Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return

Storch, h. c. Volker; Zimmermann, Birgit; Resch, Bastian; Tykocinski, Lars-Oliver; Moradi, Babak; Horn, Patrick; Kaya, Ziya; Blank, Norbert; Rehart, Stefan; Thomsen, M.; Lorenz, Hanns‐Martin; Neumann, Elena; Tretter, Theresa

doi:10.1136/annrheumdis-2014-206965

Cited by 31 publications

(28 citation statements)

References 71 publications

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“…The transmembrane subunit of a HERV-K(HML2) sequence was reported to inhibit T cells activation in a similar way to the HIV ISD, influencing cytokine release and immune gene expression ( 107 ). Similarly, a HERV-H Env protein (Env-59) ISD showed anti-inflammatory potential in a mouse model of arthritis ( 103 ), being inversely related to the level of pathogenic effectors (such as IL-6 and TLR7) in human autoimmune rheumatic diseases ( 104 ). Furthermore, a recently described HERV LTR (HERVP71A, locus 6p22.1) was shown to serve as a tissue-specific enhancer for HLA-G gene expression in human extravillous trophoblasts, at the fetal-maternal interface, inhibiting the natural killer cell cytotoxicity and conferring immune tolerance to the developing placenta ( 106 ).…”

Section: Hervs As Inhibitors Of Innate Immunitymentioning

confidence: 99%

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

2018

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About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

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Section: Hervs As Inhibitors Of Innate Immunitymentioning

confidence: 99%

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

2018

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“…Fibroblasts express adhesion molecules and secrete cytokines and chemokines (1). Moreover, they directly influence the proliferation, differentiation, activation, or survival of virtually all immune cells (2)(3)(4)(5)(6)(7)(8). Fibroblasts can activate endothelial cells of the surrounding microvessels and thereby indirectly promote the recruitment of immune cells (1).…”

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confidence: 99%

Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism

Tykocinski

Lauffer

Bohnen

et al. 2017

The Journal of Immunology

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The development of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Fibroblasts possess the capacity to suppress T cell responses, although the molecular mechanisms of this suppression remain incompletely understood. In this study, we aimed to define the mechanisms by which noninflammatory SF modulate Th cell responses and to determine the immunosuppressive efficacy of RASF. Hence, the influence of SF from osteoarthritis or RA patients on total Th cells or different Th cell subsets of healthy donors was analyzed in vitro. We show that SF strongly suppressed the proliferation of Th cells and the secretion of IFN-γ in a cell contact-independent manner. In cocultures of SF and Th cells, tryptophan was completely depleted within a few days, resulting in eukaryotic initiation factor 2α phosphorylation, TCRζ-chain downregulation, and proliferation arrest. Blocking IDO1 activity completely restored Th cell proliferation, but not IFN-γ production. Interestingly, only the proliferation of Th1 cells, but not of Th2 or Th17 cells, was affected. Finally, RASF had a significantly lower IDO1 expression and a weaker Th cell suppressive capacity compared with osteoarthritis SF. We postulate that the suppression of Th cell growth by SF through tryptophan catabolism may play an important role in preventing inappropriate Th cell responses under normal conditions. However, expansion of Th17 cells that do not induce IDO1-mediated suppression and the reduced capacity of RASF to restrict Th cell proliferation through tryptophan metabolism may support the initiation and propagation of synovitis in RA patients.

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“…Nevertheless, our data reveal that plasma cell differentiation leads to an increased propensity of IL‐36α expression. In inflamed tissues FLS interact with invading B cells and may lead to destructive features in RA . Additionally, B cells have been demonstrated to migrate through FLS layers (RA and ordinary FLS) supporting pseudoemperipolesis that prolong survival .…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts

et al. 2017

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The IL-1 family member IL-36α has proinflammatory and pathogenic properties in psoriasis. IL-36α binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36α. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36α-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36α and stimulation increased IL-36α in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36α by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36α-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints.

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Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return

Abstract: Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.

Cited by 31 publications

References 71 publications

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism

Interleukin‐36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts

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