bluuebunny/crossref_metadata_2025_split huggingface dataset:
An autoimmune risk variant in PTPN22 alters tolerance at multiple checkpoints during naive B cell development
Authors: Metzler Genita , Dai Tony , Thouvenel Chris , Khim Jit , Rawlings David J 
Published: January 2023

Abstract
A missense risk variant (R620W) in the tyrosine phosphatase PTPN22 is strongly associated with multiple autoimmune diseases. To model this variant in vivo, we generated knock-in mice expressing the analogous variant (R619W) in murine Ptpn22. Expression of the variant significantly altered lymphocyte function and led to the development of systemic autoimmunity. Further, B lineage-restricted variant expression was sufficient to promote autoimmunity (Dai et al. JCI 2013). In the current study, we performed a detailed assessment of the impact of the variant on B cell tolerance, including its impact on the establishment of the naive repertoire. Utilizing a bone marrow (BM) chimera model, variant expressing B cells exhibited a competitive advantage over wild-type (WT) cells at multiple checkpoints, beginning in the BM and continuing in the periphery. Interestingly, while follicular (FM) B cells maintain this competitive advantage, marginal zone (MZ) B cells do not. In addition, using single cell BCR cloning, we observed a similar differential phenotype, where FM B cells are highly enriched for self-reactivity, while MZ B cells are less autoreactive than WT controls. Using a range of analyses to assess cell signaling, surface receptor expression, cell cycle and gene expression, we provide evidence that the risk variant regulates a complex interplay between the BCR and CD40 co-receptor pathways, culminating in a uniquely autoreactive pre-GC repertoire with important implications for subsequent development of autoimmunity.
Targeting antigen experienced B lymphocytes to retard type 1 diabetes progression in NOD mice
Authors: Leeth Caroline McPhee , Hasham Muneer , Ratiu Jeremy , Zhu Jing , Chapman Harry , Branca Jane , Mills Kevin , Serreze David 
Published: January 2023

Abstract
While CD4+ and CD8+ T lymphocytes are ultimately responsible for the destruction of insulin-producing beta cells resulting in clinical type 1 diabetes (T1D), B lymphocytes are also critical pathogenic players in T1D development in NOD mice and likely also in humans. The role of B lymphocytes in this disease is primarily through antigen presentation, presenting diabetogenic peptide to autoreactive T lymphocytes. It is not known if changes in antigen affinity of plasma membrane bound immunoglobulin molecules are important for B lymphocyte diabetogenicity. We generated NOD mice deficient in AID, an enzyme crucial for affinity maturation, and found that T1D development was greatly inhibited in these novel mutant mice. While insulitis was still evident, progression to glucosuria did not occur. The phenotype of these AIDnull B lymphocytes differed from standard NOD as did the T lymphocyte populations. With the knowledge that affinity maturation is important to the development of T1D, we targeted maturing B lymphocytes using a small molecule inhibitor of the RAD51 complex, DIDS. NOD mice treated with this agent were protected from T1D development: Total B lymphocyte numbers were maintained with a reduction in the marginal zone subset. Insulitis was reduced in the treated mice. Circulating insulin autoantibodies (IAA) are indicative of impending diabetes development; however, IAA positive mice receiving DIDS treatment did not develop T1D. These results suggest that targeting antigen-experienced B lymphocytes during their maturation process may be a viable approach in T1D.
BANK1 Controls IgG Production Through TLR7-Dependent STAT1 Activation in a Lupus Model
Authors: Wu Ying-Yu , Kumar Ramesh , Iida Ryuji , Bagavant Harini , Alarcon-Riquelme Marta 
Published: January 2023

Abstract
The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6.Sle1.yaa mouse, a lupus model that develops disease through exacerbated TLR7 expression. Crosses of B6.Sle1.yaa with Bank1−/−mice maintained several B and myeloid cell phenotypes close to normal levels in wild-type mice. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. Bank1 deficiency did modify frequencies of MZ B cells and splenic B cells, as well as expression of CXCR4 by follicular helper T cells. Bank1 deficiency did not modify frequencies of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from B6.Sle1.yaa.Bank1−/−mice had lost strong induction of Ifnb, Ifna4, Irf1, 7, 9, Aicda and Stat1 gene expression following TLR7 agonist stimulation, compared with B6.Sle1.yaa mice. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from B6.Sle1.yaa.Bank1−/− mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, Bank1 deficiency in B6.Sle1.yaa mice reduced the production of IgG2c after in vitro TLR7 agonist stimulation. Our results demonstrate that Bank1 controls TLR7-mediated type I interferon production, leading to positive feedback loop on IFNAR and IFN I-mediated gene expression, including Tlr7 gene. Combined with the control of the nuclear translocation of IRF7, and the modulation of transcription and STAT1 phosphorylation, Bank1 contributes to IgG production during development of autoimmune disease.
Identification of Trex1 interacting proteins and endogenous DNA substrates
Authors: Crowl John T , Brunette Rebecca , Stetson Daniel B 
Published: January 2023

