bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of B cell development and immune tolerance by the MiTF family of transcription factors (159.12)
Authors: Lopez Ocasio Maria , Huan Chongmin , Gottesman Susan , Roman Christopher 
Published: January 2023

Abstract
B cell activation is tightly regulated by transcription factors (TFs) that control gene expression programs determining plasma and memory cell development. Dysregulation of these programs can lead to autoantibody production. MiTF, a member of the MiT family of transcription factors that includes TFEC and the CD40L regulators TFE3 and TFEB, is important in restraining plasma cell development by repressing IRF4. This was demonstrated in MiTFmi/mi bone marrow chimeras being necessary because the mi allele is a dominant negative mutation that causes osteopetrosis due to defective MiTF-dependent osteoclast development. However, because the MiTFmi protein could inhibit other MiTF family members and affect other hematopoietic cells, we are developing B cell specific MiT family inactivation models that obviate bone marrow transplantation. One, a single transgene model, exploits B cell-specific expression of an artificial trans-dominant negative protein (TDN) that forms inactive heterodimers with all MiT members. In preliminary data, we observed several defects in these mice, including splenomegaly, elevated numbers of spontaneous Germinal Centers and plasma cells, and perturbations in the distribution of B cell subsets not observed in the transplantation model. These data show a B cell subset specific dependency on the MiT family and the possible contribution of other MiT family members.
Significant association of specific DRB1 & DQB1 sequence feature variant types with systemic sclerosis autoantibodies types and racial groups (159.20)
Authors: Scheuermann Richard , Marthandan Nishanth , Guidry Paula , Thomson Glenys , Arnett Frank , Karp David 
Published: January 2023

Abstract
The sequence feature variant type (SFVT) approach to genetic association analysis has previously identified parts of HLA proteins that are associated with development of a variety of autoimmune diseases. Using the SFVT approach, we analyzed DRB1 and DQB1 typing data in a cohort of patients with Systemic Sclerosis (SSc). While no traditional class II alleles were significant across three racial groups (African American, Caucasian and Hispanic), 23 related DRB1 SFVTs were found in common. We also found that while more than 80% of the same sequence features (SFs) were significantly associated with the presence of either anti-centromere or anti-topoisomerase antibodies for each of the loci, only 2 (3%) and 5 (8%) of the risk-associated variant types (VTs) for DRB1 and DQB1, respectively, were shared, indicating that the same SFs but different VTs are associated with the presence of the different autoantibodies. Intriguingly, several protective anti-topoisomerase VTs corresponded to the risky anti-centromere VTs. We found that SFVTs that differ by only a few amino acids can give rise to different autoantibodies in SSc patients (e.g. association of the antigen binding motif 67L_70Q_71R with anti-centromere, versus association of 67F_70D_71R with anti-topoisomerase). Tools in ImmPort (www.immport.org) for the conversion of four-digit HLA typing data into an SFVT data matrix and the calculation of chi-squared association statistics were used for the analysis.
Localized and peripheral autoantibodies: evidence of humoral autoimmunity in patients with inclusion body myositis (159.21)
Authors: Ray Arundhati , Willis Simon , Bradshaw Elizabeth , Goldstein Jonathan , Lundberg Ingrid , Nowak Richard , Ploegh Hidde , O'Connor Kevin 
Published: January 2023

Abstract
Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The disease is viewed to be T cell mediated. However, emerging data suggests that B cells may play a role in IBM. To further the understanding of IBM immunopathology and explore the role of the humoral autoimmune response in IBM, we searched for autoantibodies both in the periphery and at the site of tissue damage. Peripheral autoantibodies that recognized muscle-derived cells were demonstrated in IBM serum using both immunohistochemistry and flowcytometry. To focus on the site of tissue injury, we examined the immunoglobulin-secreting plasma cells that infiltrate IBM muscle. A series of single, tissue-associated plasma cells were isolated from IBM muscle. Recombinant immunoglobulins (rIgG) produced from these cells were used as molecular tools to search for autoantigens. Flow cytometry and immunoblotting revealed that these tissue-derived rIgGs recognized human muscle tissue-associated antigens. To identify the target of the rIgGs, a multi-step protein separation scheme and mass spectrometry were employed. Desmin, a major intermediate filament protein expressed in muscle, was identified as a candidate autoantigen for one IBM rIgG. Specificity to desmin was confirmed with a solid-phase assay. Collectively, these data indicate that IBM autoimmunity includes a humoral component.
Investigating the role of MZB and B1 Cells in Sjögren’s Disease (159.22)
Authors: Shen Long , Xuan Jingxiu , Suresh Lakshmanan , Ambrus, Jr. Julian 
Published: January 2023

