bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD8+ T cell effector activity is localized within the pulmonary interstititum, not the airspaces, during influenza infection (92.9)
Authors: Hufford Matthew , Kim Taeg , Sun Jie , Braciale Thomas 
Published: January 2023

Abstract
CD8+ cytolytic T lymphocytes (CTLs) play a crucial role in the resolution of respiratory viral infections through their ability to eliminate infected cells and to release potent anti-viral cytokines. In the influenza viral model, CD8+ CTL effector activity is believed to be focused on respiratory epithelial cells, since these cells are the principal cell types supporting influenza replication. Utilizing the prototypical T cell anti-viral cytokine, IFNγ, as a measure of CD8+ CTL effector activity, we evaluated the tempo of the CD8+ CTL response to influenza infection in vivo in two compartments, the airways overlying the respiratory epithelium and the infected lung interstitium. Surprisingly, CD8+ CTL effector activity was localized not to the respiratory epithelium but within the pulmonary interstitium. We were able to establish, utilizing bone marrow chimeric mice, that infiltrating inflammatory cells of hematopoietic origin were the primary stimulus of CD8+ CTL effector activity. Additionally, we further demonstrated that lung resident CD11c+ cells, likely macrophages and/or dendritic cells, were triggering CD8+ CTL anti-viral activity. These observations suggest that inflammatory mononuclear cells are serving as the primary antigen presenting cells for effector CD8+ CTLs responding within the lungs to infection. CD8+ CTL recognition of infected respiratory epithelial cells appears to serve only a secondary role in orchestrating the pro-inflammatory T cell response.
A CD23+/CD21high B cell population selectively accumulates in the lymph nodes draining inflamed joints in the human TNF- α transgenic mouse model of rheumatoid arthritis (93.18)
Authors: Moshkani Safiehkhatoon , Li Jie , Kuzin Igor , Proulx Steven , Xing Lianping , Schwarz Edward , Bottaro Andrea 
Published: January 2023

Abstract
Clinical benefits from anti-TNF and B cell depletion therapy in the treatment of rheumatoid arthritis (RA) highlight the important roles of both TNF-α and B cells in the pathogenesis of RA. However, the precise role of B cells in pathogenesis of RA is not yet defined. Human TNF-α transgenic mice (hTNFtg) develop a chronic inflammatory-erosive joint disease similar to RA, and provide a useful model for studying disease pathogenesis. During progression of the disease in the knee of hTNFtg mice, the adjacent popliteal lymph node (PLN) increases in volume and cellularity and undergoes significant histological changes. These changes are accompanied by a major expansion in a polyclonal B cell subset with a unique surface phenotype (CD23+, CD21high, IgMhigh, IgD+, CD1d+), which is found specifically in the nodes draining affected joints. Interestingly, the same B cell population is also found in PLNs of K/BxN mice with an etiologically distinct, autoantigen-dependent form of arthritis. Here we will discuss the features of this new population in the context of arthritis and other inflammatory conditions.
Transgenic Expression of the RNA-sensing Molecule MDA-5 Accelerates Autoimmunity in the Lupus-prone FcgammaR2-Deficient Mouse (93.20)
Authors: Crampton Steve , Deane Jonathan , Hasty Karen , Otubusin Owokunile , Bolland Silvia 
Published: January 2023

Abstract
Nucleic-acid sensing molecules provide a first line of defense against microbial infections, but recent studies have shown that their inappropriate activation could promote autoimmunity. MDA-5 senses virally-derived RNA in the cytoplasm, which leads to type one interferon (IFN) production, recently shown to be associated with systemic lupus erythematosus. Here, we have generated mice with multiple copies of Ifih1, the gene that encodes MDA-5, and crossed them to the lupus-prone FcgammaRIIB-/- mouse. Mice with enhanced MDA-5 expression and FcgammaRIIB deficiency have accelerated autoimmunity with splenomegaly and anti-nuclear antibodies in their serum compared to FcgammaRIIB-deficient mice alone. They also display elevated levels of splenic plasma and germinal center B cells, indicating possible early autoreactive B cell formation. Bone marrow and splenic macrophage/monocytes from MDA5 transgenic animals also display an activated phenotype, characterized by elevated Ly6A/E, PDCA-1 and CD80 expression. B cells from MDA-5-transgenic animals also express elevated levels of type one IFN signature genes. These results suggest that increased expression of MDA-5 could exacerbate lupus, possibly through the early production of type one IFN.
Lung antigen presenting cells in human emphysema (93.21)
Authors: Shan Ming , Cheng Han-Fang , Corry David , Kheradmand Farrah 
Published: January 2023

