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Article ; Online: B cells take the front seat: dysregulated B cell signals orchestrate loss of tolerance and autoantibody production.

Jackson, Shaun W / Kolhatkar, Nikita S / Rawlings, David J

2015 Volume 33, Page(s) 70–77

Abstract: A significant proportion of autoimmune-associated genetic variants are expressed in B cells, suggesting that B cells may play multiple roles in autoimmune pathogenesis. In this review, we highlight recent studies demonstrating that even modest ... ...

Abstract	A significant proportion of autoimmune-associated genetic variants are expressed in B cells, suggesting that B cells may play multiple roles in autoimmune pathogenesis. In this review, we highlight recent studies demonstrating that even modest alterations in B cell signaling are sufficient to promote autoimmunity. First, we describe several examples of genetic variations promoting B cell-intrinsic initiation of autoimmune germinal centers and autoantibody production. We highlight how dual antigen receptor/toll-like receptor signals greatly facilitate this process and how activated, self-reactive B cells may function as antigen presenting cells, leading to loss of T cell tolerance. Further, we propose that B cell-derived cytokines may initiate and/or sustain autoimmune germinal centers, likely also contributing, in parallel, to programing of self-reactive T cells.
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Autoantibodies/immunology ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmune Diseases/metabolism ; Autoimmunity/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cytokines/metabolism ; Germinal Center/immunology ; Germinal Center/metabolism ; Humans ; Immune Tolerance ; Signal Transduction
Chemical Substances	Autoantibodies ; Cytokines
Language	English
Publishing date	2015-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2015.01.018
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Article ; Online: BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells.

Metzler, Genita / Kolhatkar, Nikita S / Rawlings, David J

Current opinion in immunology

2015 Volume 37, Page(s) 46–53

Abstract: The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies ... ...

Abstract	The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies demonstrating the central role of the B cell antigen receptor (BCR), in coordination with other key pro-survival signals mediated by CD40, BAFF-R, TACI and/or TLRs, in regulating both negative and positive selection of autoreactive B cells. In particular, we show how altered antigen or co-stimulatory signaling can facilitate positive selection of transitional B cells with self-reactive BCRs, ultimately leading to their entry into the mature, naive B cell compartment. We propose a model wherein altered receptor signals (due to inherited genetic changes) leads: first, to enhanced positive selection of autoreactive cells into the naïve B cell repertoire; subsequently, to an increased probability of pathogenic germinal center responses in individuals with a broad range of autoimmune disorders.
MeSH term(s)	Animals ; Autoantigens/immunology ; Autoimmunity/genetics ; B-Lymphocytes/immunology ; Cell Differentiation/genetics ; Clonal Selection, Antigen-Mediated ; Germinal Center/physiology ; Humans ; Mutation/genetics ; Receptor Cross-Talk ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction/genetics
Chemical Substances	Autoantigens ; Receptors, Antigen, B-Cell
Language	English
Publishing date	2015-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2015.10.001
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Article ; Online: Efficacy, immunogenicity, and safety of an oral influenza vaccine: a placebo-controlled and active-controlled phase 2 human challenge study.

Liebowitz, David / Gottlieb, Keith / Kolhatkar, Nikita S / Garg, Shaily J / Asher, Jason M / Nazareno, Jonathan / Kim, Kenneth / McIlwain, David R / Tucker, Sean N

The Lancet. Infectious diseases

2020 Volume 20, Issue 4, Page(s) 435–444

Abstract: Background: Influenza is an important public health problem and existing vaccines are not completely protective. New vaccines that protect by alternative mechanisms are needed to improve efficacy of influenza vaccines. In 2015, we did a phase 1 trial of ...

