A5088597500- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Systemic Lupus Erythematosus Research
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Monoclonal and Polyclonal Antibodies Research
- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Glycosylation and Glycoproteins Research
- Diabetes and associated disorders
- Inflammasome and immune disorders
- Cancer Immunotherapy and Biomarkers
- Immunodeficiency and Autoimmune Disorders
- Viral Infections and Outbreaks Research
- Blood groups and transfusion
- Transgenic Plants and Applications
- Viral Infections and Vectors
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Cancer-related gene regulation
- Galectins and Cancer Biology
- Hepatitis B Virus Studies
- Erythrocyte Function and Pathophysiology
- Cytomegalovirus and herpesvirus research
- T-cell and Retrovirus Studies
Biomed Research Institute
2024
Scripps Research Institute
2009-2022
University of California, San Diego
2009
University Hospital of Lausanne
2000-2001
Inserm
1997
University of Lausanne
1996
San Diego State University
1994
Scripps Clinic
1991-1992
Institut Pasteur
1989-1991
Scripps Health
1991
Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine contribution these pleiotropic molecules, we created congenic NZB mice lacking α-chain IFN-α/βR, common receptor for multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA kidney disease, and mortality. These reductions...
Development of tumor immunotherapies focuses on inducing autoimmune responses against tumor-associated self-antigens primarily encoded by normal, unmutated genes. We hypothesized that such could be elicited T cell homeostatic proliferation in the periphery, involving expansion cells recognizing self-MHC/peptide ligands. Herein, we demonstrate sublethally irradiated lymphopenic mice transfused with autologous or syngeneic showed growth inhibition when challenged melanoma colon carcinoma...
Development of tumor immunotherapies focuses on inducing autoimmune responses against tumor-associated self-antigens primarily encoded by normal, unmutated genes. We hypothesized that such could be elicited T cell homeostatic proliferation in the periphery, involving expansion cells recognizing self-MHC/peptide ligands. Herein, we demonstrate sublethally irradiated lymphopenic mice transfused with autologous or syngeneic showed growth inhibition when challenged melanoma colon carcinoma...
Using the Unc93b1 3d mutation that selectively abolishes nucleic acid-binding Toll-like receptor (TLR) (TLR3, -7, -9) signaling, we show these endosomal TLRs are required for optimal production of IgG autoAbs, IgM rheumatoid factor, and other clinical parameters disease in 2 lupus strains, B6-Fas(lpr) BXSB. Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement. The slightly reduced complete Freund's adjuvant (CFA)-mediated antigen...
In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these required vivo for disease development, and their contribution is restricted hyperproduction type I IFNs. To address issues, we created lupus-predisposed mice lacking IFN regulatory factor 8 (IRF8) or carrying a mutation impairs peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB...
Two monoclonal IgM natural autoantibodies (E7 and D23) obtained from the fusion of normal, nonimmunized, BALB/c mouse spleen cells nonsecreting myeloma were selected on basis their polyreactivity with auto- xenoantigens chemical haptens. Nucleotide sequence analysis variable constant regions heavy light chains showed following. (i) The antibodies arise different genetic elements very low or no homology--E7 a heavy-chain region (VH) family 36-60 kappa light-chain (V kappa) group 19--whereas...
Abstract The demonstration in humans and mice that nucleic acid-sensing TLRs type I IFNs are essential disease mediators is a milestone delineating the mechanisms of lupus pathogenesis. In this study, we show Ifnb gene deletion does not modify progression NZB mice, thereby strongly implicating IFN-α subtypes as principal pathogenic effectors. We further document long-term treatment male BXSB with an anti–IFN-α/β receptor Ab mouse origin reduced serologic, cellular, histologic manifestations...
A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models lupus. Here, we demonstrate reduction homozygous even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication. In contrast to SLC15A4, SLC15A3 did not diminish type I interferon (IFN-I) production by TLR-activated plasmacytoid dendritic cells (pDCs), indicating divergence...
Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect endothelial cells, but are generally considered noncytopathic. Thus, mechanism virus-induced injury remains unclear. Using lymphocytic choriomeningitis variant clone 13, a prototype we show here that lethal leakage...
Among T cell subsets, gamma delta cells uniquely display an Ag receptor-based tissue distribution, but what defines their preferential homing and homeostasis is unknown. To address this question, we studied the resources that control in secondary lymphoid organs. We found alpha beta are controlled by partially overlapping resources, because acute homeostatic proliferation of was inhibited intact compartment, both populations were dependent on IL-7 IL-15. Significantly, to undergo...
The effect of thymic selection on the expressed human T-cell antigen receptor beta-chain variable region (V beta) gene repertoire was examined by using a multiprobe RNase protection assay. relative abundance transcripts for 22 V beta genes (encompassing 17 20 subfamilies) within thymus, and among thymuses, variable. On basis presence corresponding mRNAs, no genomic deletions were detected, but several coding polymorphisms identified. Analysis mature subsets revealed absence complete...
Implantation of pieces human fetal liver and thymus into SCID mice results in the development a thymus-like organ, which sustained lymphopoiesis is reproducibly observed. In this model, T cell can be experimentally manipulated. To study influence thymic selection on repertoire, receptor (TCR) V beta gene repertoire double-positive (CD4+CD8+) single-positive (CD4+CD8- CD4-CD8+) cells was analyzed SCID-hu using multiprobe ribonuclease protection assay. TCR diversity thymocytes found to...
A characteristic feature of systemic lupus erythematosus is the accumulation activated/memory T and B cells. These G0/G1-arrested cells express high levels cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation apoptosis, produce large amounts proinflammatory cytokines. Herein, we show that ablation p21 in lupus-prone mice allows these reenter cell cycle undergo leading autoimmune disease reduction. Absence resulted enhanced Fas/FasL-mediated activation-induced death,...
Lupus is characterized by disturbances in lymphocyte homeostasis, as demonstrated the marked accumulation of activated/memory T cells. Here, we provide evidence that proliferation CD8+ precursors for accumulating CD4–CD8– cells MRL-Faslpr lupus-predisposed mice is, part, driven commensal antigens. The ensuing lymphadenopathy associated with increased production IL-7 due to expansion fibroblastic reticular cells, primary source this cytokine. excess not, however, consumed permanent...
Abstract Nucleic acid (NA)–sensing TLRs (NA-TLRs) promote the induction of anti-nuclear Abs in systemic lupus erythematosus. However, extent to which other nonnuclear pathogenic autoantibody specificities that occur and independently autoimmune diseases depend on NA-TLRs, immune cells require NA-TLRs autoimmunity, remains be determined. Using Unc93b13d lupus-prone mice lack NA-TLR signaling, we found all examined, even anti-RBC, required NA-TLRs. Furthermore, document B were for development...