DNA Damage Response Signals Transduce Stress From Rheumatoid Arthritis Risk Factors Into T Cell Dysfunction

Shao, Lan

doi:10.3389/fimmu.2018.03055

Cited by 18 publications

(16 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cancer cells often exhibit dysregulations in DNA repair mechanisms. However, several studies also indicated enhanced DNA damage and DNA repair deficiencies in lymphocytes from RA patients [75][76][77][78]. In addition to studies investigating the role of different JAK inhibitors on DNA damage response pathways in primary cells from healthy donors or cancer cell lines, future trials also need to address the impact of JAKi on lymphocytes from patients with RA.…”

Section: Discussionmentioning

confidence: 99%

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Reddig

Voss

Guttek

et al. 2021

JCM

View full text Add to dashboard Cite

Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Reddig

Voss

Guttek

et al. 2021

JCM

View full text Add to dashboard Cite

show abstract

“…The deficiency of pATM we observe in CVID B cells does not result in the neurodegenerative phenotype found in ataxia telangiectasia, so this is a less severe dysfunction and may reflect immune cell-specific deficiency. Recent evidence has implicated DDR pathways in inflammation [ 10 , 59 ] and rheumatoid arthritis [ 60 – 63 ]. In rheumatoid arthritis T cells, reduced ATM was identified at baseline [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…In rheumatoid arthritis T cells, reduced ATM was identified at baseline [ 63 ]. ATM deficiency prevented T cell proliferation and promoted premature apoptosis [ 60 , 61 ]. A failure to induce pATM in the rheumatoid arthritis B cells 1 h post-irradiation was associated with skewed kappa light chain usage and an increased prevalence of CD21 lo B cells, a subset associated with CVID [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders

et al. 2021

View full text Add to dashboard Cite

Purpose Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients. Methods Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls. Results Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis. Conclusion These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

show abstract

“…The role of oxidative DNA damage and aberrations of the DDR/R network have been long studied in RA [137]. Initial studies reported overexpression and tissue-specific mutations of p53, a central molecule in DNA repair and regulator of apoptosis, in the synovium of patients with RA [138,139].…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

View full text Add to dashboard Cite

The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

show abstract

DNA Damage Response Signals Transduce Stress From Rheumatoid Arthritis Risk Factors Into T Cell Dysfunction

Cited by 18 publications

References 85 publications

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Contact Info

Product

Resources

About