bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do autoreactive memory B cells form as a consequence of extrafollicular activation? (130.18)
Authors: Sweet Rebecca , Herlands Robin , Shlomchik Mark 
Published: January 2023

Abstract
Memory B cells could be responsible for chronic autoimmunity, as suggested by results in SLE patients and SLE-prone mice: The frequency of AM14 RF transgenic B cells fluctuates in the peripheral blood of aged MRL/lpr mice. Activation of RF B cells in autoimmune MRL/lpr mice results in an extrafollicular response that undergoes somatic mutation. Lineage trees of RF clones suggest mutation upon secondary antigen exposure. We recently found that this response can be recapitulated in AM14 Tg mice that were exposed to IgG2a anti-chromatin Abs. The mechanism controlling extrafollicular activation and whether this response leads to a form of memory is unclear. When AM14 heavy chain knock-in B cells are transferred into non-transgenic recipients, followed by exposure to IgG2a anti-chromatin, an extrafollicular response that includes class switch ensues. We are tracking the development and function of these cells over time to determine if autoreactive resting memory B cells form, or alternatively, whether the maintenance of autoreactive B cell clones requires continuous autoantigen exposure and activation.
Supported by 1F31AI071694-01 (RAS) and AI36529 (MJS)
Identification of a single gene differentially expressed between males and females in both normal and lupus-prone mice (130.20)
Authors: Jorgensen Trine N. , Kappler John W. , Marrack Philippa 
Published: January 2023

Abstract
Systemic lupus erythematosus is an autoimmune disease with a pronounced female bias. In (NZB x NZW)F1 mice (BW), a model of spontaneous lupus-like disease, females also develop disease with a higher incidence than males, and it has been shown that sex hormones play a pivotal role. In humans, it is thought that disease development is a result of unknown environmental factors acting on a complex genetic background. We hypothesized that genes differentially expressed between males and females act in addition to lupus susceptibility genes to exert disease development in females. As autoantibody production by plasma cells is the main culprit of lupus-like disease in BW mice we focused our studies on B cells.
We analyzed the gene expression pattern of splenic B cells isolated from 9 wk old normal (B6 and Balb/c) and lupus-prone (BW) male and female mice. The results showed that 55 genes were differentially expressed between males and females in all three strains. To evaluate whether any of these genes were intrinsically different, we sorted splenic B cells from pre-pubertal (4 wk) male and female BW mice and compared genes differentially expressed in these mice with the previous data. Even less genes were found differentially expressed and only one gene, Sfi1, was consistently increased in females at both ages, suggesting that, in contrast to most of the other genes identified in 9 wk old mice, this gene is not regulated by sex hormones.
IL-17 promotes germinal center response and AID-regulated pathogenic autoantibody production in autoimmune BXD2 mice (130.21)
Authors: Hsu Hui-Chen , Yang PingAr , Wu Qi , Chen Jian , Wang John , Job Godwin , Stanus Andrea L , Lorenz Robinna G , Kolls Jay K , Mountz John D 
Published: January 2023

Abstract
We have found dramatically elevated levels of activation-induced cytidine deaminase (AID) in the B cells of generalized autoimmune BXD2 mice that develop spontaneous erosive arthritis and glomerulonepheritis. Pathogenic autoantibodies cloned from these mice exhibit extensive somatic hypermutation and the majority of them have undergone class-switch recombination, suggesting that AID activity plays an important role in the production of pathogenic autoantibodies. Sera from BXD2 mice exhibited significantly elevated IL-17, but not IFN-γ or IL-4, compared to B6 mice. FACS analysis indicates that CD4 T cells in BXD2 mice are preferentially polarized to Th17 cells and these cells also express the early activation marker, CD69, in vivo in BXD2 mice. The B cells from BXD2 mice express high levels of IL-17 receptor (IL-17R) and immunohistochemistry staining shows that B cells are in close contact with the IL-17+ cells in the spleen. Administration of AdIL-17 to 1-mo-old B6 and BXD2 mice induced the expression of AID, promoted development of GCs, and enhanced the sera titers of antibodies. In contrast, administration of AdIL-17R:Fc to 10-mo-old BXD2 mice suppressed the expression of AID, down-modulated the percentage of PNA+Fas+ GC B cells, and suppressed the sera titers of antibodies. Our results provided a unique pathogenic function of IL-17 in that it positions IL-17 as a critical cytokine that regulates GC B cell response and the production of pathogenic autoantibodies.
The NOD.H2h4 mouse shows characteristics of human Sjogren’s Syndrome (130.26)
Authors: Burek C. Lynne , Talor Monica V. , Sharma Rajni B. , Rose Noel R. 
Published: January 2023