Abstract
We have previously demonstrated that IL14a transgenic mice (IL14aTG) reproduce features of Sjogren’s disease (SD) seen in patients in the same relative time frame, including autoantibodies, early destruction of the salivary and lachrymal glands, infiltration of the salivary and lachrymal glands with lymphocytes, lymphocytic pneumonia, mild renal disease and eventually lymphoma (J.Immunol. 177: 5676, 2006 and Clin. Immunol. 130:304, 2009). We have more recently demonstrated that lymphotoxin is an important early mediator of salivary gland injury in IL14aTG mice and patients with SD (J.Immunol. 185: 6355, 2010). In our current studies we investigate the role of MZB and B1 cells in SD in IL14aTG mice. We demonstrate that IL14aTG mice lacking MZB cells (IL14aTG.CD19Cre.RBPj-/-) do not develop any features of SD up to the ages of 18 months. However, IL14aTG mice lacking Bruton’s tyrosine kinase (btk; IL14aTG.btk-/-), and hence B1 cells, develop more severe and accelerated SD with B cell lymphomas by 10 months of age, about 3 months earlier than IL-14a TG mice. Our hypothesis is that MZB and MZB precursors (MZBP) trafficking in the salivary and lachrymal glands are critical for inducing SD. Mice lacking B1 cells via the deletion of Bruton’s tyrosine kinase (btk) have accelerated SD because of increased numbers of MZB and MZBP along with decreased numbers of regulatory B cells. Current studies are evaluating these hypotheses.
A unifying principle for autoantigenicity: Transforming self-molecules into autoantigens by association with dermatan sulfate polysaccharide (159.25)
Authors: Wang Julia , Roehrl Michael 
Published: January 2023

Abstract
Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are chronic and disabling diseases that affect hundreds of millions of people worldwide. Despite great advances in biomedical research, etiology and pathogenesis of systemic autoimmune diseases have remained mysterious. In particular, the question of why and how a small, seemingly disparate subset of self-molecules become autoantigenic holds a key to understanding the basic principles of autoimmunity. Based on our recent data, we propose a unifying principle for autoantigenicity. We discovered that dermatan sulfate (DS) is an important functional link between cell turnover, autoantigens (autoAgs), autoAbs, autoreactive B-1a cells, and autoimmunity. By selectively interacting with autoAgs released from apoptotic/dead cells, DS can tether many autoAg molecules along its polymeric chain and convert singular self-molecules into multivalent polymer-like antigens, thus changing the “self”-nature of this molecule. Polymeric DS-autoAg complexes are potent stimulators of autoreactive B-1a cells that secrete autoAbs and present autoAgs to autoreactive T cells. This principle provides a mechanistic explanation for how only certain self-molecules derived from dead cells become autoantigenic. This principle also explains how microbial pathogens may convert self-molecules to autoantigens and provides clues to how environmental factors may contribute to autoimmunity and trigger autoimmune diseases.
The accumulated VH replacement products contribute to the generation of auto/polyreactive antibodies in systemic lupus erythematosus (P1721) (159.3)
Authors: Li Song , Yu Yangsheng , Fan Run , Liao Hongyan , Wang Zhixin , Yue Yinshi , Huang Lin , Guo Sara , Hearth-Holmes Michelene , Cannella Amy , Chatham W. Winn , Kimberly Robert , Klassen Lynell , O’Dell James , Carter Robert , Su Kaihong , Zhang Zhixin 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is characterized by the over-production of high affinity autoantibodies. However, it is not clear how these autoantibodies are generated and selected. VH replacement is originally considered as a receptor editing process to change unwanted non-functional immunoglobulin heavy chain (IgH) genes or IgH genes encoding self reactive BCRs. Our sequence analysis shows that VH replacement products are highly enriched in IgH genes derived from different autoimmune diseases, including SLE. In this study, we performed single cell RT-PCR to study the functional antibody repertoires in active SLE patients. Analysis of 180 recombinant antibodies derived from SLE patients showed that 19.0% of the antibodies derived from naïve B cells and 56.9% of the antibodies derived from plasmablasts are autoreactive. In contrast, only 7.7% and 17.4% of the antibodies derived from naïve B cells and plasmablast B cells are autoreactive in healthy donors. The VH replacement products are significantly increased in IgH genes obtained from SLE patients (20%) compared to that in healthy controls (10%). Importantly, the accumulated VH replacement products in SLE patients have long CDR3 regions enriched with positively charged amino acids; 74% of them directly encode anti-nuclear antigen or polyreactive antibodies. Based on these results, we conclude that the accumulated VH replacement products in SLE patients contribute to the generation of auto/polyreactive antibodies in SLE.
Mechanisms for non-antigen specific rheumatoid factor B cell activation in the NZM2410 mouse model of lupus (159.9)
Authors: Sang Allison , Morel Laurence 
Published: January 2023