Abstract
Detection of DNA by cytosolic nucleic acid sensors activates the interferon stimulatory DNA (ISD) pathway, an antiviral response mediated by the production of type I interferons (IFN). This process is critical for host defense against viral pathogens but must be tightly regulated to avoid the chronic production of interferon, which can lead to autoimmunity. Three-prime repair exonuclease 1 (Trex1) is a crucial regulator of the ISD pathway, and the absence of functional Trex1 in both mice and humans leads to the development of autoimmune disease. Multiple DNA species have been proposed as the endogenous, cell-intrinsic substrates of Trex1. However, the in vivo identity of Trex1 substrates and the biological processes that generate them remain unknown. In order to definitively identify DNA that uniquely accumulates in the absence of Trex1, we have used a high-throughput, unbiased deep sequencing method. Additionally, to explore the functional requirements for Trex1 we have used a yeast two-hybrid screen to identify novel Trex1 interacting proteins.
Cytokine-mediated regulation of oligodendrocyte metabolism
Authors: Minchenberg Scott B , Massa Paul T 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a debilitating autoimmune disease characterized by inflammatory-mediated demyelination in the central nervous system. Our primary goal is to understand how inflammatory processes can lead to oligodendrocyte dysfunction, axonal degeneration, and demyelination in the CNS. Our lab discovered that the protein tyrosine phosphatase SHP-1, a major negative regulator of the immune system, is expressed in oligodendrocytes and plays an essential role in regulating STAT1 and STAT3 activation in oligodendrocytes. Importantly, it has recently been discovered that both STAT1 and STAT3 are important transcriptional regulators of metabolic genes. Metabolic regulation is particularly important for oligodendrocytes because lipid synthesis is required for the production and maintenance of the myelin sheath and energetic support for axons. Using freshly isolated O4+ oligodendrocytes, we determined that SHP-1 deficient oligodendrocytes have significantly reduced glycolysis and oxidative phosphorylation (OXPHOS) relative to oligodendrocytes of wild type mice. We were able to show that in vivo treatment with IFN-γ, a potent activator of STAT1, is able to down regulate wild type oligodendrocyte metabolism without diminishing oligodendrocyte viability. Further, when oligodendrocytes of SHP-1-deficient mice were treated with IL-10, a potent STAT3 activator, we were able to rescue metabolic deficits in SHP-1-deficient oligodendrocytes suggesting that SHP-1 is a major regulator of oligodendrocyte metabolism via regulation of STAT1 and STAT3 activation.
Dysregulation of TCR signal fine-tuning molecules due to increased ubiquitination in systemic autoimmune disease
Authors: Singh Ram Raj , Bui Viet , Prasad Priti , Ranganath Veena , Halder Ramesh , Pinkhasov Julia 
Published: January 2023

Abstract
T cell selection is primarily determined by the avidity of T cell receptor (TCR) for self-ligand-MHC. Evidence suggests that besides the TCR, there are other signal regulating molecules that play a role in establishing signal threshold in T cells during the process known as TCR tuning, which modulates the intensity of TCR signaling. Here, we determined the expression of putative TCR signal fine-tuning molecules (TFT) in mice and humans with systemic autoimmune diseases, and investigated their role in T-cell signaling defects and mechanisms of their alteration. We found the expression levels of a battery of TFTs to be reduced on thymocytes in young MRL/lpr and MRL+/+ mice compared to C3H controls. MRL Thymocytes displayed signaling defects, which were corrected by TFT agonists. In the periphery, T-cells in the diseased MRL mice exhibited an unexpectedly drastic reduction in the TFTs, which correlated with an increased responsiveness to TCR stimulation and to weak antigenic ligands. TFT expression was also reduced in T cells from patients with rheumatoid arthritis as compared to controls, particularly in elderly patients who experience more severe disease than younger patients. The reduced expression of TFTs in MRL peripheral T cells was due to their increased ubiquitination, which led to degradation of these molecules. Blocking proteasomal degradation using MG132 restored their expression. Finally, MRL-lpr mice had increased E3 ubiquitin ligases that associated with the TFTs expression. Thus, the ability of T cells to alter their signal threshold by altering the expression of TFTs via their post-translational modification mediated by E3 ligases may be a novel mechanism for T cells to escape tolerance and trigger autoimmune disease.
Endosome-to-cytoplasm pathway via Sec61 and proteasomal degradation as an essential component of antigen cross-presentation and the lupus tissue injury in systemic lupus erythematosus (SLE): Extension of our self-organized criticality theory
Authors: Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract

Objective
We propose that SLE can be induced upon repeated immunization with any antigens in the mice normally not prone to SLE, in which newly generated autoantibody-inducing CD4 T cell (aiCD4 T cell) helps the generation of CTL via antigen cross-presentation and induces lupus tissue injury. Here we dissect the molecular mechanism of antigen cross-presentation.

Methods
Bone marrow-derived dendritic cell (BMDC) or splenic DC (spDC) was cultured with OVA, and inhibitor of Sec61 Exotoxin A (Exo A) or inhibitor of proteasome MG132. Mice were repeatedly immunized with OVA to induce SLE as in PLoS ONE 4:e8382, 2009 with/without Exo A or MG132, and immunoprecipitation or immunoblotting studies were performed.

Results
We show that accumulated antigen in the cytoplasm up-regulates the amount of cross-presentable antigen, thereby enhancing tissue injuries of SLE, in which Sec61 is responsible for endosome-to-cytoplasm transport of antigen: in the first, the amount of endosomal Sec61 and the amount of cytoplasmic OVA were increased in spDC after repeated immunization with OVA. Second, cytoplasmic OVA was increased after co-culture with inbibitor of proteasome MG132 in BMDC, but disappeared after adding inhibitor of Sec61 Exo A. Third, the generation of CTL and the development of lupus nephritis were both inhibited in vivo after repeated immunization with OVA in the presence of Sec61 inhibitor Exo A or proteasome inhibitor MG132.

Conclusion
For antigen cross-presentation, antigen must be transported from endosome to cytoplasm via Sec61 and then degraded through proteasome. The increase of endosomal Sec61 facilitates antigen cross-presentation, thereby contributing to the pathology of SLE.
Constitutive expression of the NKG2D ligand RAE1ɛ within pancreatic islets ameliorates autoimmune diabetes development in non-obese diabetic mice
Authors: Sharma Neekun , Markiewicz Mary A. 
Published: January 2023

Abstract
Type 1, or autoimmune, diabetes is driven by T cell-mediated destruction of the insulin-producing β cells in pancreatic islets. The natural killer cell activating receptor NKG2D and its ligands are implicated in this process. However, the mechanism by which NKG2D-NKG2D ligand interaction affects diabetes development is poorly understood. Transgenic expression of the NKG2D ligand retinoic acid early transcript 1ɛ (RAE1ɛ) in β-islet cells of the pancreas induces the recruitment of cytotoxic T lymphocytes (CTLs) to the islets in mice. Surprisingly, however, we report here that the severity of spontaneous autoimmune diabetes is decreased in non-obese diabetic (NOD) mice expressing RAE1ɛ in islets (RIP-RAE1ɛ NOD). Interestingly, NKG2D expression is reduced on the surface of CD8T cells within the pancreas of RIP-RAE1ɛ NOD mice compared with control NOD mice. We further demonstrate that the NKG2D ligand H60a is expressed on T cells within the pancreas of wild-type NOD mice. Together, these results demonstrate that transgenic expression of RAE1ɛ in islets leads to down-regulation of NKG2D surface expression on CD8T cells, likely resulting in decreased ability of the cells to respond to NKG2D engagement by H60a naturally expressed in the pancreas. These findings suggest that interaction between NKG2D and NKG2D ligands, both expressed on islet-infiltrating T cells, plays an important role in the pathology associated with autoimmune diabetes.
Blood relatives with incomplete lupus are distinguished from unaffected relatives and relatives with classified disease by altered autoantibodies, soluble inflammatory and regulatory mediators, and clinical features
Authors: Munroe Melissa , Young Kendra A , Norris Jill M , Aberle Teresa , Roberts Virginia C , Guthridge Joel M , Kamen Diane L , Gilkeson Gary S , Weisman Michael H , Ishimori Mariko L , Wallace Daniel J , Karp David R , Sivils Kathy L , Harley John B , James Judith A 
Published: January 2023

