Scientific background
Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily targeting the joints. Unlike the wear-and-tear damage seen in osteoarthritis, RA occurs when the immune system mistakenly attacks the body’s tissues, particularly the membrane lining the joints - the synovium. This immune response triggers inflammation and swelling, eventually destroying cartilage and bone within the joints. While the exact cause of RA remains unknown, genetic predispositions, hormonal factors, and environmental triggers such as infections or smoking are thought to contribute to its development. RA affects approximately 1% of the global population, can manifest at any age, and is more prevalent in women than in men. Treatment for RA focuses on symptom management, slowing disease progression, and improving quality of life. Common treatments include disease-modifying antirheumatic drugs (DMARDs), biologics, and nonsteroidal anti-inflammatory drugs (NSAIDs), which help reduce inflammation and prevent further joint damage.
Challenges in Diagnosing Rheumatoid Arthritis: The Key Role of Anti-Citrullinated Protein Antibodies
Early diagnosis and intervention are critical in preventing long-term disability. However, diagnosing a complex polygenic disease like rheumatoid arthritis (RA)—where multiple core genes contribute modestly to overall risk—poses challenges due to the combined influence of genetic, environmental factors, and common symptoms, as illustrated in Figure 1. Together, these factors increase the likelihood of developing the disease. Recent research also explores the possibility of RA being an omnigenic disease. The omnigenic model suggests that all genes expressed in disease-relevant cells may influence disease risk, even if their effect is small or indirect.
A significant amount of work has been done to improve the detection of the disease. In 1998, G.A. Schellekens and colleagues discovered that anti-citrullinated protein antibodies (ACPA) are present in individuals with rheumatoid arthritis (RA) because they are part of the immune system's response to specially modified citrullinated proteins (explained below), which are altered during inflammation.
Citrullination, or CIR (as shown in Figure 2) plays a crucial role in maintaining normal immune function, skin keratinization, neuron insulation, and the plasticity of the central nervous system, particularly in gene regulation. Abnormal citrullination has been associated with conditions such as rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, and recent research underscores its involvement in tumorigenesis.
Subsequent studies have shown that ACPA are found in 70�80% of individuals with the disease, making it the most reliable biomarker for the early detection of RA. ACPA can be detected in the blood years before the onset of RA symptoms. Their high specificity for RA has led to the development of the anti-CCP test, which is now routinely used in clinical practice to help identify individuals at risk of developing the disease.
Exploring the ACPA nature, mechanism, and tridimensional structure
ACPA are a type of autoantibody produced by the immune system in response to the individual's own proteins, primarily associated with rheumatoid arthritis. These antibodies specifically target proteins that have undergone citrullination, a process in which the amino acid arginine is converted into citrulline (see Figure 2).
The structure of ACPA, as an immunoglobulin G (IgG) antibody, follows the typical immunoglobulin fold found in all antibodies (see Figure 3). The amino acid sequence of ACPA determines its specificity for citrullinated epitopes. Like other antibodies, ACPA consists of both heavy and light chains, each composed of variable (V) and constant (C) regions. The constant regions are well conserved between antibodies. The V regions are responsible for antigen binding, and in ACPA, the sequence within the complementarity-determining regions (CDRs) (see Figure 4) of the variable regions is essential for recognizing citrullinated proteins. These CDRs typically consist of six loops on either the light (L) or heavy (H) chains: L1, L2, L3, H1, H2, and H3. The typical antibody sequence includes:
- 2 heavy chains: approximately 400�500 amino acids long, with a variable domain (VH) at the N-terminus, followed by three constant domains (CH1, CH2, CH3).
- 2 light chains: approximately 200�250 amino acids long, consisting of a variable domain (VL) and one constant domain (CL).
The secondary structure of ACPA primarily consists of β-sheets and loops. Antibodies contain multiple β-sandwiches, which result from the association of two β-sheets. All antibodies, not just ACPA, exhibit these characteristic β-sandwiches and consequently this type of β-sandwich is called the immunoglobulin fold.
The antibody structure is organised into three regions connected by a hinge: two “Fab� (fragment antigen-binding) regions and one “Fc� (fragment crystallisable) region. In the Fc region is generally found the binding site to immune cells. The overall structure is stabilised by disulfide bonds and non-covalent interactions. The number and the positions of disulfide bonds in antibodies vary depending on the subclass, as explained by Hongcheng Liu and Kimberly May. All four IgG subclasses have been observed for ACPAs.
The structural details of how the ACPA Fab antibody binds to the citrullinated peptide is illustrated in Figure 4, showing the positioning of the peptide and highlighting the molecular interactions. The heavy chain of the ACPA Fab is depicted in grey , and the light chain is shown in blue. Both chains are involved in forming the antigen-binding paratope, the specific area where the peptides bind.
Adam Bellaïche
About the artwork
Clara de Sancha, 16, is a student at The Leys School in Cambridge, UK, studying biology at A-level. She is most fascinated by the beauty of art inspired by science. She appreciates how the PDB Art project helped her convey the elegance of molecular biology, making her learning even more enjoyable.
View the artwork in the .
Structures mentioned in this article