Abstract
Systemic lupus erythematosus is characterized by the presence of autoantibodies, including rheumatoid factor (RF), due to a breakdown in B cell tolerance. In the AM14 model, the AM14 transgenic heavy chain combined to Vκ8 produces a RF specific for IgG2aa. Contrary to the MRL/lpr lupus model, RF B cell activation required the presence of chromatin-IgG immune complexes (ICs), but could occur in the absence of the IgG2aa autoantigen in the B6.NZM2410.Sle1.Sle2.Sle3 (TC) strain, which contains the three major NZM2410-derived lupus susceptibility loci (Sle1, Sle2, Sle3). Treatment of young TC.AM14 and control B6.AM14 mice with a TLR7/9 antagonist did not decrease RF B cell activation after immunization with antigen non-specific anti-chromatin ICs. Splenic DCs from mice injected with anti-chromatin hybridomas showed elevated expression of IL-6 and IFN-γ mRNA in TC mice in comparison to B6 controls. B cell co-cultures with TC-derived BMDCs induced greater B cell proliferation than B6-derived BMDCs. Finally, B cell activation of aged AM14 mice expressing Sle1 or Sle2 showed that while Sle1 promoted antigen specific activation, Sle2 induced B-cell activation is polyclonal in nature. Therefore, our results show that while cognate-antigen independent RF B cell activation is not affected by inhibition of TLR7/9 signaling, it is enhanced by DC-derived cytokines and the expression of the Sle loci.
A role for immune deficiency in the mass mortality of the Caribbean sea urchin Diadema antillarum-a?(160.10)
Authors: Beck Gregory , Miller Robert , Ebersole John 
Published: January 2023

Abstract
Immune responses and diseases of marine invertebrates in natura are not well understood, and studies linking this knowledge to ecological events are rare. An epidemic nearly eliminated the long spined sea urchin Diadema antillarum-a from the Caribbean in 1983, with limited recovery since. Loss of this keystone grazer is a major factor in the ensuing shift from living coral to algae-covered rock on Caribbean reefs. Our studies of immune responses of four Caribbean sea urchin species suggest that a deficiency in the Diadema immune system may have played a role in the mass mortality. Using coelomocytes, we tested humoral responses of the urchins with classic stimulators in several assays. All urchin coelomocytes responded to stimulators with one statistically significant exception: Diadema did not respond as vigorously to lipopolysaccharide. This suggests a defect in immune response that is specific to Diadema and independent of stressors associated with particular environments. This inability of Diadema to respond to lipopolysaccharide provides the first evidence of a deficient immune response in a natural population of a marine invertebrate, and may help explain why Caribbean Diadema antillarum-a was vulnerable to an epidemic. Recovery of Diadema allows us to addresses questions on how recovery may be influenced by immunological processes. Further investigation of phylogenetic and geographic patterns in immunity of marine organisms may help us predict future epidemics.
Immunogenicity evaluation of in silico identified Mycobacterium avium subsp paratuberculosis recombinant proteins that were upregulated under stress conditions (160.3)
Authors: Gurung Ratna , Purdie Auriol , Begg Douglas , Whittington Richard 
Published: January 2023

