Structural Basis of Cross‐Reactivity of Anti–Citrullinated Protein Antibodies

Ge, Changrong; Xu, Bingze; Liang, Bibo; Lönnblom, Erik; Lundström, Susanna L.; Zubarev, Roman A.; Ayoglu, Burcu; Nilsson, Peter; Skogh, Thomas; Kastbom, Alf; Malmström, Vivianne; Klareskog, Lars; Toes, René; Rispens, Theo; Dobritzsch, Doreen; Holmdahl, Rikard

doi:10.1002/art.40698

Cited by 64 publications

(70 citation statements)

References 47 publications

(64 reference statements)

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“…In support of this, an amino acid motif critical for ACPA binding has been identi ed (22). Crystal structure of monoclonal ACPAs demonstrated the conformation that binds different citrullinated peptides (23). Taken together these speculate that the avidity of ACPA is primarily determined by its binding strength to the core-epitope.…”

Section: Discussionmentioning

confidence: 88%

Hierarchy in the Avidity and Cross-reactivity of Anti-citrullinated Protein Antibodies in the Serum of Patients With Rheumatoid Arthritis

Haraguchi

Yamada

Sakuragi

et al. 2020

Preprint

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BackgroundFine specificity of anti-citrullinated protein antibodies (ACPAs), in which cross-reactivity exists, varies among patients with rheumatoid arthritis (RA), but it is unclear whether the mechanism of ACPA production is same or different among individuals. Since avidity of serum antibody reflects the direction of immune response, we compared the levels of avidity and cross-reactivity between various ACPAs in a cohort of RA patient.MethodsSera from 180 RA patients positive for anti-cyclic citrullinated peptide (CCP) 2 antibody were screened for positivity of antibodies against CCP1, and citrullnated fibrinogen (cFib), enolase (cEno), and vimentin (cVim) peptides. Avidity of the four ACPAs, and some autoantibodies and antibodies against foreign antigens was determined by an elution assay using sodium thiocyanate solution. Cross-reactivity between different ACPAs was estimated by measuring the inhibition of binding by competitor peptides. ResultsThe prevalence of anti-CCP1, anti-cFib, anti-cEno, and anti-cVim antibodies in the anti-CCP2-positive RA cohort were 37.7%, 38.3%, 15.6%, and 23.9%, respectively. The avidity of ACPAs, except for anti-cVim antibody, was significantly lower than that of antibodies against foreign antigens, while there was a large variety in the avidity of other autoantibodies. At individual levels, the avidity of anti-cVim was significantly higher than that of other ACPAs, and there was a significant correlation in the avidity of anti-CCP and anti-cFib antibodies. Substantial extent of cross-reactivity was seen between different ACPAs, which also showed a fixed hierarchy.ConclusionThe fixed hierarchy in the avidity and cross-reactivity between different ACPAs suggests that the mechanism underlying ACPA production is common to all RA patients. Presence of a dominant antigen that induces whole ACPA response is speculated.

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Section: Discussionmentioning

confidence: 88%

Hierarchy in the Avidity and Cross-reactivity of Anti-citrullinated Protein Antibodies in the Serum of Patients With Rheumatoid Arthritis

Haraguchi

Yamada

Sakuragi

et al. 2020

Preprint

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“…For instance, substantial amount of research has been dedicated to find out the most important antigen(s) recognized by ACPA, in hope of finding a “predictive antigen.” However, diagnostic assays for ACPA detection have employed various cyclic citrullinated antigens, indicating that the presence of citrulline—but not one specific citrullinated epitope—is required for recognition by ACPA. The neighboring position of glycine resulting in the Cit‐Gly motif has been shown to be preferential, but not obligatory for recognition by ACPA . Consequently, many citrullinated proteins have been shown to be recognized by ACPA, for example, fibrinogen, vimentin, α‐enolase, and collagen type II .…”

Section: Anti‐citrullinated Protein Antibodiesmentioning

confidence: 99%

“…The neighboring position of glycine resulting in the Cit-Gly motif has been shown to be preferential, but not obligatory for recognition by ACPA. 33,34 Consequently, many citrullinated proteins have been shown to be recognized by ACPA, for example, fibrinogen, 35 vimentin, 36 α-enolase, 37 and collagen type II. 38 Initially, there were reports suggesting a specific F I G U R E 1 Evolution of RA and development of autoimmunity.…”

Section: Anti -Citrullinated Protein Antibod Ie Smentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

112

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

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“…Taking this model further, autoantibodies against citrullinated IgG could trigger the development of the entire ACPA repertoire, due to epitope spreading and the extensive cross‐reactivity and general citrulline reactivity of ACPAs . In this scenario, citrullinated IgG would be “antigen zero” of ACPA development.…”

mentioning

confidence: 99%

New Relationships for Old Autoantibodies in Rheumatoid Arthritis

Shelef

2019

Arthritis & Rheumatology

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Structural Basis of Cross‐Reactivity of Anti–Citrullinated Protein Antibodies

Cited by 64 publications

References 47 publications

Hierarchy in the Avidity and Cross-reactivity of Anti-citrullinated Protein Antibodies in the Serum of Patients With Rheumatoid Arthritis

Hierarchy in the Avidity and Cross-reactivity of Anti-citrullinated Protein Antibodies in the Serum of Patients With Rheumatoid Arthritis

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

New Relationships for Old Autoantibodies in Rheumatoid Arthritis

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