• CIDP
• diagnostic criteria
• immunology
• pathophysiology
• treatment

• Cell therapy
• Osteoarthritis
• SynNotch
• Synthetic biology

• Cartilage, Articular/physiology
• Cartilage, Articular/metabolism
• Animals
• Mesenchymal Stem Cells/metabolism
• Regenerative Medicine/methods
• Chondrocytes/metabolism
• Osteoarthritis/therapy
• Mice
• Collagen Type II
• Receptors, Notch
• Coculture Techniques
• Cells, Cultured
• Humans

• I01 BX005195 BLRD VA
• P30 CA068485 NCI NIH HHS
• P30 DK058404 NIDDK NIH HHS
• R21 AR079683 NIAMS NIH HHS

• Collagen-induced arthritis
• Humoral immunity
• IgG
• Schistosoma mansoni
• Trichinella spiralis

• Animals
• Trichinella spiralis/immunology
• Male
• Mice
• Immunoglobulin G/blood
• Arthritis, Experimental/immunology
• Schistosomiasis mansoni/immunology
• Trichinellosis/immunology
• Mice, Inbred DBA
• Immunity, Humoral
• Schistosoma mansoni/immunology
• Collagen Type II/immunology
• Antibodies, Helminth/blood

• 3Rs
• Rheumatoid arthritis
• TNF
• clinical score
• murine models of arthritis

• 19859 Versus Arthritis
• 20843 Versus Arthritis
• MR/P021220/1 Medical Research Council
• NC/S001646/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research

• Neurology
• autoimmune disease
• chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
• intravenous immunoglobulin

The angiotensin AT₂ receptor (AT₂R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT₂R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT₂R-stimulation with the selective non-peptide AT₂R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4⁺FoxP3⁺ cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4⁺IL-17A⁺ and CD4⁺IFN-gamma⁺ T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT₂R-stimulation promotes the expansion of CD4⁺ regulatory T cells and suppresses IL-17A production. Thus, AT₂R-stimulation may represent an attractive treatment strategy for arthritis.

• Animals
• Arthritis, Experimental/chemically induced
• Arthritis, Experimental/drug therapy
• Forkhead Transcription Factors/metabolism
• Imidazoles
• Interleukin-17/metabolism
• Mice
• Mice, Inbred DBA
• RNA, Messenger/metabolism
• Receptor, Angiotensin, Type 2/metabolism
• Sulfonamides
• T-Lymphocytes, Regulatory/immunology
• Thiophenes
• Up-Regulation

• Deutsche Forschungsgemeinschaft

Bone erosion is one of the primary features of inflammatory arthritis and is caused by excessive differentiation and activation of osteoclasts. Fc gamma receptors (FcγRs) have been implicated in osteoclastogenesis. Our recent studies demonstrate that joint-deposited lupus IgG inhibited RANKL-induced osteoclastogenesis. FcγRI is required for RANKL-induced osteoclastogenesis and lupus IgG-induced signaling transduction. We reviewed the results of studies that analyzed the association between FcγRs and bone erosion in inflammatory arthritis. The analysis revealed the dual roles of FcγRs in bone destruction in inflammatory arthritis. Thus, IgG/FcγR signaling molecules may serve as potential therapeutic targets against bone erosion.

• FcγRs
• autoantibodies
• bone erosion
• inflammatory arthritis
• osteoclasts

• Cia9 locus
• Fc gamma receptor
• FcγR2b
• FcγR3
• collagen-induced arthritis

• Alleles
• Animals
• Arthritis, Experimental/genetics
• Autoimmune Diseases/genetics
• Cell Line, Tumor
• Cells, Cultured
• Disease Models, Animal
• Genetic Predisposition to Disease/genetics
• Haplotypes/genetics
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• Polymorphism, Genetic/genetics
• Receptors, IgG/genetics

• 24721 Cancer Research UK

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1β-stimulated primary human FLS, as well as IL-1β–induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro. Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody–induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)-specific antibody levels were similarly reduced in TRYP- and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-κB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.

