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  1. Article: Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus.

    Ukadike, Kennedy C / Najjar, Rayan / Ni, Kathryn / Laine, Amanda / Wang, Xiaoxing / Bays, Alison / Taylor, Martin S / LaCava, John / Mustelin, Tomas

    Mobile DNA

    2023  Volume 14, Issue 1, Page(s) 5

    Abstract: Background: Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, ( ... ...

    Abstract Background: Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, (iii) whether the cells express L1-dependent interferon and interferon-stimulated genes, and (iv) the effect of inhibition of L1 ORF2p by reverse transcriptase inhibitors.
    Results: L1 ORF1p was detected by flow cytometry primarily in SLE CD66b
    Conclusions: We identified L1Hs loci that are transcriptionally active in SLE neutrophils, and a reduction in the epigenetic silencing mechanisms that normally counteract L1 transcription. SLE neutrophils contained L1-encoded ORF1p protein, as well as activation of the type I interferon system, which was inhibited by treatment with reverse transcriptase inhibitors. Our findings will enable a deeper analysis of L1 dysregulation and its potential role in SLE pathogenesis.
    Language English
    Publishing date 2023-05-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2536054-1
    ISSN 1759-8753
    ISSN 1759-8753
    DOI 10.1186/s13100-023-00293-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Expression of Envelope Protein Encoded by Endogenous Retrovirus K102 in Rheumatoid Arthritis Neutrophils.

    Laine, Amanda / Wang, Xiaoxing / Ni, Kathryn / Smith, Sarah E B / Najjar, Rayan / Whitmore, Leanne S / Yacoub, Michael / Bays, Alison / Gale, Michael / Mustelin, Tomas

    Microorganisms

    2023  Volume 11, Issue 5

    Abstract: Many patients suffering from autoimmune diseases have autoantibodies against proteins encoded by genomic retroelements, suggesting that normal epigenetic silencing is insufficient to prevent the production of the encoded proteins for which immune ... ...

    Abstract Many patients suffering from autoimmune diseases have autoantibodies against proteins encoded by genomic retroelements, suggesting that normal epigenetic silencing is insufficient to prevent the production of the encoded proteins for which immune tolerance appears to be limited. One such protein is the transmembrane envelope (Env) protein encoded by human endogenous retrovirus K (HERV-K). We reported recently that patients with rheumatoid arthritis (RA) have IgG autoantibodies that recognize Env. Here, we use RNA sequencing of RA neutrophils to analyze HERV-K expression and find that only two loci with an intact open-reading frame for Env, HERV-K102, and K108 are expressed, but only the former is increased in RA. In contrast, other immune cells express more K108 than K102. Patient autoantibodies recognized endogenously expressed Env in breast cancer cells and in RA neutrophils but not healthy controls. A monoclonal anti-Env antibody also detected Env on the surface of RA neutrophils but very little on the surface of other immune cells. We conclude that HERV-K102 is the locus that produces Env detectable on the surface of neutrophils in RA. The low levels of HERV-K108 transcripts may contribute only marginally to cell surface Env on neutrophils or other immune cells in some patients.
    Language English
    Publishing date 2023-05-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms11051310
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Autoantibodies Against Unmodified and Citrullinated Human Endogenous Retrovirus K Envelope Protein in Patients With Rheumatoid Arthritis.

    Wang, Xiaoxing / Hefton, Amanda / Ni, Kathryn / Ukadike, Kennedy C / Bowen, Michael A / Eckert, Mary / Stevens, Anne / Lood, Christian / Mustelin, Tomas

    The Journal of rheumatology

    2021  Volume 49, Issue 1, Page(s) 26–35

    Abstract: Objective: Autoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if ... ...

    Abstract Objective: Autoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K.
    Methods: Immunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase 4 (PAD4). Sera from 100 patients with RA, plasma from 32 patients with juvenile idiopathic arthritis (JIA), and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory variables of the patients.
    Results: We replicated and expanded upon published data suggesting that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating myeloperoxidase-DNA complexes indicative of nonapoptotic neutrophil cell death. Further, most of the patients with RA, but not those with JIA, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease.
    Conclusion: Our data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA.
    MeSH term(s) Arthritis, Rheumatoid ; Autoantibodies ; Child ; Endogenous Retroviruses ; Gene Products, env ; Humans ; Protein-Arginine Deiminase Type 4
    Chemical Substances Autoantibodies ; Gene Products, env ; Protein-Arginine Deiminase Type 4 (EC 3.5.3.15)
    Language English
    Publishing date 2021-08-01
    Publishing country Canada
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 194928-7
    ISSN 1499-2752 ; 0315-162X
    ISSN (online) 1499-2752
    ISSN 0315-162X
    DOI 10.3899/jrheum.201492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1168: 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)
    Zs.MO 135: Show issues

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  4. Article ; Online: Autoantibodies against citrullinated serum albumin in patients with rheumatoid arthritis.