Abstract
Blood relatives (Rel) of lupus patients have increased risk of systemic lupus erythematosus (SLE). Some have autoantibodies and clinical features, but do not meet ≥ 4 ACR criteria needed to reach SLE classification (incomplete lupus, ILE). This study examined individuals enrolled in the Lupus Family Registry and Repository who only met 3 ACR classification criteria during medical record review. ILE patients (n=77) were matched to unaffected Rel and unrelated controls (Ctls), with a subset of ILE patients (n=55) matched to medical record-confirmed SLE patients. ILE patients had significantly higher SLE-specific screening questionnaire (CSQ) scores than unaffected Rel and Ctls (p≤0.0001). A number of soluble mediators that positively correlated with CSQ scores were highest in ILE patients, including SCF (p=0.0001), BLyS (p=0.0018), MCP-3 (p=0.0167), and TNFRI (p=0.0196), as well as ANA titer (p&lt;0.01) and number of lupus-associated autoantibodies (p&lt;0.01). Comparing ILE vs. SLE patients, SLE patients had higher rates of arthritis, serositis, and renal disease (p≤0.004), number of autoantibody specificities (p&lt;0.004), and levels of BLyS (p=0.0138), IL-2Rα (p=0.0201), IP-10 (p=0.0269), and TNFRII (p=0.0309). Yet, ILE patients had higher levels of the regulatory mediator TGF-β (p=0.0454). Identification of factors which discern relatives at increased risk of transitioning to classified SLE may be beneficial to curtail inflammatory damage.
Reduced IL-2R signaling in T1D subjects is pervasive in the memory CD4 T effector compartment and is mediated through intrinsic mechanisms
Authors: Thorpe Jerill Z , Schwedhelm Katharine , Pickett Melissa , Greenbaum Carla J , Cerosaletti Karen , Buckner Jane H , Long S. Alice 
Published: January 2023

Abstract
The IL-2/IL-2R pathway is strongly implicated in type 1 diabetes (T1D). Yet, identifying the functional significance and underlying mechanisms of altered IL-2R signaling in T1D has been challenging due to variance in the subjects, cell types and the assays utilized. We performed a large, well-matched, cross-sectional study of control and T1D subjects (n&gt;75 subjects per group), with an optimized IL-2/pSTAT5 assay (internal control CoV &lt;7%). We found reduced responses to IL-2 in memory CD4 Treg and Teff cell populations of T1D subjects relative to controls. Known genetic risk alleles accounted for some, but not all, of the reduction in pSTAT5. To determine additional factors underlying reduced IL-2R signaling, we interrogated CD4 Teff cells of control and T1D subjects held constant for risk alleles associated with IL-2R signaling. IL-2 signaling in T1D memory CD4 Teff cells remained significantly lower than controls after in vitro activation and proliferation, suggesting a role for intrinsic factors. These intrinsic factors were not caused by divergence to MAPK or Akt signaling pathways, as measured by western blot. Instead, differences in basal activation state prior to in vitro activation correlated with IL-2 response, as measured by targeted flow and qPCR of activation and negative regulation. Thus, multiple factors including genetics, disease and activation state contribute to natural variation in IL-2 responsiveness, requiring precise assays and well-defined cohorts to reach solid conclusions. These findings offer a better understanding of the mechanisms contributing to reduced IL-2R signaling in T1D and have implications for development of more targeted IL-2-based therapies and stratification of patients for therapy.
Immune cells encounter with α-synuclein fuels neurodegeneration in Parkinson’s disease
Authors: Pandey Manoj K , Gross Christina , Caballero Madison , McKay Mary A , Tiwari Durgesh , Schroeder Lindsay M , Gurtler Michael A , Burrow Thomas A 
Published: January 2023

