Tetraspanin CD53 modulates lymphocyte trafficking but not systemic autoimmunity in Lyn‐deficient mice

2021 ◽  
Author(s):  
Louisa Yeung ◽  
Timothy A Gottschalk ◽  
Pam Hall ◽  
Evelyn Tsantikos ◽  
Rebecca H Gallagher ◽  
...  
Keyword(s):  
Lymphocyte Trafficking ◽  
Systemic Autoimmunity ◽  
Deficient Mice

scholarly journals Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice

2010 ◽  
Vol 207 (12) ◽  
pp. 2767-2778 ◽  
Author(s):  
Thomas Tiller ◽  
Juliane Kofer ◽  
Cornelia Kreschel ◽  
Christian E. Busse ◽  
Stefan Riebel ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Compartment ◽  
Fc Gamma Receptor ◽  
Gamma Receptor ◽  
Systemic Autoimmunity ◽  
Bone Marrow Plasma ◽  
Ig G ◽  
Deficient Mice

Abnormalities in expression levels of the IgG inhibitory Fc gamma receptor IIB (FcγRIIB) are associated with the development of immunoglobulin (Ig) G serum autoantibodies and systemic autoimmunity in mice and humans. We used Ig gene cloning from single isolated B cells to examine the checkpoints that regulate development of autoreactive germinal center (GC) B cells and plasma cells in FcγRIIB-deficient mice. We found that loss of FcγRIIB was associated with an increase in poly- and autoreactive IgG+ GC B cells, including hallmark anti-nuclear antibody–expressing cells that possess characteristic Ig gene features and cells producing kidney-reactive autoantibodies. In the absence of FcγRIIB, autoreactive B cells actively participated in GC reactions and somatic mutations contributed to the generation of highly autoreactive IgG antibodies. In contrast, the frequency of autoreactive IgG+ B cells was much lower in spleen and bone marrow plasma cells, suggesting the existence of an FcγRIIB-independent checkpoint for autoreactivity between the GC and the plasma cell compartment.

Cas-L/Hef1 Is Required for Marginal Zone B Cell Maintenance and Lymphocyte Trafficking.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3920-3920
Author(s):  
Sachiko Seo ◽  
Takashi Asai ◽  
Toshiki Saito ◽  
Takahiro Suzuki ◽  
Motoshi Ichikawa ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Cell Number ◽  
Lymphoid Organs ◽  
Adhesion Assay ◽  
Lymphocyte Migration ◽  
Lymphocyte Trafficking ◽  
Deficient Mice

Abstract Cas-L (Crk-associated substrate lymphocyte type) which is also known as Hef1 (human enhancer of filamentation 1) was first identified as a protein tyrosine-phosphorylated upon stimulation of b1 integrin. Cas-L possesses a single Src homology (SH) 3 domain and multiple YXXP motifs (substrate domain) as a member of Cas protein family, and is well expressed in peripheral lymphocytes. Previous studies suggest that Cas-L might be involved in Bcr-Abl positive leukemia and adult T cell leukemia. However, the biological function of Cas-L in lymphocytes is little known. We generated Cas-L-deficient mice using a gene targeting strategy. The mice showed a deficit of marginal zone (MZ) B cells and a decrease of cell number in secondary lymphoid organs. To elucidate the mechanism of the MZ B cell defect, the reciprocal bone marrow transfer assays were performed. The results revealed that the defect of MZ B cells in Cas-L-deficient mice is cell autonomous. Next, we analyzed B cell receptor signaling by measurement of intracellular Ca2+ concentration and lymphocyte proliferation. However, we could not find any significant differences between wild type and Cas-L-deficient mice. Cas-L-deficient lymphocytes showed reduced chemotactic response to CXCL12 and CXCL13. The adhesion assay also showed the decreased adhesiveness to VCAM-1 and ICAM-1, which are important for retention of MZ B cells in spleen. Moreover, we found that the lymphocyte trafficking to spleen and lymph nodes was altered in Cas-L-deficient mice. Thus, Cas-L affects homeostasis of MZ B cells and peripheral lymphoid organs, which is considered to be relevant to impaired lymphocyte migration and adhesion.

scholarly journals Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production

2016 ◽  
Vol 113 (50) ◽  
pp. E8131-E8140 ◽  
Author(s):  
Kaoru Morita ◽  
Tomohisa Okamura ◽  
Mariko Inoue ◽  
Toshihiko Komai ◽  
Shuzo Teruya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Lupus Erythematosus ◽  
Mice Model ◽  
Mild Phenotype ◽  
Humoral Immune ◽  
Germinal Center Reaction ◽  
Systemic Autoimmunity ◽  
Deficient Mice

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

scholarly journals CD22 × Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

2010 ◽  
Vol 184 (7) ◽  
pp. 3618-3627 ◽  
Author(s):  
Julia Jellusova ◽  
Ute Wellmann ◽  
Kerstin Amann ◽  
Thomas H. Winkler ◽  
Lars Nitschke
Keyword(s):  
Cell Numbers ◽  
Systemic Autoimmunity ◽  
Deficient Mice

scholarly journals Suppression of systemic autoimmunity by the innate immune adaptor STING