    Hefton, Amanda / Liang, Shu Ying / Ni, Kathryn / Carter, Victoria / Ukadike, Kennedy / Lood, Christian / Mustelin, Tomas

    Journal of translational autoimmunity

    2019  Volume 2, Page(s) 100023

    Abstract: Rheumatoid arthritis (RA) is a chronic, potentially debilitating, inflammatory disease that primarily affects synovial joints. While the etiology of RA remains incompletely understood, it is clear that the disease is autoimmune in nature. A hallmark of ... ...

    Abstract Rheumatoid arthritis (RA) is a chronic, potentially debilitating, inflammatory disease that primarily affects synovial joints. While the etiology of RA remains incompletely understood, it is clear that the disease is autoimmune in nature. A hallmark of RA is that the specific epitopes on self-antigens that are targeted by the immune system are often modified by arginine deimination, also referred to as citrullination. In fact, anti-citrullinated protein autoantibodies (ACPA) at high enough titers are diagnostic of RA and appear to have many different targets. Here, we report that RA patients have IgG autoantibodies that react with human serum albumin (HSA) when it had been citrullinated by protein arginine deiminase (PAD) 4, but not by PAD2. Unmodified albumin was not recognized by autoantibodies. In a cohort of 79 RA patients, 38% had anti-citrullinated HSA (anti-cit-HSA) reactivity above the cut-off of the average plus two standard deviations in a healthy subject cohort (n = 16). The titers of these autoantibodies correlated with ACPA status and seropositivity. There was also a trend toward correlation with the presence of radiographic joint erosions, but this did not reach statistical significance. Finally, patients with anti-cit-HSA were more frequently treated with biologics and combination regimens than patients without these autoantibodies. We conclude that ACPA directed against citrullinated albumin exist in a subset of RA patients. Because of the abundance of albumin, its modification by citrullination, as well as autoantibodies binding to it, may have deleterious consequences for the health of affected RA patients.
    Language English
    Publishing date 2019-11-11
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2589-9090
    ISSN (online) 2589-9090
    DOI 10.1016/j.jtauto.2019.100023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: IgG and IgA autoantibodies against L1 ORF1p expressed in granulocytes correlate with granulocyte consumption and disease activity in pediatric systemic lupus erythematosus.

    Ukadike, Kennedy C / Ni, Kathryn / Wang, Xiaoxing / Taylor, Martin S / LaCava, John / Pachman, Lauren M / Eckert, Mary / Stevens, Anne / Lood, Christian / Mustelin, Tomas

    Arthritis research & therapy

    2021  Volume 23, Issue 1, Page(s) 153

    Abstract: Background: Most patients with systemic lupus erythematosus (SLE) have IgG autoantibodies against the RNA-binding p40 (ORF1p) protein encoded by the L1 retroelement. This study tested if these autoantibodies are also present in children with pediatric ... ...

    Abstract Background: Most patients with systemic lupus erythematosus (SLE) have IgG autoantibodies against the RNA-binding p40 (ORF1p) protein encoded by the L1 retroelement. This study tested if these autoantibodies are also present in children with pediatric SLE (pSLE) and if the p40 protein itself could be detected in immune cells.
    Methods: Autoantibodies in the plasma of pSLE patients (n = 30), healthy children (n = 37), and disease controls juvenile idiopathic arthritis (JIA) (n = 32) and juvenile dermatomyositis (JDM) (n = 60), were measured by ELISA. Expression of p40 in immune cells was assessed by flow cytometry. Markers of neutrophil activation and death were quantitated by ELISA.
    Results: IgG and IgA autoantibodies reactive with p40 were detected in the pSLE patients, but were low in healthy controls and in JIA or JDM. pSLE patients with active disease (13 of them newly diagnosed) had higher titers than the same patients after effective therapy (p = 0.0003). IgG titers correlated with SLEDAI (r = 0.65, p = 0.0001), ESR (r = 0.43, p = 0.02), and anti-dsDNA antibodies (r = 0.49, p < 0.03), and inversely with complement C3 (r = -0.55, p = 0.002) and C4 (r = -0.51, p = 0.006). p40 protein was detected in a subpopulation of CD66b
    Conclusions: Children with active SLE have elevated IgG and IgA autoantibodies against L1 p40, and this protein can be detected in circulating granulocytes in both pediatric and adult SLE patients. P40 expression and autoantibody levels correlate with disease activity. Markers of neutrophil activation and death also correlate with these autoantibodies and with disease activity, suggesting that neutrophils express L1 and are a source of p40.
    MeSH term(s) Adult ; Autoantibodies ; Child ; Humans ; Immunoglobulin A ; Immunoglobulin G ; Lupus Erythematosus, Systemic ; Neutrophils
    Chemical Substances Autoantibodies ; Immunoglobulin A ; Immunoglobulin G
    Language English
    Publishing date 2021-05-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2107602-9
    ISSN 1478-6362 ; 1478-6354
    ISSN (online) 1478-6362
    ISSN 1478-6354
    DOI 10.1186/s13075-021-02538-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5490: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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