Abstract
GBA1 mutations and increases of neuronal α-synulcein protein (α-syn) are the hallmark of Parkinson’s disease (PD). However, the mechanism, by which Gba1 mutation and or excess release of α-syn trigger neurodegeneration in PD is still wanted. Using Gba1 mouse model (D409V/null), we have observed increased level of α-syn and enhanced brain recruitment of inflammatory subsets of CD11chiCD11b+ CD86+DCs and CD3+CD4+ CD69+ T cells and their association with increased loss of CD45−CD11b− MAP2+ neurons and cognitive dysfunction. Performing adoptive transfer experiments, (e.g., WT cells → WT mice and Gba1 cells → Gba1 mice), augmented brain invasion of DCs and T cells, and neuronal cells destruction have been observed in Gba1 mouse. Searching the mechanism by which infiltrated immune cells could propagate brain inflammation in PD, DCs and CD4+T cells purified from WT and Gba1 mouse were used to perform their ex-vivo stimulation with α-syn and cytokines were measured. These data showed that α-syn treated Gba1 mouse immune cells cause marked increased generation of pro - inflammatory cytokines (e.g., IFNγ, TNFα, and IL6). Supernatant obtained from α-syn stimulated WT and Gba1 mouse DCs and CD4+T cells were used to perform in vitro stimulation of cortical neurons. These data showed that α-syn treated Gba1 mouse cells trigger increased neuronal death suggesting that increased brain penetration of immune cells and their encounter with α-syn propagate neurodegeneration in PD. Targeting DCs and / or CD4+ T cell function could be potential therapy to stop inflammation and neurodegeneration in PD.
TLR7 signaling drives development of a unique population of hemophagocytic macrophages associated with anemia
Authors: Akilesh Holly Marie , Buechler Matthew , Sun Xizhang , Whalen Elizabeth , Mason Michael , Elkon Keith B , Hamerman Jessica A 
Published: January 2023

Abstract
Toll-like receptor (TLR) 7 activity is associated with myeloid expansion in the autoimmune disease Systemic Lupus Erythematosus (SLE), yet how this contributes to severe anemia, often seen in SLE complication, is unclear. Transcriptional and functional assays indicate that TLR7 signaling in the common myeloid progenitor (CMP) preferentially skews lineage choice towards a hemophagocytic macrophage. Transgenic mice that overexpress Tlr7 and develop SLE-like disease exhibited increased hemophagocytic macrophages and progressively developed anemia. Interestingly, in these mice, we observed not only conventional hemophagocytic macrophage populations known as red pulp macrophages (RPM), but also an inflammation-induced hemophagocytic macrophage population (HPM). Unlike RPM that are primarily yolk sac-derived and require the transcription factor Spi-C for their development, we have found that HPM are monocyte-derived and do not require Spi-C. Additionally, TLR7 drives an expansion of hemophagocytic CD11bhi bone marrow macrophages (BMM) that are not found in the absence of TLR7 signaling. Although it has been shown that pathological conditions including excess heme overload can drive monocytes to differentiate to hemophagocytic macrophages, this is the first account of inflammation driving this process. These findings uncover a novel mechanism by which TLR7 signaling participates in hemophagocytic macrophage differentiation from monocytes and may account for one of the mechanisms driving anemia during chronic inflammation and chronic autoimmune diseases such as SLE.
‘Innate and T lymphocyte developmental pathways independent of Common lymphoid progenitors’
Authors: Ghaedi Maryam , Steer Catherine Anna , Martinez-Gonzalez Itziar , Halim Timotheus You Fu , Abraham Ninan , Takei Fumio 
Published: January 2023

Abstract
Lymphocytes are believed to develop from a population of committed lymphoid progenitors termed common lymphoid progenitors (CLPs). However, upstream lymphoid progenitors termed lymphoid-primed multi-potent progenitors (LMPPs) are more efficient than CLPs in differentiating into group 2 innate lymphoid cells (ILC2s) and T cells, suggesting that alternative pathways for the development of these cells exist. In this study, we divided LMPPs into CD127− (LMPP-s) and CD127+ (LMPP+s) subsets and compared them with Ly6D+ and Ly6D− CLPs. Adult LMPP+s differentiated into ILCs and T cells more rapidly and efficiently than other progenitors in transplantation assays. Development of ILC2s and T cells is highly active during neonatal period. In this period CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into ILC2s and T cells. ILC2s generated in neonates persist in adults. These results suggest that the majority of ILCs and T cells develop from LMPP+s via CLP-independent pathways.