Decreased expression of miR-29 family associated with autoimmune myasthenia gravis

Abstract Background Myasthenia gravis (MG) is a rare autoimmune disease mainly mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. The thymus is the effector organ, and its removal alleviates the symptoms of the disease. In the early-onset form of MG, the thymus displays functional and morphological abnormalities such as B cell infiltration leading to follicular hyperplasia, and the production of AChR antibodies. Type-I interferon (IFN-I), especially IFN-β, is the orchestrator of thymic changes observed in MG. As Dicer and miR-29 subtypes play a role in modulating the IFN-I signalization in mouse thymus, we investigated their expression in MG thymus. Methods The expression of DICER and miR-29 subtypes were thoroughly investigated by RT-PCR in human control and MG thymuses, and in thymic epithelial cells (TECs). Using miR-29a/b-1-deficient mice, with lower miR-29a/b-1 expression, we investigated their susceptibility to experimental autoimmune MG (EAMG) as compared to wild-type mice. Results DICER mRNA and all miR-29 subtypes were down-regulated in the thymus of MG patients and DICER expression was correlated with the lower expression of miR-29a-3p. A decreased expression of miR-29 subtypes was similarly observed in MG TECs; a decrease also induced in TECs upon IFN-β treatment. We demonstrated that miR-29a/b-1-deficient mice were more susceptible to EAMG without higher levels of anti-AChR IgG subtypes. In the thymus, if no B cell infiltration was observed, an increased expression of Ifn-β associated with Baff expression and the differentiation of Th17 cells associated with increased expression of Il-6, Il-17a and Il-21 and decreased Tgf-β1 mRNA were demonstrated in miR-29a/b-1-deficient EAMG mice. Conclusions It is not clear if the decreased expression of miR-29 subtypes in human MG is a consequence or a causative factor of thymic inflammation. However, our results from the EAMG mouse model indicated that a reduction in miR-29a/b1 may contribute to the pathophysiological process involved in MG by favoring the increased expression of IFN-β and the emergence of pro-inflammatory Th17 cells.

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Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection

Journal of Virology ◽

10.1128/jvi.02976-14 ◽

2015 ◽

Vol 89 (9) ◽

pp. 4748-4759 ◽

Cited By ~ 13

Author(s):

Haifeng C. Xu ◽

Jun Huang ◽

Vishal Khairnar ◽

Vikas Duhan ◽

Aleksandra A. Pandyra ◽

...

Keyword(s):

B Cells ◽

Viral Infection ◽

B Cell ◽

Viral Infections ◽

Type I Interferon ◽

Type I ◽

Interferon Production ◽

Immune Priming ◽

Adaptive Immune ◽

Deficient Mice

ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

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Experimental autoimmune myasthenia gravis induction in B cell-deficient mice

International Immunology ◽

10.1093/intimm/10.9.1359 ◽

1998 ◽

Vol 10 (9) ◽

pp. 1359-1365 ◽

Cited By ~ 19

Author(s):

H Li

Keyword(s):

Myasthenia Gravis ◽

B Cell ◽

Experimental Autoimmune Myasthenia Gravis ◽

Autoimmune Myasthenia ◽

Deficient Mice ◽

Experimental Autoimmune

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Driving T Cell Development in the Thymus.

Blood ◽

10.1182/blood.v104.11.3860.3860 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3860-3860

Author(s):

