New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins

doi:10.1016/j.jbspin.2015.10.003

Joint Bone Spine

Volume 83, Issue 1, January 2016, Pages 11-17

https://doi.org/10.1016/j.jbspin.2015.10.003 Get rights and content

Abstract

Citrullination, carbamylation and oxidation are posttranslational modifications of proteins that produce neoepitopes. Rheumatoid arthritis (RA) is an autoimmune disease of which one distinctive feature is the development of B-cell-mediated immunity against these neoepitopes. Antibodies to citrullinated proteins (ACPAs) were identified nearly two decades ago and are now widely used in clinical practice. The identification of additional citrullinated proteins as potential autoantibody targets has suggested new pathophysiological hypotheses and prompted studies of potential associations with disease severity or specific disease patterns. Carbamylation is a nonenzymatic posttranslational modification that produces homocitrullines, against which newly identified autoantibodies different from ACPAs have been found in over 15% of patients with RA. Finally, the development of antibodies to oxidized type II collagen reflects immunization against collagen modified by oxidation in relation to intraarticular oxidative stress. These new autoantibodies are both sensitive and specific and may therefore serve as early disease markers and as useful tools for therapeutic monitoring.

Section snippets

The ACPA family

Citrulline is an amino acid produced by posttranslational deimination of arginine residues under the effect of enzymes known as peptidylarginine deiminases (PADs) (Fig. 1). The presence of citrulline is the chief modification recognized by ACPAs [5], [6]. Citrullination is a natural process that occurs during keratinization, apoptosis, and inflammation. The two PADs 2 and 4 are expressed in the synovial membrane [7] and can induce citrullination. Citrullination is not specific of RA but,

The carbamylation mechanism

Carbamylation is a posttranslational modification consisting in the nonenzymatic binding of cyanic acid to the free NH₂ groups of proteins, converting the lysine residues to homocitrulline (Fig. 2). Carbamylation occurs ubiquitously in the presence of cyanic acid, at a low level in healthy individuals. The main source of cyanic acid is spontaneous degradation of urea. Under normal physiological conditions, the concentrations of urea and cyanic acid are too low to cause significant protein

Mechanism underlying protein oxidation

Oxidative stress causes the production of reactive oxygen species (ROSs) in large amounts that overwhelm the neutralization capabilities of the body and cause damage to cell membranes, lipids, nucleic acids, and extracellular matrix components such as proteoglycans and collagens. Under physiological conditions, ROSs play a key role in intracellular signal transmission, apoptosis, ion transport systems, homeostasis, and wound healing, as well as in all the mechanisms involved in the inflammatory

Disclosure of interest

The authors declare that they have no competing interest.

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Citation Excerpt :
The facilitators of tissue damage are highly activated macrophages, fibroblasts and osteoclasts, with several different types of tissue-intrusive synovial fibroblasts [4,5]. Recent work has revealed that posttranslationally modified self-proteins are the preferred target of autoantibodies [6] and mechanisms targeting tissue inflammation towards selected joints remain poorly understood [7,8]. Imaging studies with positron emission tomography/computed tomography (PET/CT), a method tracking the utilization of the glucose analogue (18)-F-fluorodeoxyglucose, document tracer enrichment in the inflamed joints, but also in central lymphoid organs [9,10], emphasizing the heterogeneity of tissue environments hosting pathogenic immune responses.
In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATP^low, NADPH^high, ROS^low T-cells hyperproliferate and are forced into premature senescence. ATP^high, ROS^high macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.
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ReviewNew autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins

Abstract

Section snippets

The ACPA family

The carbamylation mechanism

Mechanism underlying protein oxidation

Disclosure of interest

J Immunol Methods

Trends Biochem Sci

Osteoarthritis Cartilage

Clin Chim Acta

Autoimmun Rev

Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis

Ann Intern Med

Immunoblotting detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis

J Rheumatol

The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies

J Clin Invest

Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies

J Clin Invest

Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis

Immunol Rev

The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues

J Immunol

Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation

Arthritis Rheum

The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation

J Clin Periodontol

Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis

Arthritis Rheum

Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule

J Immunol

Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins

Arthritis Rheum

The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis

Arthritis Rheum

Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins

Ann Rheum Dis

Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis

Arthritis Rheum

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative

Ann Rheum Dis

A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis

Ann Rheum Dis

Anti-CCP2 antibodies: an overview and perspective of the diagnostic abilities of this serological marker for early rheumatoid arthritis

Clin Rev Allergy Immunol

Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors

Arthritis Rheum

Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis

Arthritis Rheum

Repeated anticitrullinated protein antibody and rheumatoid factor assessment is not necessary in early arthritis: results from the ESPOIR cohort

J Rheumatol

Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review

Rheumatology

Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression

Ann Rheum Dis

Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study

Arthritis Rheum

Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study

Ann Rheum Dis

A prediction rule for the development of arthritis in seropositive arthralgia patients

Ann Rheum Dis

The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis

Arthritis Rheum

Antibodies to mutated citrullinated vimentin and disease activity score in early arthritis: a cohort study

Arthritis Res Ther

Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis

Ann Rheum Dis

Association of anticyclic citrullinated peptide antibodies and/or rheumatoid factor status and clinical presentation in early arthritis: results from the ESPOIR cohort

J Rheumatol

Five-year favorable outcome of patients with early rheumatoid arthritis in the 2000s: data from the ESPOIR cohort

J Rheumatol

Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP)

Ann Rheum Dis

IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies

Ann Rheum Dis

Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis

Arthritis Rheumatol

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA

Ann Rheum Dis

Review
New autoantibodies associated with rheumatoid arthritis recognize posttranslationally modified self-proteins