bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of IL-1beta secretion by defensins (100.11)
Authors: Shi Jishu , Aono Shelly , Lu Wuyuan , Ouellette Andre J , Wang Lei , Lenz Stephen , Elson Charles O 
Published: January 2023

Abstract
Impaired expression of antimicrobial peptides α defensins and overproduction of proinflammatory cytokine IL-1β have been associated with inflammatory bowel disease (IBD). In this study, we examine the interactions between defensins and IL-1β and the role of defensin-deficiency in the pathogenesis of IBD. It was found that matrix metalloproteinase-7 deficient (MMP-7−/−) mice, which produce procryptdins but not mature cryptdins (α-defensins) in the intestine, were more susceptible to dextran sulfate sodium (DSS)-induced colitis. Furthermore, the baseline and DSS-induced IL-1β production in the intestine are significantly up-regulated in MMP-7−/− mice compared with that in WT mice. To elucidate the molecular mechanism for the increased IL-1β production in defensin-deficiency in vivo, we evaluated the effect of defensins on IL-1β posttranslational processing and release. It was found that α defensins, including human neutrophil defensin HNP-1, human Paneth cell defensin HD-5, and mouse Paneth cell defensins cryptdin-3 and cryptdin-4, can block the release of IL-1β from LPS-activated monocytes. However, TNF α expression and release from LPS-activated monocytes are not affected by defensins. Unlike α defensins, human β defensins and mouse procryptdins do not have any effect on IL-1β processing and release. Thus, α-defensins may play an important role in intestinal homeostasis by controlling the production of IL-1β.
Through melanocortin 1 receptor (MC1r), alpha-melanocyte stimulating hormone (α-MSH) regulates macrophage function (100.2)
Authors: Taylor Andrew W , Li Dayu 
Published: January 2023

Abstract
The neuropeptide α-MSH suppresses macrophage innate inflammatory activity, their drive to activate Th1 cells, and induce anti-inflammatory activity by the macrophages. This anti-inflammatory activity has led to evaluating the use of α-MSH peptides in therapy to suppress inflammation. Three melanocortin receptors (MCr) for α-MSH are expressed by macrophages. Although macrophages express mRNA for MC1r, MC3r, and MC5r, it is assumed that the anti-inflammatory activity of α-MSH is through MC1r or MC3r. To understand the mechanisms of α-MSH signaling in macrophages, we synthesized double stranded small interfering RNA (siRNA) to target mouse MC1r and MC3r mRNA. We knocked-down MC1r and MC3r mRNA and protein in siRNA transfected mouse macrophage cell line RAW264.7. The MC1r siRNA transfection neutralized α-MSH suppression of LPS-induced production of nitric oxide, IL-1β, TNF-α, and LPS-induced p38 and NF-κB activation. Although MC3r siRNA effectively knocked-down MC3r, it had no effect on α-MSH suppression of LPS-induced NF-κB activation. Therefore, of the three naturally expressed MCr on macrophages, it is through at least MC1r that α-MSH suppresses the prototypical LPS-induced activity in macrophages. These results with our previous reports of α-MSH regulation of T cell activity imply an important role for melanocortin proteins and receptors in immune regulation.
Supported By EY010752.
TNF-like weak inducer of apoptosis (TWEAK) in pathogenesis of autoimmune renal disease (101.7)
Authors: Gao Hua-Xin , Schwartz Noa , Campbell Sean , Burkly Linda , Jarchum Irene , Banas Bernard , Saleem Moin , Mathieson Peter , Michaelson Jennifer , Putterman Chaim 
Published: January 2023

