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Nucleotide Sequencing of Psoriatic Arthritis Tissue before and during Methotrexate Administration Reveals a Complex Inflammatory T Cell Infiltrate with Very Few Clones Exhibiting Features That Suggest They Drive the Inflammatory Process by Recognizing Autoantigens

Curran, Shane A. ; FitzGerald, Oliver M. ; Costello, Patrick J. ; [et al.]

The American Association of Immunologists ; 2004

In: The Journal of Immunology Vol. 172, No. 3 ( 2004-02-01), p. 1935-1944

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 172, No. 3 ( 2004-02-01), p. 1935-1944

Abstract: Psoriatic arthritis is an interesting MHC class I allele associated autoimmune disease where injury is likely mediated exclusively by T cells. We used TCR β-chain nucleotide sequencing to gain insight into the adaptive immune events responsible for this injury and determine whether the numerous oligoclonal expansions of this disease represent extreme determinant spreading among driving clones that recognize autoantigen or were non-Ag-driven, inflammation-related expansions. Because methotrexate suppresses but does not eliminate this inflammation, we hypothesized that clones persisting during methotrexate treatment would likely drive the inflammation. Seventy-six percent of the T cell clones in active tissue were polyclonal and unexpanded, accounting for 31% of transcripts. They were decreased greatly by methotrexate. Strikingly, most expanded clones in the inflamed joint did not persist during methotrexate treatment, were found only in inflammatory sites, exhibited no structural homology to one another, and were either CD4 or CD8 in lineage, suggesting they were non-autoantigen-driven, inflammation-related expansions. Only 12% of the expanded clones could be grouped into clonal sets distinguished by structurally homologous CDR3 β-chain amino acid motifs suggesting Ag drive. These were exclusively CD8 in lineage, persisted during methotrexate administration, and were present in both joint fluid and blood implying they were candidate driver clones that recognized an autoantigen. However, a major set of putative driver clones exhibited a previously described EBV-specific β-chain motif, emphasizing that the dominant feature of the disease was activation of multiple clones apparently lacking specificity for an inciting autoantigen.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.172.3.1935

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2004

detail.hit.zdb_id: 1475085-5

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Psoriatic Arthritis Joint Fluids Are Characterized by CD8 and CD4 T Cell Clonal Expansions that Appear Antigen Driven

Costello, Patrick J. ; Winchester, Robert J. ; Curran, Shane A. ; [et al.]

The American Association of Immunologists ; 2001

In: The Journal of Immunology Vol. 166, No. 4 ( 2001-02-15), p. 2878-2886

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 4 ( 2001-02-15), p. 2878-2886

Abstract: The CD8 αβT cell receptor repertoire in joint fluid of individuals with active psoriatic arthritis contained an average of 32 major oligoclonal expansions in many variable genes of the TCR β chain (BV) families, as shown by β-chain CDR3 length analysis. Interestingly, a small number of oligoclonal expansions were shared between simultaneous samples of joint fluid and blood; however, most expansions found in joint fluid were not identifiable in blood emphasizing the immunologic specificity of the clonal events for the inflamed joint at a given point of time. The CD4 T cell joint fluid repertoire contained fewer and smaller oligoclonal expansions also largely restricted to the joint, suggesting that CD4 T cells participate perhaps by interacting cognitively to generate the CD8 clones. The inferred amino acid sequence of a single CD8 oligoclonal expansion revealed that they usually are composed of one or a few structurally related clones at the amino acid sequence level with β-chains that encode identical or highly homologous CDR3 motifs. These were not shared among patients. Moreover, several clones that encoded the same amino acid sequence were found to be structurally distinct at the nucleotide level, strongly implying clonal selection and expansion is operating at the level of specific TCR-peptide interactions. The findings support a model of psoriatic arthritis inflammation involving extensive and selective Ag, likely autoantigen, driven intra-articular CD4, and CD8 T cell clonal expansions.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.166.4.2878

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2001

detail.hit.zdb_id: 1475085-5

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Activation of Nuclear Orphan Receptor NURR1 Transcription by NF-κB and Cyclic Adenosine 5′-Monophosphate Response Element-Binding Protein in Rheumatoid Arthritis Synovial Tissue

McEvoy, Alice N. ; Murphy, Eithne A. ; Ponnio, Tiia ; [et al.]

The American Association of Immunologists ; 2002

In: The Journal of Immunology Vol. 168, No. 6 ( 2002-03-15), p. 2979-2987

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 168, No. 6 ( 2002-03-15), p. 2979-2987

Abstract: Modulation of the NURR subfamily of nuclear receptors may be an important mechanism regulating pathways associated with inflammatory joint disease. We examined the signaling mechanisms through which inflammatory mediators, produced by rheumatoid arthritis (RA) synovial tissue, contribute to the regulation of the NURR subfamily. Markedly enhanced expression of NURR1 is observed in synovial tissue of patients with RA compared with normal subjects. Modulation by proinflammatory mediators in primary RA and normal synoviocytes shows that PGE2, IL-1β, and TNF-α markedly enhance NURR1 mRNA and protein levels in contrast to other subfamily members, NUR77 and NOR-1. We have established that transcriptional activation of the NURR1 gene by IL-1β and TNF-α requires a proximal promoter region that contains a consensus NF-κB DNA-binding motif. IL-1β- and TNF-α-induced NF-κB binding to this site is due predominantly to p65-p50 heterodimer and p50 homodimer subunit protein complexes. We further demonstrate a direct CREB-1-dependent regulation by PGE2 situated at promoter region −171/−163. Moreover, analyses confirm the presence of CREB-1 and NF-κB p50 and p65 subunit binding to the NURR1 promoter under basal conditions in freshly explanted RA synovial tissue. In summary, enhanced NF-κB- and CREB-1-binding activity on the NURR1 promoter by inflammatory mediators delineates novel mechanisms in the regulation of NURR1 transcription. PGE2-, TNF-α-, and IL-1β-dependent stimulation of the NURR1 gene implies that NURR1 induction represents a point of convergence of at least two distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.168.6.2979

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2002

detail.hit.zdb_id: 1475085-5

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