Abstract	Background: Influenza is an important public health problem and existing vaccines are not completely protective. New vaccines that protect by alternative mechanisms are needed to improve efficacy of influenza vaccines. In 2015, we did a phase 1 trial of an oral influenza vaccine, VXA-A1.1. A favourable safety profile and robust immunogenicity results in that trial supported progression of the vaccine to the current phase 2 trial. The aim of this study was to evaluate efficacy of the vaccine in a human influenza challenge model. Methods: We did a single-site, placebo-controlled and active-controlled, phase 2 study at WCCT Global, Costa Mesa, CA, USA. Eligible individuals had an initial A/California/H1N1 haemagglutination inhibition titre of less than 20 and were aged 18-49 years and in good health. Individuals were randomly assigned (2:2:1) to receive a single immunisation of either 10 Results: Between Aug 31, 2016, and Jan 23, 2017, 374 individuals were assessed for eligibility, of whom 179 were randomly assigned to receive either VXA-A1.1 (n=71 [one individual did not provide a diary card, thus the solicited events were assessed in 70 individuals]), IIV (n=72), or placebo (n=36). Between Dec 2, 2016, and April 26, 2017, 143 eligible individuals (58 in the VXA-A1.1 group, 54 in the IIV group, and 31 in the placebo group) were challenged with influenza virus. VXA-A1.1 was well tolerated with no serious or medically significant adverse events. The most prevalent solicited adverse events for each of the treatment groups after immunisation were headache in the VXA-A1.1 (in five [7%] of 70 participants) and placebo (in seven [19%] of 36 participants) groups and tenderness at injection site in the IIV group (in 19 [26%] of 72 participants) Influenza-positive illness after challenge was detected in 17 (29%) of 58 individuals in the VXA-A1.1 group, 19 (35%) of 54 in the IIV group, and 15 (48%) of 31 in the placebo group. Interpretation: Orally administered VXA-A1.1 was well tolerated and generated protective immunity against virus shedding, similar to a licensed intramuscular IIV. These results represent a major step forward in developing a safe and effective oral influenza vaccine. Funding: Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority.
MeSH term(s)	Administration, Oral ; Adult ; Double-Blind Method ; Female ; Headache/etiology ; Healthy Volunteers ; Humans ; Immunogenicity, Vaccine ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza Vaccines/immunology ; Influenza Vaccines/therapeutic use ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; Male ; Middle Aged ; Placebos ; Safety ; Vaccination
Chemical Substances	Influenza Vaccines ; Placebos
Language	English
Publishing date	2020-01-21
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(19)30584-5
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Article ; Online: TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism.

Gut

2024

Abstract: Objective: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and ...

Abstract	Objective: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment. Design: We identified Results: Hepatic Conclusion: Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.
Language	English
Publishing date	2024-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2023-331396
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Zs.A 160: Show issues

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Article ; Online: Human influenza virus challenge identifies cellular correlates of protection for oral vaccination.

Cell host & microbe

2021 Volume 29, Issue 12, Page(s) 1828–1837.e5

Abstract: Developing new influenza vaccines with improved performance and easier administration routes hinges on defining correlates of protection. Vaccine-elicited cellular correlates of protection for influenza in humans have not yet been demonstrated. A phase-2 ...

Abstract	Developing new influenza vaccines with improved performance and easier administration routes hinges on defining correlates of protection. Vaccine-elicited cellular correlates of protection for influenza in humans have not yet been demonstrated. A phase-2 double-blind randomized placebo and active (inactivated influenza vaccine) controlled study provides evidence that a human-adenovirus-5-based oral influenza vaccine tablet (VXA-A1.1) can protect from H1N1 virus challenge in humans. Mass cytometry characterization of vaccine-elicited cellular immune responses identified shared and vaccine-type-specific responses across B and T cells. For VXA-A1.1, the abundance of hemagglutinin-specific plasmablasts and plasmablasts positive for integrin α4β7, phosphorylated STAT5, or lacking expression of CD62L at day 8 were significantly correlated with protection from developing viral shedding following virus challenge at day 90 and contributed to an effective machine learning model of protection. These findings reveal the characteristics of vaccine-elicited cellular correlates of protection for an oral influenza vaccine.
MeSH term(s)	Double-Blind Method ; Humans ; Immunity ; Immunity, Cellular ; Immunization ; Influenza A Virus, H1N1 Subtype ; Influenza A virus ; Influenza Vaccines/immunology ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; L-Selectin/metabolism ; STAT5 Transcription Factor/metabolism ; T-Lymphocytes ; Vaccination ; Vaccines, Inactivated/immunology ; Virus Shedding
Chemical Substances	Influenza Vaccines ; SELL protein, human ; STAT5 Transcription Factor ; Vaccines, Inactivated ; L-Selectin (126880-86-2)
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2021.10.009
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Zs.A 6578: Show issues

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Article ; Online: CD4+ T cells and CD40 participate in selection and homeostasis of peripheral B cells.

Schwartz, Marc A / Kolhatkar, Nikita S / Thouvenel, Chris / Khim, Socheath / Rawlings, David J

Journal of immunology (Baltimore, Md. : 1950)

2014 Volume 193, Issue 7, Page(s) 3492–3502

Abstract: Control of peripheral B cell development and homeostasis depends critically on coordinate signals received through the BAFFRs and BCRs. The extent to which other signals contribute to this process, however, remains undefined. We present data indicating ... ...