• arthritis
• c-Jun N-terminal kinase
• collagen antibody-induced arthritis
• collagen-induced arthritis
• inflammation
• kinase inhibitor
• tryptanthrin
• tryptanthrin-6-oxime

• DAMPs
• FcγRs
• S100A8/A9
• alarmins
• autoantibodies
• bone erosion
• immune complexes
• osteoclasts
• osteoimmunology
• rheumatoid arthritis

• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/metabolism
• Autoimmune Diseases/pathology
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Hypersensitivity/drug therapy
• Hypersensitivity/metabolism
• Hypersensitivity/pathology
• Indazoles/pharmacology
• Indazoles/therapeutic use
• Male
• Mice
• Phosphorylation/drug effects
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Rats
• Receptors, Fc/metabolism
• Signal Transduction/drug effects
• Syk Kinase/antagonists & inhibitors

Pro- and anti-inflammatory effector functions of IgG antibodies (Abs) depend on their subclass and Fc glycosylation pattern. Accumulation of non-galactosylated (agalactosylated; G0) IgG Abs in the serum of rheumatoid arthritis and systemic lupus erythematosus (SLE) patients reflects severity of the diseases. In contrast, sialylated IgG Abs are responsible for anti-inflammatory effects of the intravenous immunoglobulin (pooled human serum IgG from healthy donors), administered in high doses (2 g/kg) to treat autoimmune patients. However, whether low amounts of sialylated autoantigen-reactive IgG Abs can also inhibit autoimmune diseases is hardly investigated. Here, we explore whether sialylated autoantigen-reactive IgG Abs can inhibit autoimmune pathology in different mouse models. We found that sialylated IgG auto-Abs fail to induce inflammation and lupus nephritis in a B cell receptor (BCR) transgenic lupus model, but instead are associated with lower frequencies of pathogenic Th1, Th17 and B cell responses. In accordance, the transfer of small amounts of immune complexes containing sialylated IgG Abs was sufficient to attenuate the development of nephritis. We further showed that administration of sialylated collagen type II (Col II)-specific IgG Abs attenuated the disease symptoms in a model of Col II-induced arthritis and reduced pathogenic Th17 cell and autoantigen-specific IgG Ab responses. We conclude that sialylated autoantigen-specific IgG Abs may represent a promising tool for treating pathogenic T and B cell immune responses in autoimmune diseases.

• IgG glycosylation
• ST6gal1
• Th17
• autoimmunity
• immunosuppression
• rheumatoid arthritis
• sialylation
• systemic lupus erythematosus

Osteoclast-mediated bone erosion is a central feature of rheumatoid arthritis (RA). Immune complexes, present in a large percentage of patients, bind to Fcγ receptors (FcγRs), thereby modulating the activity of immune cells. In this study, we investigated the contribution of FcγRs, and FcγRIV in particular, during antigen-induced arthritis (AIA).

AIA was induced in knee joints of wild-type (WT), FcγRI,II,III^−/−, and FcγRI,II,III,IV^−/− mice. Bone destruction, numbers of tartrate-resistant acid phosphatase-positive (TRAP⁺) osteoclasts, and inflammation were evaluated using histology; expression of the macrophage marker F4/80, neutrophil marker NIMPR14, and alarmin S100A8 was evaluated using immunohistochemistry. The percentage of osteoclast precursors in the bone marrow was determined using flow cytometry. In vitro osteoclastogenesis was evaluated with TRAP staining, and gene expression was assessed using real-time PCR.

