased spleen bacterial burden, decreased epithelial cell proliferation and disrupted mucosal architecture. These findings offer insights into the protective role that IL-22 plays on mediating intestinal mucosal host defense and how critical IL-22 signaling is to intestinal cell differentiation and attenuating infectious colitis.