scholarly journals A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis

2009 ◽  
Vol 106 (37) ◽  
pp. 15867-15872 ◽  
Author(s):  
Paul A. Monach ◽  
Wolfgang Hueber ◽  
Benedikt Kessler ◽  
Beren H. Tomooka ◽  
Maya BenBarak ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Immune Complexes ◽  
Protein Microarrays ◽  
Normal Serum ◽  
Intracellular Protein ◽  
Cartilage Surface ◽  
Diversity Of Components ◽  
Arthritic Joints ◽  
Proteins And Peptides

Deposits of Ig and complement are abundant in affected joints of patients with rheumatoid arthritis (RA) and in animal models of RA in which antibodies are demonstrably pathogenic. To identify molecular targets of the Igs deposited in arthritic joints, which may activate local inflammation, we used a combination of mass spectrometry (MS) and protein microarrays. Immune complexes were affinity-purified from surgically removed joint tissues of 26 RA and osteoarthritis (OA) patients. Proteins complexed with IgG were identified by proteomic analysis using tandem MS. A striking diversity of components of the extracellular matrix, and some intracellular components, copurified specifically with IgG from RA and OA tissues. A smaller set of autoantigens was observed only in RA eluates. In complementary experiments, IgG fractions purified from joint immune complexes were tested on protein microarrays against a range of candidate autoantigens. These Igs bound a diverse subset of proteins and peptides from synovium and cartilage, different from that bound by normal serum Ig. One type of intracellular protein detected specifically in RA joints (histones H2A/B) was validated by immunohistology and found to be deposited on the cartilage surface of RA but not OA joints. Thus, autoantibodies to many determinants (whether deposited as “neoantigens” or normal constituents of the extracellular matrix) have the potential to contribute to arthritic inflammation.

scholarly journals Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-α antibody in a murine model of rheumatoid arthritis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Kiyomitsu Katsumata ◽  
Jun Ishihara ◽  
Kazuto Fukunaga ◽  
Ako Ishihara ◽  
Eiji Yuba ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Injection Site ◽  
Therapeutic Efficacy ◽  
Local Administration ◽  
Systemic Injection ◽  
Binding Peptide ◽  
Ecm Proteins ◽  
Peptide Conjugation ◽  
Arthritic Joints

Abstract Background Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model. Methods α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated α-TNF (PlGF-2123-144-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse. Results PlGF-2123-144 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose. Conclusion These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

scholarly journals Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 35
Author(s):  
Sahar Aghakhani ◽  
Naouel Zerrouk ◽  
Anna Niarakis
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Systems Biology ◽  
Healing Process ◽  
Metabolic Reprogramming ◽  
Critical Event ◽  
Wound Healing Process ◽  
Computational Systems Biology ◽  
Structural Framework ◽  
Computational Systems

Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

Expression of extracellular matrix components and cytokine receptors in human fibrocytes during rheumatoid arthritis

2021 ◽  
pp. 1-12
Author(s):  
Dorra Elhaj Mahmoud ◽  
Wajih Kaabachi ◽  
Nadia Sassi ◽  
Amel Mokhtar ◽  
Lobna Ben Ammar ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Cytokine Receptors ◽  
Extracellular Matrix Components ◽  
Matrix Components

THU0024 Human Mast Cells Stimulated with IL-33 and Immune Complexes Down-Regulate Monocyte Activation in Rheumatoid Arthritis

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 201.2-201
Author(s):  
F. Rivellese ◽  
J. Suurmond ◽  
K. Habets ◽  
A.L. Dorjée ◽  
A. de Paulis ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mast Cells ◽  
Immune Complexes ◽  
Monocyte Activation ◽  
Human Mast Cells

scholarly journals COMPARISON of five assays for immune complexes in the RHEUMATIC DISEASES. An Assessment of Their Validity for Rheumatoid Arthritis

1982 ◽  
Vol 25 (10) ◽  
pp. 1156-1166 ◽  
Author(s):  
J. Steven McDougal ◽  
Marjorie Hubbard ◽  
Frederic C. Mcduffie ◽  
Phyllis L. Strobel ◽  
S. Jay Smith ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatic Diseases ◽  
Immune Complexes

THU0445 High ultrasonographic scores persist among patients with rheumatoid arthritis in clinical remission with normal serum MMP-3 values

2013 ◽  
Vol 71 (Suppl 3) ◽  
pp. 305.3-306
Author(s):  
T. Okano ◽  
T. Koike ◽  
M. Tada ◽  
Y. Sugioka ◽  
K. Mamoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Remission ◽  
Normal Serum

scholarly journals Characterisation of the size and composition of circulating immune complexes in patients with rheumatoid arthritis.

1991 ◽  
Vol 50 (4) ◽  
pp. 231-236 ◽  
Author(s):  
R A Mageed ◽  
J R Kirwan ◽  
P W Thompson ◽  
D A McCarthy ◽  
E J Holborow
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Complexes ◽  
Circulating Immune Complexes
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