FcγRI,II,III,IV^−/− mice showed decreased bone erosion compared with WT mice during AIA, whereas both the humoral and cellular immune responses against methylated bovine serum albumin were not impaired in FcγRI,II,III,IV^−/− mice. The percentage of osteoclast precursors in the bone marrow of arthritic mice and their ability to differentiate into osteoclasts in vitro were comparable between FcγRI,II,III,IV^−/− and WT mice. In line with these observations, numbers of TRAP⁺ osteoclasts on the bone surface during AIA were comparable between the two groups. Inflammation, a process that strongly activates osteoclast activity, was reduced in FcγRI,II,III,IV^−/− mice, and of note, mainly decreased numbers of neutrophils were present in the joint. In contrast to FcγRI,II,III,IV^−/− mice, AIA induction in knee joints of FcγRI,II,III^−/− mice resulted in increased bone erosion, inflammation, and numbers of neutrophils, suggesting a crucial role for FcγRIV in the joint pathology by the recruitment of neutrophils. Finally, significant correlations were found between bone erosion and the number of neutrophils present in the joint as well as between bone erosion and the number of S100A8-positive cells, with S100A8 being an alarmin strongly produced by neutrophils that stimulates osteoclast resorbing activity.

FcγRs play a crucial role in the development of bone erosion during AIA by inducing inflammation. In particular, FcγRIV mediates bone erosion in AIA by inducing the influx of S100A8/A9-producing neutrophils into the arthritic joint.

The online version of this article (10.1186/s13075-018-1584-1) contains supplementary material, which is available to authorized users.

• Bone erosion
• Experimental arthritis
• FcγRs
• Immune complexes
• Neutrophils
• Osteoclast
• S100A8

• antibodies
• collagen
• disease pathways
• experimental arthritis
• glycosylation
• rheumatoid arthritis
• therapy

• Animals
• Anti-Citrullinated Protein Antibodies/immunology
• Antibody Specificity/immunology
• Antigen-Antibody Complex/immunology
• Antirheumatic Agents/pharmacology
• Antirheumatic Agents/therapeutic use
• Arthritis/complications
• Arthritis/drug therapy
• Arthritis/etiology
• Arthritis/metabolism
• Autoantibodies/immunology
• Autoantigens/immunology
• Cartilage Oligomeric Matrix Protein/immunology
• Collagen Type II/immunology
• Epitopes/immunology
• Epitopes/metabolism
• Glucose-6-Phosphate Isomerase/immunology
• Glycosylation
• Humans
• Immunoglobulin G/immunology
• Molecular Targeted Therapy
• Pain/etiology
• Signal Transduction/drug effects

• Lactobacillus helveticus SBT2171
• autoantibody production
• collagen-induced arthritis
• pro-inflammatory cytokines
• rheumatoid arthritis

• Anti-glomerular basement membrane
• Autoimmunity
• Basement membrane

The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors or reside on cell surfaces. Complement components have many biologic functions and their activation can eventually damage the plasma membranes of cells and some bacteria. Although a direct link between complement activation and autoimmune diseases has not been found, there is increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases that may have autoimmune linkage. The inhibition of complement may therefore be very important in a variety of autoimmune diseases since their activation may be detrimental to the individual involved. However, a complete and long-term inhibition of complement may have some contra side effects such as increased susceptibility to infection. The site of complement activation will, however, determine the type of inhibitor to be used, its route of application and dosage level. Compared with conventional drugs, complement inhibitors may be the best option for treatment of autoimmune diseases. The review takes a critical look at the relative merits of therapies being developed to tackle inappropriate complement activation that are likely to result in sporadic autoimmune diseases or worsen already existing one. It covers the complement system, general aspects of complement inhibition therapy, therapeutic strategies and examples of complement inhibitors. It concludes by highlighting on the possibility that a better inhibitor of complement activation when found will help provide a formidable treatment for autoimmune diseases as well as preventing one.

• Activation
• Autoimmune diseases
• Complement
• Inhibitors
• Therapy

To evaluate the ability of the glycolytic enzyme alpha-enolase (ENO1) or its immunodominant peptide (pEP1) to reduce the severity of CIA in DBA/1 mice when injected in a prophylactic way.

Mice were treated with mouse ENO1 or pEP1 one day prior to collagen II immunization. Clinical assessment was evaluated using 4 parameters (global and articular scores, ankle thickness and weight). Titers of serum anti-ENO1, anti-cyclic citrullinated peptides (anti-CCP) and anti-CII (total IgG and IgG1/IgG2a isotypes) antibodies were measured by ELISA at different time-points. Disease activity was assessed by histological analysis of both anterior and hind paws at the end of experimentation.