Abstract
Mycobacterium avium subsp paratuberculosis (MAP) is the causative agent of Johne’s disease (JD) in ruminants. It is known to enter a dormant phase outside the host typically on soil and survive inside the host macrophage. In vitro experiments have reported differential regulation of certain MAP proteins when exposed to stressors similar to dormancy. It is believed that in vivo regulation of dormancy genes and associated proteins by MAP may play an important role in evading the host defence mechanisms and the host may also mount an immune response against these dormancy related proteins. Evaluation of such proteins may provide insight to host-pathogen interaction during the course of MAP infection and may be of diagnostic interest. A group of dormancy genes upregulated under stress conditions were examined using in silico analysis to identify B and T-cell epitopes. Five potential candidate genes based on epitope prediction results were selected and cloned. Recombinant proteins were produced, purified and evaluated for their immunogenicity using a panel of sera from sheep with a spectrum of JD and sheep free of MAP infection by detection of serum antibodies. Individually, the five proteins were found to have the ability to partially discriminate between sera from sheep unexposed and exposed to MAP infections. This study showed that the MAP proteins upregulated under in vitro stress conditions were recognised by host immune system.
The pig heavy and light chain immunoglobulin repertoires provide insights into the adaptive immune response against porcine reproductive and respiratory syndrome virus (PRRSV). (160.4)
Authors: Schwartz John , Murtaugh Michael , Abrahante Juan 
Published: January 2023

Abstract
Antibody responses are critical to effective immunity to viral infections. Thus, extensive efforts have been directed to characterize antibody responses, including neutralizing antibodies, to PRRSV infection, in the expectation of elucidating key insights into protective and cross-protective immunity. Despite these efforts, the role of antibody responses in PRRSV immune protection remains poorly understood due, in part, to the lack of specific information about porcine immunoglobulin structures. To address this limitation, we characterized the expressed heavy and light chain immunoglobulin repertoires in healthy and PRRSV-infected pigs using amplicon-based 454 high-throughput sequencing. Bioinformatic analysis of approximately 450,000 heavy chain reads revealed differential heavy chain variable gene (IGHV) usage specific to PRRSV infection, including several exceptionally common immunoglobulin sequences representing clonally expanded B cell populations. The total richness of the heavy chain repertoire was approximately 3.5x105, equivalent to that reported in humans, suggesting that the swine antigen-binding repertoire is similarly complex, despite lack of diversity in the porcine IGHV framework regions. Initial analysis of over 13,000 light chain reads confirms that pigs use only two lambda J-C cassettes and are heavily reliant on a single kappa J gene. Further analysis of the light chain repertoire and its response to PRRSV infection is pending.
Cellular responses of the long-spined sea urchin (Diadema antillarum-a)(160.9)
Authors: DeFilippo John , Ebersole John , Beck Gregory 
Published: January 2023

Abstract
The long-spined sea urchin (Diadema antillarum-a) began dying on coral reefs near the Panama Canal in 1983, and over the next year they virtually disappeared from the Caribbean Sea. Present evidence suggests that a water-borne pathogen was responsible. Since their die-off Diadema densities remain low, and as they facilitate coral recruitment and persistence by controlling macroalgae, its loss has contributed to the transformation of living coral reefs in the Caribbean to barren algae-covered rock. Our preliminary on-site studies of the humoral responses of the urchins showed that Diadema coelomocytes did not respond to lipopolysaccharide as vigorously as did other common Caribbean sea urchins (Tripneustes ventricosa, Echinometra lucunter, and E. viridis). We then studied the cellular immune responses of coelomocytes and coelomic fluid of Diadema and those of the other urchins unaffected by die-off. Light microscopy revealed differences in coelomocyte populations of the predominant urchins of the Caribbean. We used flow cytometry to investigate differences in cellular composition and responses of coelomocytes in phagocytosis assays. It is hoped that this research will increase insight into one of the most devastating and ecologically important die-offs ever recorded, as well as provide the information required to understand whether weakened immunity was involved in the mass mortality of Diadema antillarum-a, and whether strengthening of immunity has occurred since then.
Loss of IFN-gamma 3’untranslated region AU-rich element affects B220+ B cell and plasmacytoid dendritic cell populations in novel murine lupus model (161.3)
Authors: Hodge Deborah , Berthet Cyril , Coppola Vincenzo , Shirota Hidekazu , Reynolds Della , Klinman Dennis , Young Howard 
Published: January 2023