Abstract
Lupus nephritis (LN), which manifests histologically by glomerulonephritis, tubulointerstitial inflammation and mesangial cell proliferation, is a major cause of mortality and morbidity in systemic lupus (SLE). TNF ligands and receptors are important in the pathogenesis of LN; furthermore, we recently found that TWEAK, a member of the TNF ligand superfamily, was significantly increased in urine from patients with active LN as compared to patients with inactive renal disease. We studied the effects of TWEAK in human kidney cells including mesangial cells (MC), podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. TWEAK induces kidney cells to secret multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1a, GM-CSF, ICAM-1, and VCAM-1. Cytokine production is primarily mediated through NF-kB activation, and could be inhibited by novel anti-TWEAK mAb. TWEAK-stimulated chemokines induced PBMC migration, especially monocyte/macrophages, which may then infiltrate into lupus kidneys in vivo. Furthermore, we found that TWEAK promotes MC proliferation. In conclusion, TWEAK may play a pathogenic role in the development of LN by enhancing renal inflammation and MC proliferation. Furthermore, blocking TWEAK/Fn14 interactions may be a promising therapeutic target in LN and perhaps other immune-mediated renal diseases.
Characterization of the interaction between human LAIR-1 and collagens. (101.8)
Authors: Tang Xiaobin , Narayanan Sriram , Coligan John E. , Borrego Francisco 
Published: January 2023

Abstract
Human leukocyte-associated Ig-like receptor-1 (LAIR-1) is an immunoreceptor tyrosine based inhibitory motif (ITIM) containing inhibitory receptor that is expressed on the majority of PBMCs and thymocytes. The ligand for LAIR-1 has recently been identified as collagens. Since collagens represent the most abundant type of proteins in vertebrates it is reasonable to think that LAIR-1 could have a very important role in controlling many aspects of the immune response. To study the interaction of LAIR-1 with collagens, we use a reporter cell system expressing a chimeric receptor composed of the extracellular domain of LAIR-1 and the transmembrane and cytoplasmic domains of the CD3æ chain. Using this reporter system we have found that both purified collagens type I and type IV are ligands for LAIR-1. Moreover, we have also found that LAIR-1 can interact with collagen type IV that is present in the extracellular matrix and basement membranes. In addition, we have identified a pivotal residue in the extracellular domain of LAIR-1 that could be required for a functional interaction with collagens type I and type IV. Then, by confocal microscopy, we have observed the accumulation and polarization of LAIR-1-EGFP at the binding sites with collagens type I and IV and matrigel. This polarization is very fast and dynamic in nature. An analysis of the role of ITIM motifs in the interaction of LAIR-1 with collagens will be discussed.
Surprising Kinetics of the T cell Response to HY (102.25)
Authors: Tyznik Aaron Jacob , Bevan Michael J 
Published: January 2023

Abstract
Cooperation of CD4+ and CD8+ T cells is required for the development of primary effector and memory CD8+ T cells following immunization with non-inflammatory immunogens. In this study, we characterized endogenous CD4+ and CD8+ T cell responses to male-specific minor histocompatibility (HY) antigens. We find that male cells are rejected 10–12 days after transfer into female mice of the same strain, and this rejection coincides with the expansion and effector function of CD8+ CTLs to two H-2Db-restricted epitopes. While anti-male CD4+ T cell responses are readily detectable day 5 post-transfer, CD8+ T cell response are not detectable until day 10. The early CD4+ T cell response is not dependent on direct presentation of antigen by donor male cells, but depends on processing and presentation of the male cells by female APC. The primary and recall CD8+ T cell responses and rejection of HY incompatible cells are dependent on a sustained CD4+ T cell response and the absence of this response is not replaced by inflammation or treatment with anti-CD40 agonist Ab. Unexpectedly, HY-specific CD4+ T cells are also capable of efficiently lysing target cells in vivo. The delay in the CD8 effector response can be largely abrogated by depleting T cells from the male inoculum, and we further demonstrate that donor CD8+ T cells in particular suppress or veto the host anti-HY CD8+ T cell responses.
Treatment of autoimmune diseases in MRL/lpr mice by allogenic bone marrow transplantation plus adult thymus transplantation (102.4)
Authors: Hosaka Naoki , Miyake Takashi , Cui Wenhao , Nishida Teruhisa , Takaki Takashi , Inaba Muneo , Ikehara Susumu 
Published: January 2023

