Cartilage-binding antibodies initiate joint inflammation and promote chronic erosive arthritis

Li, Yanpeng; Tong, Dongmei; Liang, Peibin; Lönnblom, Erik; Viljanen, Johan; Xu, Bingze; Nandakumar, Kutty Selva; Holmdahl, Rikard

doi:10.1186/s13075-020-02169-0

Cited by 20 publications

(16 citation statements)

References 42 publications

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“…In the future, a chronic arthritis mouse model, which is established by injecting cocktail of cartilage-specific antibodies and appropriate adjuvant (e.g. lipopolysaccharide or mannan) ( 41 ), will be used to investigate whether any potential adverse effects happened and further evaluate the therapeutic safety of long-term systemic FGL1 treatment.…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

Lin

et al. 2021

Front. Immunol.

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Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1β and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo. We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.

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Section: Discussionmentioning

confidence: 99%

Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

Lin

et al. 2021

Front. Immunol.

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“…The scoring started from day 8 and was recorded every day. Collagen antibody-induced arthritis (CAIA): pathogenic anti-COL2 antibodies (M2139, ACC1, 15A, L10D9) were produced by corresponding hybridomas and then purified based on affinity chromatography [ 24 ]. After purification, antibodies were dialyzed in PBS and then concentrated to 10 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Two major genes associated with autoimmune arthritis, Ncf1 and Fcgr2b, additively protect mice by strengthening T cell tolerance

Zhong

Luo

et al. 2022

Cell. Mol. Life Sci.

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A breach of T cell tolerance is considered as a major step in the pathogenesis of rheumatoid arthritis. In collagen-induced arthritis (CIA) model, immunization with type II collagen (COL2) leads to arthritis in mice through T cells responding to the immunodominant COL2259–273 peptide. T cells could escape from thymus negative selection because endogenous COL2259–273 peptide only weakly binds to the major histocompatibility complex class II (MHCII) molecule Aq. To investigate the regulation of T cell tolerance, we used a new mouse strain BQ.Col2266E with homozygous D266E mutations in the Col2 gene leading to a replacement of the endogenous aspartic acid (D) to glutamic acid (E) at position 266 of the COL2259–273 peptide, resulting in stronger binding to Aq. We also established BQ.Col2264R mice carrying an additional K264R mutation changed the lysine (K) at position 264 to eliminate the major TCR recognition site. The BQ.Col2266E mice were fully resistant to CIA, while the BQ.Col2264R mice developed severe arthritis. Furthermore, we studied two of the most important non-MHCII genes associated with CIA, i.e., Ncf1 and Fcgr2b. Deficiency of either gene induced arthritis in BQ.Col2266E mice, and the downstream effects differ as Ncf1 deficiency reduced Tregs and was likely to decrease expression of autoimmune regulator (AIRE) while Fcgr2b did not. In conclusion, the new human-mimicking mouse model has strong T cell tolerance to COL2, which can be broken by deficiency of Fcgr2b or Ncf1, allowing activation of autoreactive T cells and development of arthritis.

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“…Collagen-induced arthritis (CIA) represents the best data package to meet Koch's postulates that also contains a crystal structure of a monoclonal autoantibody bound to its target B-cell epitope. CIA mAbs elicit arthritis in genetically engineered mice (12), and the structure of an mAb bound to the C1 epitope of type II collagen has been resolved (9). However, reversal of mAb-elicited arthritis by the exact peptide epitope seen in the crystal structure, infused or injected as a decoy, has not been reported.…”

Section: D Structures Of Auto-antigen/ Aab Complexesmentioning

confidence: 99%

Autoantibody:Autoantigen Competitor Decoys: Application to Cardiac Phenotypes

Cardozo

Boutjdir

2022

Front. Immunol.

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Autoimmune diseases are often associated with autoantibodies that abnormally target self-antigens (autoantigens). An intuitive therapeutic strategy for diseases caused by aAbs is to design decoys, or soluble molecules that target the antigen combining site of these aAbs, thereby blocking binding of aAb to self-antigen and subsequent tissue damage. Here, we review the known decoy molecules of these types, discuss newer technological opportunities afforded by monoclonal antibody and structural biology advances, and discuss the challenges to this approach. Recent opportunities relevant to this approach for cardiac phenotypes, specifically Ro-associated long QT syndrome, are discussed.

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Cartilage-binding antibodies initiate joint inflammation and promote chronic erosive arthritis

Cited by 20 publications

References 42 publications

Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

Two major genes associated with autoimmune arthritis, Ncf1 and Fcgr2b, additively protect mice by strengthening T cell tolerance

Autoantibody:Autoantigen Competitor Decoys: Application to Cardiac Phenotypes

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