Abstract
Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.
Chronic autoimmune activation in patients with mucopolysaccharidosis III (93.22)
Authors: Fu Haiyan , Killedar Smruti , al-Dahhak Roula , Rankin Chelsea , Wu Yee-Ling , Zhou Bi , Yu Chack-Yung , DiRosario Julianne , McCarty Douglas 
Published: January 2023

Abstract
Mucopolysaccharidosis (MPS) III are a group of four lysosomal storage diseases with severe neurological manifestation. While the primary pathology of MPS III is the lysosomal storage of heparan sulfates, detailed mechanisms of neuropathology are unclear. Using a mouse model, we showed that a profound neuroimmune response contributes to the CNS disease progression of MPS IIIB. Immune status in MPS III patients remains unexplored. Here, we tested peripheral blood from 12 patients with MPS III, including MPS IIIA and IIIB, to assess their immune status. White blood cell differential showed higher lymphocyte ratio (48-70%) in majority tested MPS III patients than healthy control children (41-54%). PBWC from all patients exhibited significant increase in 3H-thymidine-incorporation when stimulated ex vivo with an anti-CD3 or anti-CD40 antibody, suggesting the activation of T-cells and B-cells. Complement deposition assays showed increased levels of RBC-C4d and/or reticulocyte-C4d in majority patients, indicating an ongoing activation of the classical complement pathway. In addition, antinuclear antibodies were detected in the serum of 6 patients. No association was seen between immune activation and age/gender/disease forms. This is the first study that has demonstrated a chronic autoimmune status in MPS III patients, which may also contribute to the disease progression and may have potential as therapeutic target in these patients, as demonstrated in MPS IIIB mice.
Sydenham Chorea-derived brain autoantibody expressed in transgenic (Tg) mice targets dopaminergic neurons and reveals crossreactive anti-neuronal specificities. (93.24)
Authors: Cox Carol , Cunningham Madeleine 
Published: January 2023

Abstract
Mechanisms of pathogenesis of brain autoantibodies are not well defined as to functional aspects and targets in disease. We utilized V genes of Sydenham chorea derived mAb to investigate crossreactive specificities and in vivo targets after expression in Tg mice. Novel human mAb 24.3.1, derived from group A streptococcal autoimmune sequela, targeted dopamine D1 and D2 receptors and reacted with group A streptococcal carbohydrate epitope N-acetyl-beta-D-glucosamine. Anti-neuronal brain specificities included lysoganglioside on neuronal cell surface and abundant intracellular brain protein tubulin. Human mAb 24.3.1 has been shown to induce signal transduction in neuronal cells with increased Ca++ calmodulin dependent protein kinase II. Expression of chimeric IgG1a antibody in Tg mouse sera conferred reactivity with D1/D2 dopamine receptors and led to deposition on dopaminergic neurons in vivo in Tg mouse brain. IgG1a transgene was detected in vivo and in vitro with anti-allotypic antibodies against IgG1a. Immunofluorescent co-localization of allotype specific Tg antibodies and tyrosine hydroxylase demonstrated chimeric IgG1a 24.3.1 deposited and bound to dopaminergic neurons in Tg mouse brain in vivo. Tg sera and IgG1a reacted with neuronal antigens lysoganglioside, tubulin and dopamine receptors D1/D2. Our data support the hypothesis that in human disease, antibodies may bind neurons and alter brain function to induce movement and behavioral disorders such as SC and PANDAS.
Role of NK cells in TLR7-induced systemic autoimmune disease (93.30)
Authors: Voynova Elisaveta , Bolland Silvia 
Published: January 2023