Abstract
The objective of this study was to identify critical features of the NOD.H2h4 mouse as an appropriate model to study the pathogenesis of human Sjögren’s Syndrome. Salivary and lacrimal glands of male or female mice at different age groups were examined histologically for cellular infiltration. Sera were examined for ANA by indirect immunofluorescence on Hep2 slides and for SSA/Ro and SSB/La antibodies by ELISA. Salivary function was evaluated by measuring saliva volume following pilocarpine stimulation. At 20–24 weeks, female mice showed more frequent salivary gland infiltration than males ( 65% vs 40%), whereas male mice developed more frequent lacrimal gland infiltration (100% vs 38%). By one year, the frequency was similar in both sexes. ANA frequency increased with age, with approximately 10% of animals with ANA at six weeks, to about 80 % at 20 weeks. ANA pattern was primarily speckled. Antibodies to SSA/Ro and SSB/La were found at higher levels in year old NOD.H2h4 mice (Mean ELISA OD 0.4 ± 0.17 ) compared to 10 week old NOD.H2h4 (0.1 ± 0.14) or BALB/c mice (-0.14 ± 0.16), (p&lt;0.001) with females greater than males. Antibodies to SSA/Ro and SSB/La increased with age from 10 weeks to 20 weeks. Salivary flow following pilocarpine stimulation was reduced in NOD.H2h4mice compared to control mice (146.7ul ± 56.4ul vs 198.8 ul ± 19.3ul , p = 0.03). The NOD.H2h4 mouse exhibits both salivary and lacrimal gland infiltration, high frequency of ANA with a high proportion of SSA/Ro and SSB/La autoantibodies, and decreased salivary secretion. Taken altogether, this mouse strain appears to be an ideal candidate to study the pathogenesis of Sjögren’s syndrome.
CD8 T cells Play a Critical Role in Primary Biliary Cirrhosis of dnTGFbetaRII Mice (130.28)
Authors: Yang Guo-Xiang , Lian Zhe-Xiong , Chuang Ya-Hui , Moritoki Yuki , Ansari Aftab A. , Flavell Richard A. , Ridgway William M , Gershwin M.Eric 
Published: January 2023

Abstract
Human primary biliary cirrhosis (PBC) is characterized serologically by antimitochondrial antibodies (AMA) and histologically by an intense T cell portal infiltrate that destroys bile ducts. We have taken advantage of the PBC-like disease exhibited by dnTGFbetaRII mice and focused our attention on the liver T cell infiltrate. One major advantage to this animal model is the ability to perform cell transfer. Therefore to address the issue of T cell effector mechanisms, we isolated dnTGFbetaRII splenic CD4+ or CD8+ T cells and transferred these populations into Rag1 k/o mice. Importantly, the CD8+ T cells transfer group demonstrated a significant expansion of T cells and the presence of portal tract infiltrates in recipient mice. In contrast, although CD4+ T cells did expand in the recipient group, they did not home or focus within the portal tracts. Our results demonstrate that the impaired TGFbeta signaling pathway in these mice leads to a CD8 cytotoxic T cell population that plays a critical role in biliary cell damage. These data have implications not only for understanding TGFbeta signaling and autoimmunity in these mice, but also in developing appropriate focused immunotherapy to prevent biliary damage.
Abrogation of lupus nephritis in activation-induced cytidine deaminase-deficient MRL/lpr mice (130.3)
Authors: Jiang Chuancang , Foley Julie , Clayton Natasha , Kissling Grace , Jokinen Micheal , Herbert Ronald , Diaz Marilyn 
Published: January 2023

Abstract
Autoantibodies in systemic lupus erythematosus (SLE) patients and in mouse models of SLE are frequently found to be class switched and somatically mutated. To examine directly the role of hypermutated and isotype-switched antibodies in the pathogenesis of SLE, we generated a new MRL/lpr mouse strain deficient in the activation-induced cytidine deaminase (AID). Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG antibodies, but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype translated into a near abrogation of glomerulonephritis, minimal mononuclear cell infiltration in the kidneys, and a dramatic increase in survival, indicating that isotype-switched high affinity autoantibodies are required for the development of lupus nephritis. The dramatic decrease in mortality to levels well below levels previously reported for MRL/lpr mice lacking secreted antibodies, suggests that autoreactive IgM antibodies not only are insufficient in promoting kidney disease in MRL/lpr mice, but may also play a protective role.
This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.
The silent chemokine receptor D6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis (130.33)
Authors: Liu Liping , Graham Gerard J , Hu Taofang , Lira Sergio A , Sasse Margaret , Canasto-Chibuque Claudia , Cook Donald N 
Published: January 2023