Abstract
Interferon-gamma (IFN-g) is a key player in immunoregulation, inflammation and autoimmunity. We created a mouse with a162 nt deletion of an AU-rich element (ARE) region in the 3’UTR of the IFN-g gene. The ARE-deleted (ARE-Del) mice have chronic circulating serum IFN-g levels and develop a lupus-like disease characterized by DNA and nuclear antigen-specific autoantibodies and glomerulonephritis. B220+ B cells and plasmacytoid dendritic cells (pDCs) play a prominent role in systemic lupus erythematosus (SLE). We find alterations in both cell types. Greater B cell percentages are found in lymph nodes and thymus with a concomitant reduction in spleen. The B cells have an activated phenotype with increased CD69 and/or CD86 expression. The ARE-Del thymic B cell population is partially composed of B1a and B1b B cells and is correlated with increased thymic mRNA expression of the B cell chemoattractant, CXCL13. Splenic B cells down-regulate CD23 and CD21 with no change in surface markers CD19, B220, IgM, and IgD. The percentage of CD11c+, pDCA1+, B220+ Siglec H+ pDCs is increased in bone marrow and spleens from AU-deleted mice. Current studies are underway to further characterize the pDC population and to investigate expression of bone marrow-specific factors important for pDC development. Overall, these data demonstrate that low chronic IFN-g levels are sufficient to alter the phenotype and potentially the development of cells important for SLE disease onset and progression.
Chronic alcohol consumption increases and activates iNKT cells in B16BL6 melanoma-bearing mice (162.21)
Authors: Zhang Hui , Zhu Zhaohui , Meadows Gary 
Published: January 2023

Abstract
Drinking alcohol is a risk factor for cancer. High alcohol consumption is immunosuppressive, and relatively little is known about how it regulates antitumor immunity. Herein, we examined the effects of chronic high alcohol consumption on natural killer (NK) T cells since they play important roles in shaping antitumor immunity. We utilized a well-established mouse chronic alcohol consumption and B16BL6 melanoma transplantation model to study NKT cell regulation. We found that chronic alcohol consumption dramatically increases NK1.1+ invariant NKT (iNKT) cells in the blood of melanoma-bearing mice that were fed 20% (w/v) alcohol for 3-6 months before subcutaneous tumor inoculation. The percentage of NK1.1- iNKT cells decreased 2-4 fold in the alcohol-consuming mice compared to their water-drinking counterparts. Alcohol consumption increased the IL-4/IFN-γ ratio in iNKT cells activated in vitro with αGalCer compared to control. IFN-γ concentration in the blood 14 hours after in vivo activation of iNKT cells with αGalCer was 2-fold higher than in the blood of controls, and the expression of CD80 and CD86 on B cells and dendritic cells, and CD69 on CD4+ and CD8+ T cells was up regulated in alcohol-consuming mice compared to control. . These results indicate that chronic alcohol consumption facilitates the activation of iNKT cells in B16BL6 melanoma-bearing mice.
Aging-associated B7-DC+ B cells enhance anti-tumor immunity (162.24)
Authors: Shin Tahiro , Ludwig Sara , Zhang Bin , Curiel Tyler , Tomihara Kei 
Published: January 2023

Abstract
Because most cancer patients are aged and because immunological functions are altered during aging, it is important to account for aging-associated immunological alterations in the design of new cancer immunotherapies. We thus compared immune populations in young and aged mice and found that B7-DC+ (PD-L2/CD273) B cells, a minor population in young mice, were significantly increased in aged mice. Induction of both Th1 and Th17 cells was significantly augmented by B7-DC+ B cells from aged mice and this effect was blocked with anti-B7-DC antibodies in vitro and in vivo. Moreover, retardation of tumor growth in aged mice was largely B7-DC-dependent. Tumor growth in young mice was significantly inhibited by immunization with B7-DC+ B cells from aged mice due to increased induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs). These data indicate that B7-DC+ B cells could play an important role in aging-associated cancer immunopathology as well as other aging-associated-diseases, and further suggest that B7-DC+ B cells have potential for future cancer immunotherapy.