Abstract
An inappropriate activation of innate immune pathways can lead to systemic autoimmune disease, as illustrated by the phenotype of TLR7-overexpressing transgenic mice characterized by anti-RNA antibody production, glomerulonephritis, anemia, and a pro-inflammatory interferon signature in B cells and dendritic cells. Mixed bone marrow reconstitution experiments show that NK cells expand in TLR7tg because of the NK cell intrinsic sensitivity to TLR7 stimulation. NK cells in TLR7tg mice have an unusual phenotype: most NK1.1+ cells are DX5-, CD11c+ even though they have been confirmed to be bona fide NK cells by their cytotoxic responses and lack of T cell specific markers. In vitro stimulation of TLR7tg NK cells with TLR7 agonists induced production of TNFα, MCP-1, IFNγ and particularly IL-10. To assess the function of NK cells in developing the TLR7-induced autoimmune inflammatory condition, we have bred our TLR7tg mice to IL15-deficient mice IL-15 is necessary for development of NK cells and memory CD8 cells. We have observed that in the absence of IL15 some of the pro-inflammatory subsets such as CD11c+NK cells, Ly6C+monocytes, granulocytes, conventional DCs and memory T cells are reduced compared to TLR7tg. On the other hand, spontaenous germinal centers and lymphocyte activation occur at the same rate in the absence of IL15. This results suggest that the development of spontaneous autoreactive germinal centers is independent from the myeloid expansion in TLR7tg mice.
Crystal structure of an autoimmune TCR with optimal binding to its self-antigen - an alternative strategy for escaping negative selection (93.32)
Authors: Yin Yiyuan , Li Yili , Martin Roland , Mariuzza Roy 
Published: January 2023

Abstract
The failure to eliminate self-reactive T cells during thymic selection is a prerequisite for autoimmunity. To escape deletion, autoreactive T cell receptors (TCRs) usually form relatively unstable complexes with their self-peptide/MHC ligands. As shown previously, these TCRs adopt suboptimal binding topologies as opposed to anti-microbial TCRs. In other cases, escape can be mediated by weak binding between self-peptides and MHC. Here, we determined the crystal structure, to 2.7 Å resolution, of a human MHC class II-restricted autoimmune TCR (3C8) bound to its self-antigen, MBP 114-126/HLA-DR4. TCR 3C8, which was originally isolated from a multiple sclerosis patient, has demonstrated pathogenic potential in humanized transgenic mice. The MBP self-peptide binds HLA-DR4 with unusually low affinity. The structure showed a loose accommodation of MBP in the peptide binding groove. By contrast, 3C8 binds to MBP/HLA-DR4 at the high end of the affinity range for TCR-peptide/MHC interactions. Moreover, 3C8 engages its self-ligand via a docking mode that closely resembles the optimal binding topology of anti-foreign TCRs, but is distinct from that of other autoreactive TCRs. Thus, the 3C8-MBP/HLA-DR4 complex reveals the structural basis for an alternative strategy by which autoreactive T cells escape negative selection, yet still retain the ability to become sufficiently activated in the periphery to be pathogenic.
HLA motifs associated with autoantibody production and cross-racial similarities in systemic sclerosis using the SFVT approach (93.37)
Authors: Marthandan Nishanth , Guidry Paula , Thomson Glenys , Helmberg Wolfgang , Marsh Steven , Arnett Frank , Karp David , Scheuermann Richard 
Published: January 2023

Abstract
Significant associations have been found between specific HLA alleles and a variety of autoimmune diseases. Current studies treat each HLA allele as a single complete unit, which does not distinguish the parts of the molecule associated with disease or the production of particular autoantibodies. This approach also cannot uncover similarities in different predisposing alleles across races. We previously developed a novel approach for genetic association analysis in which HLA proteins are broken down into smaller sequence features (SF) with polymorphisms in these features categorized as variant types (VT). Using the SFVT approach, we analyzed DRB1, DQA1 and DQB1 typing data in a cohort of patients with Systemic Sclerosis (SSc) and demographically matched controls. We found similar predisposing and protective SFVTs in African Americans, Caucasians and Hispanics (e.g. the predisposing 67F_70D_71R peptide binding/TCR recognition motif) despite differences in the frequencies of predisposing and protective alleles that carry these SFVTs in these populations. In addition, we found that SFVTs that differ by only a few amino acids are significantly associated with the presence or absence of different autoantibodies in SSc patients (e.g. the antigen binding motif 9W_57D_60Y_67L was associated with anti-centromere, while 9E_57D_60Y_67F was associated with anti-topoisomerase). These results highlight the ability of the SFVT approach to shed light on the role of HLA in autoimmune disease.
Inhibition of type 1 diabetes by a Lactobacillus johnsonii mediated Th17 bias (93.4)
Authors: Lau Kenneth , Benitez Patrick , Ardisone Alexandria , Lorca Graciela , Li Nan , Sankar Dhyana , Neu Josef , Atkinson Mark , Larkin Joseph 
Published: January 2023

