T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I

Hu, Paul Q.; Oppenheim, Joost J.; Medsger, Thomas A.; Wright, Timothy M.

doi:10.1016/j.jaut.2006.03.004

Cited by 23 publications

(13 citation statements)

References 30 publications

(55 reference statements)

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“…In vivo, cryptic epitopes from fragmented forms of Topo-I seem to be mainly responsible for initiating autoreactive T cell responses [83]. However, autoreactive T cells showing different peptide specificities were also found in the blood of healthy donors with matching HLA-DR alleles [82,84].…”

Section: Autoreactive T Cellsmentioning

confidence: 99%

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

Hoffmann

Trembleau

Muller

et al. 2010

Journal of Autoimmunity

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Section: Autoreactive T Cellsmentioning

confidence: 99%

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

Hoffmann

Trembleau

Muller

et al. 2010

Journal of Autoimmunity

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“…T-cell proliferative responses were quite low (< 2000 counts per minute), unless moderate amounts of IL-2 were added to the cultures. The phenotype (cellular markers and cytokines in the supernatant) of autoreactive T cells did not differ between SSc patients and healthy controls [52]. Using pools of overlapping peptides, 13 distinct T-cell epitopes were identified throughout the topo-1 molecule (aa 316-765), which did not correlate with any specific disease manifestation.…”

Section: Autoantigen-specific Cellular Immune Response In Sscmentioning

confidence: 86%

“…To date, very few studies have addressed the presence of topo-1-specific T cells in SSc patients [49][50][51][52]. Most of these studies had significant limitations.…”

Section: Autoantigen-specific Cellular Immune Response In Sscmentioning

confidence: 99%

“…The response to topo-1 fusion proteins or synthetic oligopeptides (selected through a prediction algorithm) was weak, characterized by a high background, and occurred also in a substantial number of anti-topo-1 negative subjects (patients and healthy controls) [49,51]. More recently, Hu et al [52] were able to generate 56 topo-1-specific T-cell lines deriving from PBMCs of both SSc patients and healthy controls. T-cell proliferative responses were quite low (< 2000 counts per minute), unless moderate amounts of IL-2 were added to the cultures.…”

Section: Autoantigen-specific Cellular Immune Response In Sscmentioning

confidence: 99%

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Autoimmunity in systemic sclerosis: Current concepts

Boin¹,

Rosen

2007

Curr Rheumatol Rep

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Systemic sclerosis (SSc) is characterized by tissue fibrosis, obliterative microangiopathy, and immune abnormalities. The role of autoimmunity in generating the clinical and pathologic phenotype in SSc remains uncertain. Distinct subsets of antinuclear antibodies are selectively associated with unique disease manifestations but do not have a proven pathogenic role. A new class of autoantibodies recognizing cellular or extracellular matrix antigens has been recognized in SSc patients. They seem to directly activate pathways that may contribute to SSc-specific tissue and vascular damage. Data confirms that activation and polarization of T cells can contribute to a profibrotic environment. Also, activated immune effector cells can promote vascular obliterative damage through direct cytotoxic pathways targeting the endothelium or by inducing proinflammatory molecules. Technologies are emerging to accurately measure the autoantigen-specific T-cell response in SSc patients. Perturbed B-cell homeostasis has been reported in SSc. If confirmed in-vivo, these advances could lead to new disease-modifying therapeutic strategies directed at SSc-specific immune effector pathways.

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“…TOP1-specific CD4+ T cells have been detected in the peripheral blood of patients with scleroderma (7)(8)(9)(10), are HLA-DR restricted, and their frequency is associated with the presence, severity, and progression of lung fibrosis (11). Previous attempts to define TOP1 epitopes in patients with scleroderma using overlapping peptide/protein fragment libraries or peptides derived from in silico prediction have resulted in the identification of scattered epitopes with unspecified biological and clinical significance (7)(8)(9)(10). Therefore, although ATAassociated HLA-DRB1 alleles have been defined and TOP-I-specific CD4+ T cells have been detected in ATA-positive patients, the identification of the TOP1 epitopes driving the autoimmune process has remained elusive.…”

Section: Introductionmentioning

confidence: 99%

Definition of naturally processed peptides reveals convergent presentation of autoantigenic topoisomerase-I epitopes in scleroderma

Tiniakou

Fava

Guhr

et al. 2019

Preprint

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One Sentence Summary: Use of a novel natural antigen processing assay reveals a mechanism for the presentation of shared CD4+ T cell epitopes of topoisomerase-I in immunogenetically diverse patients with scleroderma. Abstract:Disease-associated HLA-DRB1 alleles are thought to confer risk of developing autoimmunity by favoring the presentation of select autoantigenic epitopes. However, identification of these epitopes and the principles governing their presentation has been hindered by the imprecision of currently available methods, which cannot fully recapitulate the complexity of human pathophysiology. We present a natural antigen processing assay (NAPA), which overcomes these limitations by studying the presentation of autoantigenic CD4+ T cell epitopes by monocytederived dendritic cells (mo-DCs) from patients. We applied this strategy to study the processing and presentation of topoisomerase-1 (TOP1), a prevalent autoantigen in scleroderma that is associated with lung fibrosis and high mortality. We found that a common set of 10 epitopes was presented by mo-DCs from patients with diverse HLA-DR variants, including those not previously associated with the disease. Sequence analysis revealed a shared peptide-binding motif within the HLA-DR peptide binding grooves of patients who developed anti-TOP1 autoantibodies. In addition, a subset of naturally presented TOP1 peptides were characterized by immunological promiscuity, as they could bind to diverse HLA-DR peptide binding grooves. NAPA epitopes were immunorelevant: they could stimulate autoreactive CD4+ T cells in patients, and the number of epitopes recognized correlated with lung disease severity. These findings mechanistically implicate presentation of a convergent set of TOP1 epitopes in the development of scleroderma lung disease. Precise identification of autoantigenic epitopes is key to understanding the primordial mechanisms for the loss of tolerance, studying disease-propagating autoreactive T cells, and developing antigen-specific immunotherapy.

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T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I

Cited by 23 publications

References 30 publications

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

Autoimmunity in systemic sclerosis: Current concepts

Definition of naturally processed peptides reveals convergent presentation of autoantigenic topoisomerase-I epitopes in scleroderma

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