Abstract	Control of peripheral B cell development and homeostasis depends critically on coordinate signals received through the BAFFRs and BCRs. The extent to which other signals contribute to this process, however, remains undefined. We present data indicating that CD4(+) T cells directly influence naive B cell development via CD40 signaling. Loss of CD4(+) T cells or CD40-CD40L interaction leads to reduced B cell homeostatic proliferation and hindered B cell reconstitution posttransplantation. Furthermore, we demonstrate that in the absence of CD40 signals, these events are modulated by BCR self-reactivity. Strikingly, murine models lacking CD40 reveal a broadly altered BCR specificity and limited diversity by both single-cell cloning and high-throughput sequencing techniques. Collectively, our results imply that any setting of T cell lymphopenia or reduced CD40 function, including B cell recovery following transplantation, will impact the naive B cell repertoire.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; CD40 Antigens/genetics ; CD40 Antigens/immunology ; Homeostasis/genetics ; Homeostasis/immunology ; Lymphopenia/genetics ; Lymphopenia/immunology ; Lymphopenia/pathology ; Mice ; Mice, Knockout ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology
Chemical Substances	CD40 Antigens ; Receptors, Antigen, B-Cell
Language	English
Publishing date	2014-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1400798
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Article ; Online: Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells.

Jacobs, Holly M / Thouvenel, Christopher D / Leach, Sarah / Arkatkar, Tanvi / Metzler, Genita / Scharping, Nicole E / Kolhatkar, Nikita S / Rawlings, David J / Jackson, Shaun W

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 196, Issue 9, Page(s) 3525–3531

Abstract: Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, ... ...

Abstract	Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear Abs. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remain unclear. We report that, although surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACI(+) transitional cells from BAFF-transgenic mice are characterized by an activated, cycling phenotype, and the TACI(+) cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase and T-bet, and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACI(+) transitional B cells from BAFF-transgenic mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism through which BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.
MeSH term(s)	Animals ; Autoantibodies/biosynthesis ; Autoantibodies/immunology ; Autoimmunity ; B-Cell Activating Factor/genetics ; B-Cell Activating Factor/metabolism ; B-Lymphocyte Subsets/immunology ; Lymphocyte Activation ; Mice ; Mice, Transgenic ; Precursor Cells, B-Lymphoid/immunology ; Precursor Cells, B-Lymphoid/physiology ; Transmembrane Activator and CAML Interactor Protein/genetics ; Transmembrane Activator and CAML Interactor Protein/metabolism
Chemical Substances	Autoantibodies ; B-Cell Activating Factor ; Tnfrsf13b protein, mouse ; Tnfsf13b protein, mouse ; Transmembrane Activator and CAML Interactor Protein
Language	English
Publishing date	2016--01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1600017
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Article ; Online: B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6.

Jackson, Shaun W / Jacobs, Holly M / Arkatkar, Tanvi / Dam, Elizabeth M / Scharping, Nicole E / Kolhatkar, Nikita S / Hou, Baidong / Buckner, Jane H / Rawlings, David J

The Journal of experimental medicine

2016 Volume 213, Issue 5, Page(s) 733–750

Abstract: Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their ... ...

Abstract	Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4(+) T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.
MeSH term(s)	Animals ; Autoantibodies/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Germinal Center/immunology ; Germinal Center/pathology ; Interferon-gamma/genetics ; Interferon-gamma/immunology ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/pathology ; Male ; Mice ; Mice, Knockout ; Proto-Oncogene Proteins c-bcl-6/genetics ; Proto-Oncogene Proteins c-bcl-6/immunology ; Receptors, Interferon/genetics ; Receptors, Interferon/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptors/genetics ; Toll-Like Receptors/immunology ; Interferon gamma Receptor
Chemical Substances	Autoantibodies ; BCL6 protein, human ; Bcl6 protein, mouse ; IFNG protein, mouse ; Proto-Oncogene Proteins c-bcl-6 ; Receptors, Interferon ; Toll-Like Receptors ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2016-04-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20151724
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Article ; Online: B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome.

Kolhatkar, Nikita S / Scharping, Nicole E / Sullivan, Jenna M / Jacobs, Holly M / Schwartz, Marc A / Khim, Socheath / Notarangelo, Luigi D / Thrasher, Adrian J / Rawlings, David J / Jackson, Shaun W

European journal of immunology

2015 Volume 45, Issue 10, Page(s) 2773–2779

Abstract: Patients with Wiskott-Aldrich syndrome (WAS) exhibit prominent defects in splenic marginal zone (MZ), resulting in abnormal T-cell-independent antibody responses and increased bacterial infections. B-cell-intrinsic deletion of the affected gene WAS ... ...