Abstract
MRL/lpr mice (H-2k) with Fas gene mutation develop severe autoimmune diseases, and their hematolymphoid cells such as bone marrow and spleen cells showed a low apoptotic activity by irradiation. Therefore, conventional bone marrow transplantation (BMT) cannot be used to treat autoimmune diseases in these mice (chimeric resistance). In the present study, we examine the effects of additional adult thymus transplantation (TT) from the same donor on successful BMT. When the MRL/lpr mice were lethally irradiated (9.5Gy) and reconstituted with 3 X 107 of C57BL/6 mouse (H-2b) bone marrow cells (BMCs) in conjunction with TT, the mice significantly survived long-term and showed a high donor-derived chimerism in comparison with those treated with BMT alone. Interestingly, the numbers of not only donor-derived T cells but also B cells significantly increased in the mice treated with BMT plus TT even at the early phase of BMT. The number of aberrant CD3+B220+ cells significantly decreased, and the numbers of lymphocyte subsets were also normalized 4 weeks after the treatment. Finally, the autoimmune diseases in MRL/lpr mice could be cured by BMT with TT. These results indicate that the combination of BMT plus TT can overcome the chimeric resistance and treat the autoimmune diseases in MRL/lpr mice.
Physiological levels of insulin induce receptor editing in anti-insulin B cells to maintain tolerance (128.18)
Authors: Henry Rachel A. , Thomas James W. 
Published: January 2023

Abstract
Receptor editing (RE) is now recognized to play a major role in removing newly formed, autoreactive B cells from the repertoire. Although tolerance induction by monovalent BCR interactions may include clonal ignorance or anergy, it is not known if they can induce RE. Anti-insulin B cells harboring fixed Ig transgenes show evidence of attempted RE, including increased intracellular light chains and insulin-induced elevation of RAG-2 transcripts in vivo and in vitro. To formally test whether insulin could induce RE, we generated mice in which a targeted Ig Vκ encodes an anti-insulin BCR when paired with a fixed Ig VH125 transgene. This model allows the study of tolerance induced by Vκ RE when the BCR interacts with the non-cross-linking hormone, insulin. Anti-insulin B cells show strong evidence for RE in vivo; these findings suggest that BCR engagement with physiological levels of insulin trigger RE. This outcome was confirmed using bone marrow culture to demonstrate low levels of insulin effectively drive RE in vitro. These data extend the role of RE in tolerance to include regulation of BCRs directed at autoantigens such as protein hormones present at low concentrations. Accordingly, physiologically-regulated antigens may escape tolerance during reduced physiological demand or when emerging autoimmune disease reduces self antigen availability.
Support provided by 5T32 HL069765, 5T32 GM08554, AI051448, and JDRF.
Igf2 expression is required for complete tolerance to insulin (128.19)
Authors: Hansenne Isabelle Sylvie , Renard Chantal , Geenen Vincent 
Published: January 2023

Abstract
All members of insulin gene family are transcribed in human thymus according a hierarchy whereby IGF2 expression (thymic epithelial cells/TEC) exceeds IGF1 (macrophages), which exceeds INS (medullary TEC). Type 1 and type 2 IGF receptors are expressed by thymic T-cell populations.
To further study the expression of IGF-2 in thymus, the dominance of this factor was compared to insulin, while ontogenesis of Igf2, insulin1 and insulin2 transcription was studied in Balb/c pancreas and thymus. In 4-wk old thymi, IGF-2 concentration is higher than insulin content. Ontogenesis of Igf2, insulin1 and insulin2 transcription from E13 to post-natal day 2 does not differ in Balb/c thymus and pancreas.
In a second step, tolerance to IGF-2 and insulin was assessed by immunization of Igf2−/− mice. The profile of B-cell response in Igf2−/− mice immunized with IGF-2 evidenced a T-dependent profile of anti-IGF-2 antibodies that was absent in Igf2+/+ mice. This T-dependent isotype switch indicates the presence of specific anti-IGF-2 CD4+ T cells. Cloning of these T cells failed because Igf2−/− CD4+ T cells exhibit a low rate of proliferation in presence of IGF-2. After immunization with insulin, Igf2−/− mice developed a significantly higher humoral response against insulin, indicating that Igf2 expression is necessary for complete tolerance to insulin.
Prevention of diabetes development in NOD mice is associated with the increased ability of APC to activate CD4+CD25+ regulatory T cells. (128.2)
Authors: Manirarora Jean N. , Kosiewicz Michele M. , Parnell Sarah A. , Alard Pascale 
Published: January 2023