Prophylactic injection of 100 μg of ENO1 reduced severity of CIA. Serum levels of anti-CII antibodies were reduced in ENO1-treated mice. Concordantly, ENO1-treated mice joints presented less severe histological signs of arthritis. ENO1 did not induce a shift toward a Th2 response since IgG1/IgG2a ratio of anti-CII antibodies remained unchanged and IL-4 serum levels were similar to those measured in the control group.

Pre-immunization with ENO1 or its immunodominant peptide pEP1 reduces CIA severity at the clinical, immunological and histological levels. Effects of pEP1 were less pronounced. This immunomodulatory effect is associated with a reduction in anti-CII antibodies production but is not due to a Th1/Th2 shift.

• Animals
• Arthritis, Experimental/blood
• Arthritis, Experimental/immunology
• Arthritis, Experimental/therapy
• Autoantibodies/administration & dosage
• Autoantibodies/blood
• Disease Models, Animal
• Humans
• Immunodominant Epitopes/blood
• Immunoglobulin G/blood
• Joints/drug effects
• Joints/pathology
• Mice
• Peptides/administration & dosage
• Peptides, Cyclic/blood
• Phosphopyruvate Hydratase/administration & dosage
• Phosphopyruvate Hydratase/blood
• Phosphopyruvate Hydratase/immunology

Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) derived from adipose tissue. MSCs have multiple properties including anti-inflammatory and immunomodulatory effects in various disease models and human diseases. However, the mechanisms underlying this wide range of effects need to be explored.

Collagen antibody-induced arthritis (CAIA) is a unique model in which arthritis is rapidly and strongly induced. ASCs were intraperitoneally infused into CAIA mice before or after arthritis induction. The serum levels of various cytokines, adipokines, and chemokines were measured. The expression of FC gamma receptors (FCGRs) was investigated in peritoneal macrophages ex vivo. RAW264.7 cells and ASCs were co-cultured to elucidate the direct and indirect role of ASCs on FCGR expression.

ASCs attenuated arthritis in CAIA mice. Serum levels of tumor necrosis factor α, interleukin (IL)-15, resistin, and leptin were reduced in ASC-treated CAIA mice, whereas serum levels of IL-6 and adiponectin were not affected. In peritoneal macrophages isolated from ASC-treated mice, expression of FCGRIIB, which is immunoinhibitory, was higher than that of FCGRI. Co-culture of ASCs with RAW264.7 cells modulated the expression of FCGRs. The expression patterns and timings of peak expression differed among FCGRs. Expression of FCGRIIB was higher and peaked earlier than that of FCGRI. FCGRIII expression was not affected by this co-culture.

This is a study to show that ASCs have anti-arthritic effects in CAIA mice. Modulation of FCGRs by ASCs might be a therapeutic mechanism in this antibody-associated arthritis model.

• Animals
• Antibodies/analysis
• Arthritis, Experimental/drug therapy
• Arthritis, Experimental/immunology
• Arthritis, Experimental/pathology
• Binding Sites/drug effects
• Cytokines/metabolism
• Dose-Response Relationship, Drug
• JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors
• Joints/pathology
• Male
• Matrix Metalloproteinases/biosynthesis
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Oximes/pharmacology
• Oximes/therapeutic use
• Protein Kinase Inhibitors/therapeutic use
• Quinoxalines/pharmacology
• Quinoxalines/therapeutic use
• Synovial Fluid/cytology
• Synovial Fluid/metabolism
• T-Lymphocytes, Regulatory/drug effects