Abstract
D6, a promiscuous non-signaling chemokine binding molecule expressed on lymphatic endothelium, internalizes and degrades CC chemokines, and D6−/− mice demonstrated increased cutaneous inflammation following topical phorbol ester or complete Freund’s adjuvant (CFA) injection. We report that D6−/− mice were unexpectedly resistant to induction of experimental autoimmune encephalomyelitis (EAE), due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35–55 in CFA, D6−/− mice showed reduced spinal cord inflammation and demyelination, with lower incidence and severity of EAE attacks, compared to D6+/+ littermates. In adoptive transfer studies, MOG-primed D6+/- T cells equally mediated disease in D6+/+ or D6−/− mice, while cells from D6−/− mice transferred disease poorly to D6+/- recipients. Lymph node cells from MOG-primed D6−/− mice showed weak proliferative responses and made reduced IFN-gamma, but normal IL-5. CD11c+ dendritic cells accumulated abnormally in cutaneous immunization sites of D6−/− mice. Surprisingly, D6, a ‘silent’ chemokine receptor, supports immune response generation.
Streptozocin-induced diabetes accelerated by B cells transgenic for immunoglobulin heavy chain recognizing N-acetyl-D-glucosamine (130.35)
Authors: Dizon Brian , Greenspan Neil S. , Kearney John F 
Published: January 2023

Abstract
To determine mechanisms of autoreactive B cell selection and their involvement in the pathogenesis of autoimmune diseases, we generated a novel immunoglobulin (Ig) transgenic (Tg) mouse line, HGAC 39. In these mice, B cells express an Ig heavy chain with specificity for N-acetyl-D-glucosamine (GlcNAc) found on the cell wall of Group A Streptococcus (GAS). Tg B cells responded to iv immunization by migrating from the marginal zone to the TB border, and expanding and differentiating to plasmablasts at extrafollicular foci. Since GlcNAcylated proteins are abundant within eukaryotic cells, we hypothesized that B cells with anti-GlcNAc specificities contribute to autoimmune disease by presenting GlcNAc-modified proteins to diabetogenic CD4+ and CD8+ T cells. We induced autoimmune diabetes in Tg C57BL/6 male mice with multiple low doses of streptozocin (STZ), a β cell-specific toxin that increases GlcNAcylation of intracellular proteins, and demonstrated that the presence of HGAC 39 B cells accelerates the onset of hyperglycemia and pancreatic infiltration by HGAC 39 B cells, CD4+, and CD8+ T cells. These changes were not accompanied by increases in anti-GlcNAc plasma cells or serum antibodies. Taken together, our data suggest that HGAC 39 B cells that respond to GAS immunization can also contribute to STZ-induced diabetes by mechanisms other than autoantibody secretion.
Countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes (130.36)
Authors: Saxena Vijay , Ondr Jennifer K , Magnusen Albert F , Munn David , Katz Jonathan D 
Published: January 2023

Abstract
Islets specific CD4+ T Cells receive instructional signals from antigen bearing MHC class II-expressing antigen presenting cells (APC), yet the influence of APC on autoimmune diabetes remains elusive. Herein we delineate the direct in vivo necessity for macrophages and dendritic cells in Type 1 Diabetes of the non-obese diabetic (NOD) mouse by using diphtheria toxin-mediated conditional abaltion. We find that specific loss of macrophages had no impact on diabetes or insulitis in both spontaneous and transfer model. Loss of both myeloid (mDC) and lymphoid DC (ly DC) led to protection of NOD mice from diabetes and accompanying loss of T cell activation, while specific loss of plasmacytoid DC (pDC) and Indoleamine 2,3,dioxygenase (IDO) led to breakdown in regulatory control and accelerated insultis. These data imply that autoimmune diabetes is regulated by imbalance of mDC and pDC function in vivo.
Elucidating The Role Of Insulin Receptor In Type-I Diabetes By Developing An IR Transgenic Mouse Model (130.37)
Authors: Gupta Nirdesh K , Bretz James D , McInerney Marcia F 
Published: January 2023