Abstract
CD4+CD25+regulatory T cells control the development of various autoimmune diseases. We have found previously that NOD APC are defective in their ability to activate regulatory cell function, and that appropriate APC stimulation could overcome this defect. In the present study, we examined whether NOD APC were defective in their ability to induce CD4+CD25+ regulatory T cells to express Foxp3 and Granzyme B, two molecules associated with the development and function of these cells. We found that regulatory cells from NOD mice expressed lower levels of Foxp3 mRNA and protein than regulatory cells from age-matched B6 mice and exhibit lower percentages of CD4+CD25+ regulatory T cells expressing Granzyme B. Since prevention of diabetes in NOD mice injected with complete Freund’s adjuvant (CFA) is due to activation of CD4+CD25+ regulatory T cells in the pancreatic LN, we tested the effect of CFA on the expression of these two molecules. Interestingly, the expression of Foxp3 on CD4+CD25+ regulatory T cells was increased in CFA-injected NOD mice. Moreover, APC from CFA-injected NOD mice enhanced Foxp3 expression and the percent of CD4+CD25+ regulatory T cells expressing Granzyme B in in vitro culture, suggesting that NOD APC were responsible for the impaired expression of these two molecules. Together, these data suggest that stimulation of NOD APC restores their ability to activate CD4+CD25+ regulatory T cells.
CpG ODN-induced NF-kB activation / IL-6 secretion through CD21-TLR9 dependent B cell signaling? (128.34)
Authors: Asokan Rengasamy , Chen Xiaojiang S , Holers V. Michael 
Published: January 2023

Abstract
Human CR2, a receptor for complement C3d, EBV-gp350, CD23 and IFN-ƒÑ is a B lymphocyte membrane glycoprotein that plays a central role in immunity and autoimmunity. Dysfunction or absence of CR2 promotes development of anti-DNA antibodies in models of systemic lupus erythematosus. In this study, we show that CpG ODN and TLR9 bind to CR2 using ELISA and surface plasmon resonance (SPR). Using SPR, in which carboxy-terminal biotin-tagged CR2 SCR1-4 on a streptavidin chip and CpG ODN and TLR9 as solution phase analyte were studied, the calculated equilibrium dissociation constant (kd/ka) for this binding, reveal 3.1¡Ñ10-2/5.4¡Ñ10-5 s-1 and /1.1¡Ñ10-2/2.4¡Ñ106 s-1 M-1 with a maximal KD of 571 nM and 42 nM respectively. Monoclonal antibodies developed against the first 2 short consensus repeats (SCR) blocked full-length CR2 binding to CpG ODN and TLR9 by ELISA, identically to their effect on C3d binding, indicating the first two SCR involved in this binding. Further more, treatment with chloroquine, a known inhibitor of TLR9 signaling blocks the CR2-TLR9 interaction by ELISA. We are currently determining whether, by using activation of Namalwa B cells with CpG ODN, blockade of CR2 inhibits the CpG-induced NF-kB activation and induction of IL-6 release. These data suggest that CR2 may functionally interact with TLR9 on B cells.
Serum levels of estradiol correlate with disability in men with multiple sclerosis (MS) (129.20)
Authors: Pelfrey Clara M. , Butler Robert , Cotleur Anne 
Published: January 2023