• P30 GM110732 NIGMS NIH HHS
• R01 AR047825 NIAMS NIH HHS
• P30-GM110732 NIGMS NIH HHS
• R01-AR47825 NIAMS NIH HHS

• Arthritis
• Autoimmunity
• T cells

In rodent models of inflammatory arthritis, bone erosion has been non-invasively assessed by micro-computed tomography (micro-CT). However, non-invasive assessments of paw swelling (oedema) are still based on clinical grading by visual evaluation, or measurements by callipers, not always reliable for the tiny mouse paws. The aim of this work was to demonstrate a novel straightforward 3D micro-CT analysis protocol capable of quantifying not only joint bone erosion, but also soft tissue swelling, from the same scans, in a rodent inflammatory arthritis model. Balb/c mice were divided into two groups: collagen antibody-induced arthritis (CAIA) and CAIA treated with prednisolone, the latter reflecting an established treatment in human rheumatoid arthritis. Clinical paw scores were recorded. On day 10, front paws were assessed by micro-CT and histology. Micro-CT measurements included paw volume (bone and soft tissue together) and bone volume at the radiocarpal joint, and bone volume from the radiocarpal to the metacarpophalangeal joint. Micro-CT analysis revealed significantly lower paw volume (−36%, P < 0.01) and higher bone volume (+17%, P < 0.05) in prednisolone-treated CAIA mice compared with untreated CAIA mice. Paw volume and bone volume assessed by micro-CT correlated significantly with clinical and histological scores (|r| > 0.5, P < 0.01). Untreated CAIA mice showed significantly higher clinical scores, higher inflammation levels histologically, cartilage and bone degradation, and pannus formation, compared with treated mice (P < 0.01). The presented novel micro-CT analysis protocol enables 3D-quantification of paw swelling at the micrometre level, along with the typically assessed bone erosion, using the same images/scans, without altering the scanning procedure or using contrast agents.

• Cannabinoid receptor 2
• Collagen-induced arthritis
• Rheumatoid arthritis

• Autoimmunity
• B cell
• Complex regional pain syndrome
• Fracture
• Pain

• Animals
• Arthritis, Experimental/complications
• Arthritis, Experimental/diagnostic imaging
• Bacterial Proteins/genetics
• Bacterial Proteins/physiology
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Hydrolases/genetics
• Hydrolases/physiology
• Mice
• Mice, Inbred BALB C
• Periodontitis/complications
• Periodontitis/diagnostic imaging
• Periodontitis/etiology
• Porphyromonas gingivalis/genetics
• Protein-Arginine Deiminases
• Radiography

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential.

• Fibroblasts
• Inflammation
• Spondyloarthritis

• Achilles Tendon/pathology
• Achilles Tendon/physiopathology
• Animals
• Arthritis, Experimental/complications
• Arthritis, Experimental/immunology
• Arthritis, Experimental/pathology
• Arthritis, Experimental/physiopathology
• B-Lymphocytes/immunology
• MAP Kinase Signaling System/physiology
• Magnetic Resonance Imaging
• Mechanotransduction, Cellular/physiology
• Mice
• Osteogenesis/physiology
• Sacroiliitis/etiology
• Sacroiliitis/pathology
• Spondylarthritis/complications
• Spondylarthritis/immunology
• Spondylarthritis/pathology
• Spondylarthritis/physiopathology
• Stress, Mechanical
• Stromal Cells/physiology
• T-Lymphocytes/immunology
• Tendinopathy/etiology
• Tendinopathy/immunology
• Tendinopathy/pathology
• Tendinopathy/physiopathology
• Tumor Necrosis Factor-alpha/immunology
• Weight-Bearing/physiology
• X-Ray Microtomography

• R21 AI094408 NIAID NIH HHS
• T32 HL007237 NHLBI NIH HHS
• U19 AI095230 NIAID NIH HHS

• animal models
• cell signaling
• t cell
• t cell biology
• t cell receptor

• Animals
• Arthritis, Experimental/immunology
• Arthritis, Experimental/pathology
• Arthritis, Experimental/therapy
• CD3 Complex/genetics
• Collagen Type II/immunology
• Collagen Type II/pharmacology
• GATA3 Transcription Factor/genetics
• GATA3 Transcription Factor/immunology
• Histocompatibility Antigens Class II/immunology
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/immunology
• Mice
• Mice, Knockout
• Peptides/immunology
• Peptides/pharmacology
• Protein-Tyrosine Kinases/genetics
• Protein-Tyrosine Kinases/immunology
• Receptors, Fc/genetics
• Receptors, Fc/immunology
• Syk Kinase
• T-Lymphocytes/immunology
• T-Lymphocytes/pathology
• ZAP-70 Protein-Tyrosine Kinase/genetics
• ZAP-70 Protein-Tyrosine Kinase/immunology

