Computational Biology Approach for Deciphering Etiological Pathway of Polygenic Diseases: Rheumatoid Arthritis

Rheumatoid Arthritis (RA) (OMIM ID: 180300) is an inflammatory autoimmune disease caused by immune reaction against the proliferating synovial fibroblasts. Nonsuppurative proliferation of synoviocytes frequently progresses to destroy the articular cartilages and underlying bone, resulting in permanent disability. Using system biology approach, candidate genes obtained from OMIM (Online Mendelian Inheritance in Man) and its interacting proteins were prioritized on the basis of three Gene Ontology terms (Molecular Function, Cellular component, and Biological Process) employing FunSimMat (Functional Similarity Matrix). Among the many, four prioritized proteins NFκBIL1, HCST, MICA, and MICB were selected. Amongst the prioritized genes, literature review suggested that NFκBIL-1 (Nuclear Factor-κ of B-cell Inhibitor Like protein-1) (UniProtKB ID: Q9UBC1) competes against SR (Ser-Arg) protein, ASF/SF2, in negatively regulating CD45RO gene expression in CD4 T-cells, whose overproduction would lead to cytokine outburst, thus leading to an immunological attack. ASF/SF2 mediated splicing variant, CD45RA, otherwise would have prevented overproduction of these cytokines. Overproduced cytokines such as TNF-α, IL-6, IL-15 simultaneously induces inflammatory stress in the synovial membrane and activates stress induced MICA/B (UniProtKB ID: Q29983/Q29980) through downstream signaling following TNFR1-TRAF mediated signaling pathway. Synovial expression of MICA/B enables interaction with its ligand NKG2D associated with DAP10 (UniProt KB ID: Q9UBK5) amply present on CD8+ αβ T-cells, CD4+γδ T-cells, and NK cells, thus promoting cytolysis of MICA/B expressing synoviocytes along with further production of cytokines TNF-α and IL-15. Hence, alteration in NFκBIL-1 promoter induces MICA/B expression that leads in production of cytokines could be a probable cause of chronic RA. Int. J. Appl. Sci. Biotechnol. Vol 6(4): 332--338

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CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽

10.1182/blood-2009-06-227256 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4422-4431 ◽

Cited By ~ 33

Author(s):

Georg Gruenbacher ◽

Hubert Gander ◽

Andrea Rahm ◽

Walter Nussbaumer ◽

Nikolaus Romani ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Human Blood ◽

Γδ T Cells ◽

Rapid Expansion ◽

Γδ T Cell ◽

Hla Dr ◽

Tnf Α ◽

Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

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Alterations in Gamma-Delta T Cells in Patients With Primary Biliary Cholangitis

10.21203/rs.3.rs-860724/v1 ◽

2021 ◽

Author(s):

Sha Chen ◽

Tingting Lv ◽

Guangyong Sun ◽

Shuxiang Li ◽

Weijia Duan ◽

...

Keyword(s):

T Cells ◽

Flow Cytometric Analysis ◽

Γδ T Cells ◽

Absolute Number ◽

Primary Biliary Cholangitis ◽

Gamma Delta ◽

Potential Marker ◽

Hla Dr ◽

Tnf Α ◽

Elevated Expression

Abstract Background & Aims Gamma-delta (γδ) T cells are involved in the development of diverse liver and autoimmune diseases, whereas the role of γδ T cells in primary biliary cholangitis (PBC) remains unclear. Methods We analyzed the number, phenotypes, and functional molecules of γδ T cells in PBC patients (n = 74) and sex- and age-matched healthy controls (HCs) (n = 74) by flow cytometric analysis. Results We identified two distinct functional subsets of circulating γδ T cells according to the CD3/TCRγδ complex: the TCRγδhigh and TCRγδlow subsets. Approximately three-quarters of cells in the TCRγδhigh subset were Vδ1 T cells, while Vδ2 T cells were enriched in the TCRγδlow subset in HCs. The frequency and absolute number of circulating TCRγδlow cells was significantly decreased in PBC patients compared with HCs (p < 0.001). Furthermore, the frequency of TCRγδlow cells was negatively correlated with disease severity and positively correlated with the ursodeoxycholic acid response. TCRγδlow cells exhibited a similar apoptotic and proliferative phenotype but enhanced liver-homing chemokine receptor (CXCR6) expression in PBC patients compared with HCs. In addition, both TCRγδhigh and TCRγδlow subsets were more activated in PBC compared with HCs, characterized by elevated expression levels of CD69 and HLA-DR. Finally, we found an increased granzyme B (GZMB) production and similar IFN-γ and TNF-α production of TCRγδlow cells in PBC patients compared with HCs. Conclusion The TCRγδlow subset might be a potential marker for disease progression and treatment response in PBC, which may play a crucial role in liver injury through increased CXCR6 expression and GZMB production.