2015 ◽  
Vol 112 (7) ◽  
pp. E710-E717 ◽  
Author(s):  
Shruti Sharma ◽  
Allison M. Campbell ◽  
Jennie Chan ◽  
Stefan A. Schattgen ◽  
Gregory M. Orlowski ◽  
...  
Keyword(s):  
Immune Activation ◽  
Lupus Erythematosus ◽  
Autoantibody Production ◽  
Systemic Autoimmunity ◽  
Mediate Immunity ◽  
Autoimmune Pathology ◽  
Cytokine Levels ◽  
Inflammatory Macrophages ◽  
Deficient Mice

Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.

scholarly journals Circulating Activated Platelets Reconstitute Lymphocyte Homing and Immunity in L-selectin–Deficient Mice

1998 ◽  
Vol 187 (2) ◽  
pp. 197-204 ◽  
Author(s):  
Thomas G. Diacovo ◽  
Michelle D. Catalina ◽  
Mark H. Siegelman ◽  
Ulrich H. von Andrian
Keyword(s):  
Systemic Circulation ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Immunologic Memory ◽  
Lymphocyte Trafficking ◽  
High Endothelial Venules ◽  
Inflammatory Conditions ◽  
Activated Platelets ◽  
Peripheral Lymph ◽  
Deficient Mice

Peripheral lymph nodes (PLN) are critical for immunologic memory formation in response to antigens that penetrate the skin. Blood-borne lymphocytes first encounter such antigens after they home to PLN through a multi-step adhesion process that is normally initiated by L-selectin (CD62L) in high endothelial venules (HEV). Since naive T cells can not enter PLN normally in L-selectin–deficient mice, a delayed type hypersensitivity response to cutaneously applied antigen cannot be mounted. In this study, we report that the administration of activated platelets into the systemic circulation of L-selectin knockout mice restores lymphocyte trafficking to PLN, and reconstitutes T cell–mediated immunity in response to a cutaneous antigen. These effects required platelet-expressed P-selectin that allows activated platelets to transiently form a bridge between lymphocytes and HEV, thereby enabling lymphocytes to undergo subsequent β2 integrin-dependent firm adhesion. These profound effects of platelet-mediated cell–cell interactions on lymphocyte trafficking and formation of immunologic memory may impact on a variety of autoimmune and inflammatory conditions.

scholarly journals cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

2021 ◽  
Vol 12 ◽  
Author(s):  
Mona Motwani ◽  
Jason McGowan ◽  
Jennifer Antonovitch ◽  
Kevin MingJie Gao ◽  
Zhaozhao Jiang ◽  
...  
Keyword(s):  
Host Defense ◽  
Lupus Erythematosus ◽  
Important Determinant ◽  
Murine Models ◽  
Autoantibody Production ◽  
Knock Out ◽  
Systemic Autoimmunity ◽  
Chronic Model ◽  
Sting Pathway ◽  
Deficient Mice

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.

scholarly journals Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice

2003 ◽  
Vol 198 (5) ◽  
pp. 809-821 ◽  
Author(s):  
Jorn Drappa ◽  
Lynn A. Kamen ◽  
Elena Chan ◽  
Maria Georgiev ◽  
Dalit Ashany ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Intracellular Signaling ◽  
High Titer ◽  
Interleukin 2 ◽  
Adaptor Protein ◽  
Systemic Autoimmunity ◽  
Large Numbers ◽  
Deficient Mice

T cell–specific adaptor protein (TSAd) is a T lineage–restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B cells in spleen, produce autoantibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity.

Comparison of localization of metallothionein in tissues of metallothionein-deficient mice

1995 ◽  
Vol 53 ◽  
pp. 1042-1043
Author(s):  
H. Nishimura ◽  
R Nishimura ◽  
D.L. Adelson ◽  
A.E. Michaelska ◽  
K.H.A. Choo ◽  
...  
Keyword(s):  
Metal Binding ◽  
Immunohistochemical Staining ◽  
Squamous Epithelium ◽  
Rabbit Antiserum ◽  
Slight Modification ◽  
Positive Control ◽  
Heavy Metal Binding ◽  
Critical Organ ◽  
Metal Binding Protein ◽  
Deficient Mice

Metallothionein (MT), a cysteine-rich heavy metal binding protein, has several isoforms designated from I to IV. Its major isoforms, I and II, can be induced by heavy metals like cadmium (Cd) and, are present in various organs of man and animals. Rodent testes are a critical organ to Cd and it is still a controversial matter whether MT exists in the testis although it is clear that MT is not induced by Cd in this tissue. MT-IV mRNA was found to localize within tongue squamous epithelium. Whether MT-III is present mainly glial cells or neurons has become a debatable topic. In the present study, we have utilized MT-I and II gene targeted mice and compared MT localization in various tissues from both MT-deficient mice and C57Black/6J mice (C57BL) which were used as an MT-positive control. For MT immunostaining, we have used rabbit antiserum against rat MT-I known to cross-react with mammalian MT-I and II and human MT-III. Immunohistochemical staining was conducted by the method described in the previous paper with a slight modification after the tissues were fixed in HistoChoice and embedded in paraffin.

Alterations during Positive Selection in the Thymus of nackt CD4-Deficient Mice

2000 ◽  
Vol 52 (6) ◽  
pp. 555-562 ◽  
Author(s):  
I. Nepomnaschy ◽  
G. Lombardi ◽  
P. Bekinschtein ◽  
P. Berguer ◽  
V. Francisco ◽  
...  
Keyword(s):  
Positive Selection ◽  
Deficient Mice
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