Abstract
Although it is known that resident gut flora contribute to immune system function and homeostasis, the role of gut flora in the progression of autoimmune disease is poorly understood. It has recently been shown that distinct bacterial populations are present within rodent models prone (DP) and resistant (DR) to Type 1 Diabetes (T1D). Oral Transfer of Lactobacillus johnsonii (N62) from DR rodent to DP rodents conferred T1D resistance to DP rodents. Diabetes resistance in N62 fed DP rodents was correlated to a TH17 bias within the mesenteric lymph nodes which was associated with high levels of IL6 and IL23. Moreover, In vitro assays show that Lactobacillus Johnsonii mediates high IL6 and IL10 levels in antigen presenting cells which can mediate TH17 differentiation in the presence of sufficient TCR stimulation. Together, these data suggest an interesting paradigm whereby autoimmunity can be circumvented by gut flora mediated, T cell differentiation.
Role of T cell mediated inflammation in lupus-like glomerulonephritis (GN) (93.40)
Authors: Bagavant Harini , Scindia Yogesh , Nandula Seshagiri , Deshmukh Umesh 
Published: January 2023

Abstract
Renal involvement in lupus is characterized by glomerular immune complexes, acute proliferative GN and progressive renal failure. To investigate the pathogenic role of T cells in renal lupus, an antigen-specific model of GN was established. A novel, anti-α8 integrin immunoliposomal delivery system (α8ILs) was designed for targeted delivery to the renal glomerulus. Ovalbumin loaded α8ILs (ova-α8ILs) were injected i.v. into C57BL/6 mice leading to a rapid delivery of ova in the glomerular mesangium. Injection of ova-α8ILs followed by ova-reactive transgenic OT2 cells activated in vitro, resulted in GN. On day 7 after injection, the renal cortex showed T cell, macrophage and dendritic cell infiltration. To mimic lupus GN, mice were injected with ova-α8ILs and mouse anti-ova serum forming glomerular immune complexes. This was followed by injection of naïve CSFE labeled OT2 cells. Two days after cell transfer, mice with glomerular immune complexes showed dividing OT2 cells preferentially in renal lymph nodes compared to mice given ova-α8ILs alone. Recently, macrophage infiltration into the renal interstitium has been identified as the harbinger of renal failure. Our data suggest that glomerular antigen-specific T cell infiltration may be sufficient for recruitment of macrophages into the renal cortex and the onset of progressive renal inflammation. In addition, glomerular immune complexes lead to a rapid, local activation of glomerular antigen reactive T cells.
CD4+ T cells are required for CD8+ T-cell activation but not for CD8+ T cell effector function for induction of thyrocyte hyperplasia (TEC H/P) and fibrosis (93.7)
Authors: Yu Shiguang , Sharp Gordon C. , Braley-Mullen Helen 
Published: January 2023