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Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis

International Immunopharmacology ◽

10.1016/j.intimp.2018.05.028 ◽

2018 ◽

Vol 61 ◽

pp. 140-149 ◽

Cited By ~ 9

Author(s):

Dragana Odobasic ◽

Yuan Jia ◽

Wenping Kao ◽

Huapeng Fan ◽

Xuemin Wei ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Synovial Fibroblasts ◽

Receptor Activation ◽

Effector T Cells ◽

Formyl Peptide Receptor ◽

Joint Injury ◽

Peptide Receptor ◽

Formyl Peptide

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Serum Levels of Soluble TNF-α Receptor-II (P75), Circulating γδ T-Cells and Adamantiades-behçet’s Disease Activity

Advances in Experimental Medicine and Biology - Adamantiades-Behçet’s Disease ◽

10.1007/0-306-48382-3_52 ◽

2006 ◽

pp. 261-265 ◽

Cited By ~ 7

Author(s):

Antonia V. Elezoglou ◽

Peter P. Sfikakis ◽

George Vaiopoulos ◽

Violeta Kapsimali ◽

Phaedon G. Kaklamanis

Keyword(s):

T Cells ◽

Disease Activity ◽

Behçet’S Disease ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Γδ T Cells ◽

Serum Levels ◽

Behcet's Disease ◽

Tnf Α

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Melatonin attenuates TNF-α and IL-1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

Journal of Pineal Research ◽

10.1111/jpi.12560 ◽

2019 ◽

Vol 66 (3) ◽

pp. e12560 ◽

Cited By ~ 30

Author(s):

Chien-Chung Huang ◽

Chen-Hsiang Chiou ◽

Shan-Chi Liu ◽

Sung-Lin Hu ◽

Chen-Ming Su ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Fibroblasts ◽

Cartilage Degradation ◽

Tnf Α

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Heat shock of rabbit synovial fibroblasts increases expression of mRNAs for two metalloproteinases, collagenase and stromelysin.

The Journal of Cell Biology ◽

10.1083/jcb.108.6.2037 ◽

1989 ◽

Vol 108 (6) ◽

pp. 2037-2043 ◽

Cited By ~ 41

Author(s):

B A Vance ◽

C G Kowalski ◽

C E Brinckerhoff

Keyword(s):

Rheumatoid Arthritis ◽

Heat Shock ◽

Mrna Expression ◽

Synovial Fibroblasts ◽

Concomitant Treatment ◽

Hsp 70 ◽

Inflammatory Stress ◽

Monolayer Cultures ◽

All Trans Retinoic Acid ◽

Lower Temperature

Two metalloproteinases, collagenase and stromelysin, are produced in large quantities by synovial fibroblasts in individuals with rheumatoid arthritis. These enzymes play a major role in the extensive destruction of connective tissue seen in this disease. In this study, we show that heat shock of monolayer cultures of rabbit synovial fibroblasts increases expression of mRNA for heat shock protein 70 (HSP-70), and for collagenase and stromelysin. We found that after heat shock for 1 h at 45 degrees C, the mRNA expression for HSP-70 peaks at 1 h and returns to control levels by 3 h. Collagenase and stromelysin mRNA expression is coordinate, reaching peak levels at 3 h and returning to control levels by 10 h. The increase in mRNA is paralleled by an increase in the corresponding protein in the culture medium. 3 h of heat shock at a lower temperature (42 degrees C) is also effective in inducing collagenase and stromelysin mRNAs. Concomitant treatment with phorbol myristate acetate (PMA; 10(-8) or 10(-9) M) and heat shock is not additive or synergistic. In addition, all-trans-retinoic acid, added just before heat shock, prevents the increase in mRNAs for collagenase and stromelysin. Our data suggest that heat shock may be an additional mechanism whereby collagenase and stromelysin are increased during rheumatoid arthritis and perhaps in other chronic inflammatory stress conditions.