Cristina M. Joao ◽

Brenda M. Ogle ◽

Marilia Cascalho ◽

Jeffrey L. Platt

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Development ◽

Cell Development ◽

Thymic Epithelial Cells ◽

P Value ◽

Tcr Repertoire ◽

Repertoire Diversity ◽

Deficient Mice

Abstract Background: Classic reports on lymphocyte development hold that B and T cells develop independently. This concept derives in part from the observation that patients with pure B cell immunodeficiency and hypogammaglobulinemia have a normal thymus and T cell numbers. Our recent findings however challenge this concept. We found that T cell development depends not only on the interaction of T cell precursors with thymic epithelial cells but also on other cells. Here we report that those other cells are B cells. Aims: The purpose of this study was to determine whether B cells drive T cell development and TCR diversification in the thymus. Methods: We compared the number of sub-populations of thymocytes and TCR repertoire diversity in B-cell deficient and B-cell proficient mice and in B cell deficient mice following immunoglobulin (Ig) injections. Total leucocytes numbers were determined with a Coulter counter and numbers of thymocytes sub-populations were calculated by flow cytometry analysis. TCR repertoire diversity was measured by a novel method based on hybridization of TCR Vβ specific cRNA on a gene chip platform. Results: In B-cell deficient mice the number of thymocytes was four times reduced and TCR Vβ chain diversity was up to one million times lower compared with wild type mice. Numbers and diversity were restored by treatment of the mice with gamma globulin (see table). Conclusions: T cell development and diversification is driven by B cells. Mice Number of total thymocytes (mean ± standard deviation) p Value β V TCR diversity of thymocytes (median; min.-max.) p Value C57BL/6 (wild mice) 1.3 x 108 ± 5.1 x 107N=7 4.7 x 106; 1.0 x 105 − 1.1 x 108N=5 JH−/− (B cell immunodeficient mice) 3.1 x 107 ± 1.7 x107N=7 0.002 5.9 x 102; 3.6 x 102 − 1.1 x 103N=5 0.0002 JH−/− treated with Ig 3.9 x 107 ± 1.4 x106N=2 0.20 1.1 x 105; 2.7 x 100 − 7.7 x 105N=4 0.08

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B cells enhance early innate immune responses during bacterial sepsis

Journal of Experimental Medicine ◽

10.1084/jem.20101715 ◽

2011 ◽

Vol 208 (8) ◽

pp. 1673-1682 ◽

Cited By ~ 96

Author(s):

Kindra M. Kelly-Scumpia ◽

Philip O. Scumpia ◽

Jason S. Weinstein ◽

Matthew J. Delano ◽

Alex G. Cuenca ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Inflammatory Responses ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Bacterial Sepsis ◽

Sepsis Survival ◽

Deficient Mice

Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis.

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T-Cell-Independent Humoral Immunity Is Sufficient for Protection against Fatal Intracellular Ehrlichia Infection

Infection and Immunity ◽

10.1128/iai.00705-07 ◽

2007 ◽

Vol 75 (10) ◽

pp. 4933-4941 ◽

Cited By ~ 53

Author(s):

Constantine Bitsaktsis ◽

Bisweswar Nandi ◽

Rachael Racine ◽

Katherine C. MacNamara ◽

Gary Winslow

Keyword(s):

T Cell ◽

B Cell ◽

Mhc Class Ii ◽

Humoral Immunity ◽

Bacterial Infections ◽

Class Ii ◽

Interleukin 12 ◽

Type I ◽

Wild Type ◽

Deficient Mice

ABSTRACT Although humoral immunity has been shown to contribute to host defense during intracellular bacterial infections, its role has generally been ancillary. Instead, CD4 T cells are often considered to play the dominant role in protective immunity via their production of type I cytokines. Our studies of highly pathogenic Ehrlichia bacteria isolated from Ixodes ovatus (IOE) reveal, however, that this paradigm is not always correct. Immunity to IOE infection can be induced by infection with a closely related weakly pathogenic ehrlichia, Ehrlichia muris. Type I cytokines (i.e., gamma interferon, tumor necrosis factor alpha, and interleukin-12) were not necessary for E. muris-induced immunity. In contrast, humoral immunity was essential, as shown by the fact that E. muris-infected B-cell-deficient mice were not protected from IOE challenge and because E. muris immunization was effective in CD4-, CD8-, and major histocompatibility complex (MHC) class II-deficient mice. Immunity was unlikely due to nonspecific inflammation, as prior infection with Listeria monocytogenes did not induce immunity to IOE. Antisera from both wild-type and MHC-II-deficient mice provided at least partial resistance to challenge infection, and protection could also be achieved following transfer of total, but not B-cell-depleted, splenocytes obtained from E. muris-immunized mice. The titers of class-switched antibodies in immunized CD4 T-cell- and MHC class II-deficient mice, although lower than those observed in immunized wild-type mice, were significant, indicating that E. muris can induce class switch recombination in the absence of classical T-cell-mediated help. These studies highlight a major protective role for classical T-cell-independent humoral immunity during an intracellular bacterial infection.

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