Abstract
MS occurs more frequently in women compared to men, however men are thought to deteriorate more rapidly. The underlying reasons for a sex bias in MS may relate to sex hormone effects. To determine whether hormone levels correlate with disease disability, we tested 51 untreated relapsing-remitting MS patients (31F, 20M) and 71 controls (38 F, 33M). Serum was tested for hormones (estrogen, testosterone, progesterone) and disability was assessed by the Multiple Sclerosis Functional Composite (MSFC). Testosterone (T) levels were significantly elevated in women with MS compared to female controls (p = 0.0005). 17-beta-estradiol (E2) levels strongly trended towards lower levels in male MS patients compared to male controls (p = 0.06). E2 was significantly positively correlated with T levels in all subjects except the MS males. In males with MS, E2 levels correlated with the MSFC (p = 0.011). T levels did not correlate with disability in men or women. Thus, E2 levels appear decreased in males with MS, which strongly correlates with greater disease disability. Interestingly, we observed that T levels were significantly increased in MS females and did not correlate with disability. Our findings suggest interference in hormone metabolism in patients with MS, which may contribute to altered clinical responses depending on the sex of the patient.
Supported by: NIH, NMSS, and CCF GCRC.
A distinct role for PI3Kgamma in suppressing the development and progression of experimental autoimmune encephalomyelitis (EAE) (129.30)
Authors: Gatson NaTosha N , Ji H , Gienapp I E , Song F , Papenfuss T L , Camps M , Ruckle T , Zimmerer J L , Shawler T M , Lu B , Gerard C , Kithcart A P , Powell N , Fischer A J , Satoskar A , Rommel C , Whitacre C C 
Published: January 2023

Abstract
Phosphoinositide 3-kinases (PI3K) are intracellular signaling proteins involved in cellular responses such as chemotaxis, proliferation and apoptosis. Selective inhibitors of the PI3Kγ-isoform have recently become available. This study explores the role of PI3Kγ in the development and progression of EAE. PI3Kγ +/+ (wt) and PI3Kγ −/− (ko) mice were immunized for EAE using myelin oligodendrocyte glycoprotein p35-55 (MOG) and assessed for clinical signs, CNS histopathology and T cell activation. WT mice showed a progressive disease course with elevations in inflammatory cytokines increased CNS mononuclear infiltrates. In contrast, ko mice exhibited a delayed onset and dramatically less severe EAE course characterized by decreased T cell activation and inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-12p40, IL-6, IL-17 and MCP-1). Male ko mice were significantly more protected than ko females. Adoptive transfer of MOG-activated T cells into ko recipients show that ko mice are resistant to passive disease induction. Interestingly, wt recipients of ko donors immunized for EAE were also protected. Furthermore, adoptive transfer of activated GFP+ T cells show marked decreased infiltration of GFP+ T cells into the CNS. Taken together, these findingssuggest that depletion of PI3Kγ results in a down-regulation of the inflammatoryresponse caused by impaired trafficking of cells critical to generation of the immune response.
(Supported by NIH grant AI 064320 and National MS Society Grant RG 3272).
Cytokines regulate miRNA expression in islet beta cells (129.41)
Authors: Mi Qing-Sheng , He Hong-Zhi , Kook-Heon Seo , Zhou Li 
Published: January 2023

Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-secreting beta cells. The immune system utilizes diverse mediators, including the cytokines, to kill pancreatic beta cells. Accumulating evidence suggests that apoptosis is themain form of beta cell death in spontaneousT1D and islet transplantation, and that the cytokines are key contributors in triggering beta cell apoptosis.MicroRNAs (miRNAs) are a recently discovered class of evolutionarily conserved small noncoding RNAs that lead to post-transcriptional repression, which is involved in the regulation of cell proliferation and cell death. To test the role of miRNAs in cytokine-mediated apoptosis, we compared the miRNA expression profile in rat insulinoma cell line INS-1 (834/40) with or without cytokine treatment, and between cytokine-resistant (INS-1res 833/15) and cytokine-sensitive (INS-1 834/40) cells, using miRNA array. We found that miRNAs were differentially regulated in cytokine-treated INS-1 834/40 compared to untreated cells, and between INS-1 834/40 and INS-1res 833/15 before or after cytokine treatments. Some of these changed miRNAs were recently reported to be linked to control cell growth and apoptosis. These results are the first evidence, to our knowledge, that cytokines can regulate miRNA expression, which suggests that these cytokine-regulated miRNAs could be involved in cytokine-mediated beta cell apoptosis. (JDRF, 5-2006-386)
Galectin 3 is required for MLD-STZ induced diabetes in mice (130.38)
Authors: Lukic Miodrag L , Al-Hakim Ahmed - , Mensah-Brown Eric - , Hsu Daniel K , Shahin Allen - 
Published: January 2023

Abstract
Galectin-3, member of ancient lectin family characterized by specific binding of β galactosides, has an antiapoptotic function in T cells, macrophages and islet cells. It was therefore of interest to evaluate the susceptibility to multiple low dose induced diabetes (MLD-STZ) in galectin (gal-3) deficient C57BL/6 mice. Gal-3 −/− and gal-3+/+ mice were treated with 5 daily injections of 40 mg/kg STZ and diabetes development evaluated by glycemia and immunohistochemistry of the pancreas. Gal-3+/+ mice developed delayed sustained and progressive hyperglucemia and mononuclear cell infiltrates in the islets. Gal-3 −/− demonstrated only mild glycemia with minimal islet pathology as evaluated by the number of infiltrating cells and insulin content. There was higher number of apoptotic cells in the islets of galectin-3 knock out than in the control gal-3+/+ mice. RT PCR analysis of pancreatic lymph node cells 17 days after diabetes induction revealed the presence of IL-23 and IL-17 in gal-3+/+ but not in Gal-3 −/− mice. TNF-α and INF-γ INOS expression was also attenuated in Gal-3 −/− mice. We concluded that antiapoptotic effect of gal-3 in diabetogenic cells favors the induction of disease. The data are also compatible with our previous finding that IL-23-Th17 axis plays a role in diabetogenesis (Eur J Immunol, 36: 216–23, 2006).
(Supported by Sheikh Hamdan Awards for Medical Research).
Anti-CD20 Therapy in NOD Model of Type 1 Diabetes (131.26)
Authors: Hu Changyun , Rodriguez Daniel , Du Wei , Ahuja Anupama. , Wong F.Susan , Shlomchik Mark , Wen Li 
Published: January 2023

Abstract
B cells play an important role in the pathogenesis of T1D although T1D is primarily a T cell mediated autoimmune disease. Apart from producing antibodies, B cells are important APCs and a rich source for production of various cytokines. Nonetheless, the precise roles of B cells in promoting diabetes onset and progression have not been defined. Rituximab targets human CD20 causing rapid and specific B cell depletion. A clinical trial is currently launched in treating T1D patients with Rituximab. However, there has not been a single preclinical study to test this particular therapy in T1D. To evaluate the efficacy of anti-CD20 in treating T1D, we have generated a transgenic NOD mouse expressing human CD20 on their B cells. This allows the use of anti-hCD20 antibody (2H7), which is closely related to Rituximab. Our preliminary data showed that a single cycle of anti-hCD20 treatment (4 injections within 10 days) to temporarily deplete B cells significantly delays and/or reduces the onset of diabetes in hCD20 transgenic NOD mice. This was seen at both the disease initiation and pre-diabetic stages. The same treatment also rendered 36% (5/14) of diabetic mice euglycemic, either transiently or for a long period. Anti-hCD20 treatment appears to induce and/or expand regulatory T cells and enhance TGF-β production. Our results provide extremely valuable in vivo information for the human studies using a similar approach.