Abstract
In the nonobese diabetic (NOD) mouse, type1 diabetes (T1D) is an autoimmune disease characterized by insulitis and T cell-mediated destruction of pancreatic islet β cells. The importance of insulin receptor (IR) expression in the pathogenesis of diabetes was examined since it was shown that IR is a chemotactic receptor capable of directing cell movement in response to insulin. Our published data shows that IR High/+ T cells aggressively transfer insulitis and diabetes while IR Low/− T cells are capable of neither. Therefore, IR may function to deliver T cells to the islet. Recently, it has been shown in NOD mice that benign insulitis can occur in the absence of T cell-MHC/Ag interactions. The object of this work is to test whether T cells overexpressing IR, can move into the pancreas based on insulin chemotaxis alone, without being targeted to the pancreas by antigenic specificity. To that end a transgenic mouse will be made wherein FLAG tagged IR expression will be targeted to all T cells. If IR expression is a mechanism to move T cells into the islet then down regulation of IR expression or blocking of chemotactic IR activity specifically in T cells, will provide a new therapeutic target to block cell movement into the pancreas, thus preventing diabetes.
CD4+ T cells mediate autoimmune disease in a new transgenic murine model induced by U1 RNA and U1-70kD ribonucleoprotein self antigens (130.4)
Authors: Hoffman Robert W , Greidinger Eric L , Zang Yun , Jaimes Kimberly , Martinez Laisel , Fernandez Irina 
Published: January 2023

Abstract
C57BL/6 mice transgenic (Tg) for the human major histocompatibility complex gene HLA-DR4 were immunized with U1 RNA and a fusion protein spanning the RNA binding domain of the U1-70kD polypeptide, control fusion protein, with or without U1-RNA, or saline. Complete serologic and histologic analyses were performed on all mice. CD4+ T cells and APCs were isolated from immunized mice using immunoaffinity columns and tested for proliferation. Either freshly isolated CD4+ T cells from immunized mice or T cell lines were adoptively transferred to unmanipulated HLA-DR4 Tg or RAG−/− mice. Freshly isolated CD4+ T cell from immunized DR4 Tg mice proliferated in response to U1-70kD and to synthetic peptides from the RNA binding domain region of the protein in the presence of irradiated autologous APCs. We found that CD4+ T cells specific for U1-70kD were able to transfer disease to unmanipulated syngeneic mice. Furthermore, using purified CD4+ T cells or T cell lines specific for U1-70kD we were able to transfer disease to RAG−/− mice in the absence of detectable B cells or autoantibodies.
In conclusion, we have developed a new model of systemic autoimmunity that is induced following a single exposure to U1-RNA and its associated RNA binding protein. Anti-U1-70kD autoantigen-specfic CD4+ T cells appear to medicate pathogenesis of disease in this model and can do so in the absence of detectable B cells or autoantibodies.
This work was supported by NIH award AR43308 (RWH), the Lupus Foundation of American (RWH) and Department of Veterans Affairs Merit Review awards (RWH & ELG).
Polarized TCR-Transgenic Th17 Cells Resemble Th1 Cells in Their Capacity to Adoptively Transfer Ocular Inflammation, but Differ in Other Biological Activities (130.44)
Authors: Cox Catherine A , Shi G. , Yin H. , Vistica B.P. , Wawrousek E.F. , Chan C-C. , Gery I. 
Published: January 2023

Abstract
The role of Th17 lymphocytes in immunopathogenic processes has been well established, although little is known about their mode of action and other biological activities. Here, we prepared polarized populations of TCR-transgenic (Tg) Th1 or Th17 cells specific against hen egg lysozyme (HEL) and compared each line for its capacity to adoptively transfer ocular inflammation into Tg recipients expressing lens-associated HEL, as well as for other biological activities. To establish each line, naive CD4+ cells were cultured in the presence of HEL and "cocktails" containing cytokines and antibodies known to drive polarization to Th1 or Th17. Successful polarization of Th1 and Th17 lines was confirmed by intracellular expression and release into the culture medium of IFNγ or IL17, respectively. Surface marker expression was determined by flow cytometry of cultured cells. Recipient eyes were examined histologically. Polarized cells were also tested for their capacity to induce splenomegaly in recipient mice (Chen et al JI 2006). Our results showed that Th1 and Th17 cells were similarly immunopathogenic, transferring ocular inflammation at doses as low as 0.2 million. Histological comparison of eyes from each group, however, revealed slight although discernible differences between Th1 and Th17 recipients. The two populations also differed in their expression of surface markers, particularly in CD49d and CD62L. Finally, Th17 cells were remarkably less efficient than Th1 cells in their capacity to induce splenomegaly in recipient mice.
Potential regulatory role for CNS-specific, autoreactive CD8+ T-cells in autoimmune demyelination (130.7)
Authors: York Nathan Ronald , Mendoza Jason P , Benagh Andrew , Karandikar Nitin J 
Published: January 2023