Abstract
IFN-γ-/-NOD.H-2h4 mice develop TEC H/P and fibrosis characterized by abnormal proliferation of thyrocytes and infiltration of thyroids by CD4+ and CD8+ T cells. CD8+ T cells are the primary effector cells for TEC H/P. CD4-/- and CD8-/- IFN-γ-/- NOD.H-2h4 mice were generated to determine if CD4+ T cells were required for activation of CD8+ T cells that induce TEC H/P and fibrosis. 60-70% of IFN-γ-/- mice given NaI water for 6-7 mo develop severe TEC H/P and fibrosis, compared to 11 of 53 (21%) CD4-/- mice and only 2 of 42 (5%) CD8-/- mice. TEC H/P incidence in CD4-/- mice given splenocytes from CD8-/- mice is similar to that of IFN-γ-/- mice (60%). Splenocytes from IFN-γ-/- donors with severe TEC H/P transfer severe TEC H/P to SCID recipients after culture in vitro for 72 hr, and purified CD8+ T cells from the same donors also transfer severe TEC H/P to SCID recipients. Splenocytes from some CD4-/- donors with severe TEC H/P can transfer severe TEC H/P to SCID recipients, but more often they transfer only minimal disease. These results suggest that CD4+ T cells are required for optimal activation of CD8+ T cells that induce TEC H/P, and they may also be important for optimal in vitro activation of CD8+ T cells that induce severe TEC H/P. In contrast, after CD8+ T cells are fully activated, CD4+ T cells are not required for their mobilization to thyroids or for effector function leading to TEC H/P and fibrosis.
Development of a novel anti-FimH vaccine using a mast cell activator as the adjuvant. (94.1)
Authors: Shelburne Christopher , Li Guojie , Staats Herman , Abraham Soman 
Published: January 2023

Abstract
Urinary tract infections (UTIs) are one of the most common bacterial infections of man. Because of their high rate of recurrence and the increase in resistance of bacteria to antibiotics, there is great interest in developing a prophylactic vaccine to limit UTIs. Unfortunately, efforts to develop such a vaccine have failed in humans, quite possibly due to the use of alum as the vaccine adjuvant which does not induce protective immune responses along the urinary tract. Here, we demonstrate that a novel anti-UTI vaccine formulation consisted of the UTI vaccine antigen FimH and a mucosal mast cell activating adjuvant compound, mastoparan-7 is able to evoke protective immune responses against UTI. This vaccine formulation induced high titer anti-FimH IgA and IgG in both the urine and serum of immunized mice that were protective against subsequent challenge of the bladder site with uropathogenic E. coli. These anti-FimH responses were comparable to those elicited by FimH vaccine formulations containing cholera toxin as the adjuvant, and superior to those elicited by formulations containing the adjuvants CpGs or alum. These studies suggest that formulation of an anti-UTI vaccine with a MC activator and the FimH antigen might result in a successful anti-UTI vaccine in humans.
β-arrestins mediate lipopolysaccharide-induced inflammatory response and endotoxemia in mice (94.10)
Authors: Parameswaran Narayanan , Gonipeta Babu , Parvataneni Sitaram , Appledorn Daniel , Patial Sonika , Gangur Venugopal , Amalfitano Andrea , Porter Katie 
Published: January 2023

Abstract
β-arrestins are scaffolding proteins recently implicated as negative regulators of Toll-like receptor-4 (receptor for lipopolysaccharide from gram-negative bacteria) signaling in macrophages and fibroblasts. Unexpectedly, we find that β-arrestin-1 (β-arr-1) and -2 knockout mice are protected from endotoxic shock and lethality. Consistent with this, LPS-induced inflammatory cytokine (IL-1β, IL-12p40, IL-4, IL-5 and IFNγ) levels in the plasma are markedly inhibited in both β-arr-1 and -2 knockout mice, compared to the wild types. To identify the possible mechanisms involved, we examined the effect of LPS-induced cytokine production in CD11b+ and CD11b- splenocytes. Both splenocyte populations from β-arr-2 knockout mice showed a marked decrease LPS-induced IL1-β, IL-12p40, IL-5 and IFNγ whereas these cytokines were inhibited in the β-arr-1 knockout only in the CD11b- cells, when compared to wild type splenocytes. Further experiments on the signaling pathways indicate that the role of β-arrestins is independent of MAPK and IκBα pathways in both splenocyte populations. Interestingly LPS-induced increase in histone acetyl transferase activity in the spleen is significantly inhibited in both β-arr-1 and -2 knockout mice, suggesting chromatin modification as one potential mechanism. Taken together, these results indicate that both β-arrestins have overlapping but non-redundant and cell-type-specific roles in regulating LPS-induced inflammatory cytokine production in vivo.