Abstract	Patients with Wiskott-Aldrich syndrome (WAS) exhibit prominent defects in splenic marginal zone (MZ), resulting in abnormal T-cell-independent antibody responses and increased bacterial infections. B-cell-intrinsic deletion of the affected gene WAS protein (WASp) markedly reduces splenic MZ B cells, without impacting the rate of MZ B-cell development, suggesting that abnormal B-cell retention within the MZ accounts for MZ defects in WAS. Since WASp regulates integrin-dependent actin cytoskeletal rearrangement, we previously hypothesized that defective B-cell integrin function promotes MZ depletion. In contrast, we now report that B-cell-intrinsic deletion of the TLR signaling adaptor MyD88 is sufficient to restore the MZ in WAS. We further identify TLR7, an endosomal single-stranded RNA (ssRNA) receptor, as the MyD88-dependent receptor responsible for WAS MZ depletion. These findings implicate spontaneous activation of MZ B cells by ssRNA-containing self-ligands (likely derived from circulating apoptotic material) as the mechanism underlying MZ depletion in WAS. Together, these data suggest a previously unappreciated role for B-cell intrinsic TLR signals in MZ homeostasis, of relevance to both pathogen responses and to the development of systemic autoimmunity.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cytoskeleton/genetics ; Cytoskeleton/immunology ; Disease Models, Animal ; Integrins/genetics ; Integrins/immunology ; Lymphocyte Depletion ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Knockout ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Spleen/immunology ; Spleen/pathology ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Wiskott-Aldrich Syndrome/genetics ; Wiskott-Aldrich Syndrome/immunology ; Wiskott-Aldrich Syndrome/pathology
Chemical Substances	Integrins ; Membrane Glycoproteins ; Myd88 protein, mouse ; Myeloid Differentiation Factor 88 ; Tlr7 protein, mouse ; Toll-Like Receptor 7
Language	English
Publishing date	2015-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201545644
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation.

Jackson, Shaun W / Scharping, Nicole E / Kolhatkar, Nikita S / Khim, Socheath / Schwartz, Marc A / Li, Quan-Zhen / Hudkins, Kelly L / Alpers, Charles E / Liggitt, Denny / Rawlings, David J

Journal of immunology (Baltimore, Md. : 1950)

2014 Volume 192, Issue 10, Page(s) 4525–4532

Abstract: Systemic lupus erythematosus is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid-associated Ags. The endosomal TLRs TLR7 and TLR9 are critical for generation of Abs targeting RNA- or DNA-associated Ags, respectively. ...

Abstract	Systemic lupus erythematosus is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid-associated Ags. The endosomal TLRs TLR7 and TLR9 are critical for generation of Abs targeting RNA- or DNA-associated Ags, respectively. In murine lupus models, deletion of TLR7 limits autoimmune inflammation, whereas deletion of TLR9 exacerbates disease. Whether B cell or myeloid TLR7/TLR9 signaling is responsible for these effects has not been fully addressed. In this study, we use a chimeric strategy to evaluate the effect of B cell-intrinsic deletion of TLR7 versus TLR9 in parallel lupus models. We demonstrate that B cell-intrinsic TLR7 deletion prevents RNA-associated Ab formation, decreases production of class-switched Abs targeting nonnuclear Ags, and limits systemic autoimmunity. In contrast, B cell-intrinsic TLR9 deletion results in decreased DNA-reactive Ab, but increased Abs targeting a broad range of systemic autoantigens. Further, we demonstrate that B cell-intrinsic TLR9 deletion results in increased systemic inflammation and immune complex glomerulonephritis, despite intact TLR signaling within the myeloid compartment. These data stress the critical importance of dysregulated B cell-intrinsic TLR signaling in the pathogenesis of systemic lupus erythematosus.
MeSH term(s)	Animals ; Antibodies, Antinuclear/genetics ; Antibodies, Antinuclear/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Disease Models, Animal ; Inflammation/genetics ; Inflammation/immunology ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/pathology ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Knockout ; RNA/genetics ; RNA/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 9/genetics ; Toll-Like Receptor 9/immunology
Chemical Substances	Antibodies, Antinuclear ; Membrane Glycoproteins ; Tlr7 protein, mouse ; Tlr9 protein, mouse ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; RNA (63231-63-0)
Language	English
Publishing date	2014-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1400098
Database	MEDical Literature Analysis and Retrieval System OnLINE

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