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Characterization of γδ T Cells in Intestinal Mucosa From Patients With Early-Onset or Long-Standing Inflammatory Bowel Disease and Their Correlation With Clinical Status

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz015 ◽

2019 ◽

Vol 13 (7) ◽

pp. 873-883 ◽

Cited By ~ 5

Author(s):

Elena Lo Presti ◽

Roberto Di Mitri ◽

Filippo Mocciaro ◽

Anna Barbara Di Stefano ◽

Nunzia Scibetta ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Intestinal Mucosa ◽

Bowel Disease ◽

Early Onset ◽

Γδ T Cells ◽

Healthy Tissue ◽

Effector Memory ◽

Tnf Α ◽

Inflammatory Bowel

Abstract Background and Aims Inflammatory bowel disease [IBD] is a complex chronic inflammatory disease of the human gut with no clear aetiology. Traditionally, dysregulated adaptive immune responses play an important role even though accumulating evidence suggests a role also for innate immunity. Because of the well-known plasticity of γδ T cells, we investigated their percentage occurrence, phenotypic features and effector functions in the intestinal mucosa of early-onset and long-standing IBD patients, as compared to healthy subjects. Methods Fresh biopsies from 30 Crohn’s disease and ulcerative colitis patients were obtained and digested, and cells were analysed by flow cytometry. Results We found a reduced frequency of Vδ1 T cells in tissue from early and late IBD patients (2.24% and 1.95%, respectively, vs 5.44% in healthy tissue) but an increased frequency of Vδ2 T cells in the gut of late IBD patients (3.19% in late patients vs 1.5% in early patients and 1.65% in healthy tissue). The infiltrating Vδ2 T cells had predominant effector memory and terminally differentiated phenotypes and produced elevated levels of tumour necrosis factor-α [TNF-α] and interleukin-17 [IL-17]. The frequency of tissue Vδ2 T cells correlated with the extent of the inflammatory response and the severity of IBD. Conclusion Our study shows that tissue Vδ1 T cells are decreased in IBD patients while Vδ2 T cells are increased in the gut of IBD patients and contribute to TNF-α production. Moreover, we identify an as yet unappreciated role of Vδ2 T cells in IL-17 production in the gut of long-standing IBD patients, suggesting that they also participate in the chronic inflammatory process.

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γδ T cells provide the early source of IFN-γ to aggravate lesions in spinal cord injury

Journal of Experimental Medicine ◽

10.1084/jem.20170686 ◽

2017 ◽

Vol 215 (2) ◽

pp. 521-535 ◽

Cited By ~ 27

Author(s):

Guodong Sun ◽

Shuxian Yang ◽

Guangchao Cao ◽

Qianghua Wang ◽

Jianlei Hao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

T Cells ◽

Functional Recovery ◽

Γδ T Cells ◽

Small Subset ◽

Cell Functions ◽

Tnf Α ◽

Cord Injury ◽

Ifn Γ

Immune responses and neuroinflammation are critically involved in spinal cord injury (SCI). γδ T cells, a small subset of T cells, regulate the inflammation process in many diseases, yet their function in SCI is still poorly understood. In this paper, we demonstrate that mice deficient in γδ T cells (TCRδ−/−) showed improved functional recovery after SCI. γδ T cells are detected at the lesion sites within 24 hours after injury and are predominantly of the Vγ4 subtype and express the inflammatory cytokine IFN-γ. Inactivating IFN-γ signaling in macrophages results in a significantly reduced production of proinflammatory cytokines in the cerebrospinal fluid (CSF) of mice with SCIs and improves functional recovery. Furthermore, treatment of SCI with anti-Vγ4 antibodies has a beneficial effect, similar to that obtained with anti–TNF-α. In SCI patients, γδ T cells are detected in the CSF, and most of them are IFN-γ positive. In conclusion, manipulation of γδ T cell functions may be a potential approach for future SCI treatment.

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