• AR-55266 NIAMS NIH HHS
• AR-55661 NIAMS NIH HHS
• R01 AR043589 NIAMS NIH HHS
• R01 AR055661 NIAMS NIH HHS
• R01 AR055266 NIAMS NIH HHS

Antibodies specific for bovine type II collagen (CII) and Fcγ receptors play a major role in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). Our aim was to clarify the mechanism of immune complex-mediated inflammation and modulation of the disease. CII pre-immunized DBA/1 mice were intravenously boosted with extravidin coupled biotinylated monomeric CII-peptide epitope (ARGLTGRPGDA) and its complexes with biotinylated FcγRII/III specific single chain Fv (scFv) fragment. Disease scores were monitored, antibody titers and cytokines were determined by ELISA, and binding of complexes was detected by flow cytometry and immune histochemistry. Cytokine and chemokine secretion was monitored by protein profiler microarray. When intravenously administered into collagen-primed DBA/1 mice, both CII-peptide and its complex with 2.4G2 scFv significantly accelerated CIA and increased the severity of the disease, whereas the monomeric peptide and monomeric 2.4G2 scFv had no effect. FcγRII/III targeted CII-peptide complexes bound to marginal zone macrophages and dendritic cells, and significantly elevated the synthesis of peptide-specific IgG2a. Furthermore, CII-peptide containing complexes augmented the in vivo secretion of cytokines, including IL-10, IL-12, IL-17, IL-23, and chemokines (CXCL13, MIP-1, MIP-2). These data indicate that complexes formed by the CII-peptide epitope aggravate CIA by inducing the secretion of chemokines and the IL-12/23 family of pro-inflammatory cytokines. Taken together, these results suggest that the in vivo emerging immune complexes formed with autoantigen(s) may trigger the IL-12/23 dependent pathways, escalating the inflammation in RA. Thus blockade of these cytokines may be beneficial to downregulate immune complex-induced inflammation in autoimmune arthritis.

• Fc gamma receptor
• collagen-induced arthritis
• immune complex
• inflammation
• targeting

• R01 DK026190 NIDDK NIH HHS

The collagen antibody-induced arthritis (CAIA) model, which employs a cocktail of monoclonal antibodies (mAbs) to type II collagen (CII), has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes induces arthritis, suggesting that a combination of mAbs showing strong ability to bind mouse CII and activate the complement may effectively induce arthritis in mice. In the present study, we examined the relationship between the induction of arthritis by the combination of IgG2a (CII-6 and C2A-12), IgG2b (CII-3, C2B-14 and C2B-16) and IgM (CM-5) subclones of monoclonal antibodies (mAb) of anti-bovine or chicken CII and the ability of mAbs to activate complement and bind mouse CII.

DBA/1J mice were injected with several combinations of mAbs followed by lipopolysaccharide. Furthermore, the ability of mAbs to activate the complement and bind mouse CII was examined by ELISA.

First, DBA/1J mice were injected with the combined 4 mAbs (CII-3, CII-6, C2B-14, and CM-5) followed by lipopolysaccharide, resulting in moderate arthritis. Excluding one of the mAbs, i.e., using only CII-3, CII-6, and C2B-14, induced greater inflammation of the joints. Next, adding C2A-12 but not C2B-16 to these 3 mAbs produced more severe arthritis. A combination of five clones, consisting of all 5 mAbs, was less effective. Histologically, mice given the newly developed 4-clone cocktail had marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone. Furthermore, 4 of the 6 clones (CII-3, CII-6, C2B-14, and C2A-12) showed not only a strong cross-reaction with mouse CII but also marked activation of the complement in vitro.

The combination of 4 mAbs showing strong abilities to activate the complement and bind mouse CII effectively induced arthritis in DBA/1J mice. This in vitro system may be useful for the selection of mAbs associated with the development of arthritis.