Abstract
A great deal of our current knowledge about the immune pathogenesis of multiple sclerosis (MS) derives from work in its murine model, experimental autoimmune encephalomyelitis (EAE). The vast majority of studies in MS and EAE have focused on the role of CD4+ T cells, with the underlying assumption that MS, like EAE, is a CD4+ Th1-mediated and Th2-regulated autoimmune disease. However, several reports from us and others have implicated roles for both CD4+ and CD8+ T-cells in these diseases. In this study, we specifically dissected the role of autoreactive, CNS-specific CD8+ T-cells in EAE. Similar to our observations in MS, we saw robust induction of CNS-specific CD8+ T-cell responses in several established models of EAE (B6/MOG35-55; SJL/PLP139-151; B10.PL/MBPAc1-11). Following in vitro activation in bulk splenocyte cultures, MOG35-55-specific CD4+ T-cells, but not CD8+ T-cells, were capable of adoptively transferring EAE to naïve B6 mice. Interestingly, transfer of MOG-stimulated, but not OVA-stimulated, CD8+ T-cells resulted in inhibition of EAE induction, suggesting a regulatory, rather than pathogenic, role for these cells in this model. In conclusion, our studies reveal a novel regulatory function for CNS-specific CD8+ T-cells that are reproducibly generated during the induction of EAE.
This research was supported, in part, by grants from the National Institutes of Health and the National MS Society.
Spontaneous Gluten Dependent Blistering in DQ2 transgenic mice (130.9)
Authors: Marietta Eric Vincent , Rashtak Shadi , Pittelkow Mark R , David Chella S , Murray Joseph A 
Published: January 2023

Abstract
Background/Aim: Dermatitis Herpetiformis is the autoimmune skin manifestation of celiac disease, and similar to celiac disease, is tightly associated with HLA-DQ2 and HLA-DQ8. Previously we have generated a mouse model of DH using DQ8 transgenic mice on an NOD background. Herein, we describe a similar DH-like blistering disease that spontaneously develops in DQ2 transgenic mice.
Methods: Transgenic mice that express DQ2 on a background deficient in endogenous MHC II (Aeo) were raised on a gluten containing (GC) chow or a gluten free chow .
Results: When raised and maintained on a gluten containing chow, approximately 15% of these Aeo DQ2 mice spontaneously developed blisters on the ears and tails at about six months of age. Control Aeo mice that were also raised on a gluten containing chow did not develop this blistering disease during their lifetime. Hematoxilyn and eosin staining revealed subepidermal blisters. Immunohistochemistry revealed IgA deposits at the dermal/epidermal junction in perilesional ear tissue. However, when these mice were raised and maintained on a gluten free diet, these mice did not develop blisters.
Conclusions: This blistering disease is a gluten dependent disease that has many of the elements typically associated with Dermatitis Herpetiformis, most especially the association with the DQ2 gene.
Vaccination with Collagen-Pulsed Immature Dendritic cells Significantly Delayed the Onset and Lessened Severity of Spontaneous Polychondritis in HLA-DQ Transgenic Mice (131.10)
Authors: Sidhu Maninder , Bradley David S 
Published: January 2023

Abstract
Immature dendritic cells (iDCs) have a tolerogenic potential due to low expression of costimulatory cell surface molecules required for antigen presentation and induction of an effective immune response. Here we report that injection of iDCs pulsed with chick type II collagen (CII) significantly delayed the onset and suppressed the severity of spontaneous polychondritis in HLA-DQ6αβ8αβ tg mice. Bone marrow derived iDCs were purified, pulsed in vitro with CII and transferred to 6 wk old HLA-DQ6αβ8αβ tg mice. Controls received either un-pulsed iDCs or PBS. Both control groups developed polyarthritis at 3.5 months as we have previously reported. However, none of the mice receiving CII-loaded iDCs displayed any clinical signs of disease until 5.5 months of age, indicating the ability of the DC vaccine to significantly delay the onset of the disease. The severity of disease in CII-pulsed iDC immunized test mice remained less than controls. Interestingly, after 6.5 months of age the incidence of polyarthritis in the CII-loaded iDC group gradually increased from 25% to 87%. Total IgG levels were elevated in the CII-loaded iDC test group. None of the mice developed significant CII-specific IgG responses, indicating that the CII-loaded iDCs were not inducing a CII specific immune response. This is the first evidence of iDC therapy controlling polychondritis and suggests that iDC vaccination may provide a novel tool in the treatment of human inflammatory autoimmune disease such as relapsing polychondritis and rheumatoid arthritis.