A protein antigen causes an immunological response that produces antibodies within 4–10 days. The immunological reaction is then activated by the antibody interaction with the antigen, which forms ICs. Antibody production in the blood circulation is commonly triggered by endogenous or exogenous antigen exposure [12, 13]. Exogenous antigens are foreign proteins, whereas endogenous antigens are autoantigens that mimic foreign antigens directed at autoimmune diseases such as RA [12, 13, 28]. In both types of antigens, circulating ICs will be formed by binding antigens to antibodies, which later move out of the plasma and deposit in host tissues [13].

IC in joints can be formed by the autoantibodies observed in RA patients’ serum and synovial fluid [29]. The binding of autoantibodies to their specific target antigen forms the IC that triggers a downstream inflammatory cascade [5, 30]. RF and ACPAs are the autoantibodies identified and recognised as biomarkers for diagnosing RA [29, 31]. Autoantigens directed by several autoantibodies later can be discovered in RA, including a diverse range of components in cartilage, such as stress proteins, nuclear proteins, citrullinated proteins, and enzymes (illustrated in Figure 3). This accumulation of elements in RA demonstrates that the disease is characterised by accumulated autoreactivities in both B and T cells. These autoantigens and immunologically relevant epitopes vary in range during the disease course, and individuals’ self-antigens may differ [32, 33].

The initial autoantibodies that have been characterised in RA are RF, as a target to the Fc region of IgG, which is induced by and reactive towards IC [18, 34]. Three types of Ig are directly and indirectly involved in exhibiting RA: IgG [35], IgA [36], and IgM [37], summarised in Figure 4. The IgG RF antibodies are unique as they may form ICs by self-association without the presence of different antigenic molecules [36]. The self-association characterisation of IgG RFs has a significant implication for pathogenic disease progression in RA patients. Moreover, IgA RFs have also been identified in RA patients. By interacting with normal IgG, these polymeric IgA RFs contributed to the development of intermediate complexes [36]. Furthermore, the most common RF species in RA are IgM RFs, formed by ICs and polyclonal B-cell activators [34, 38]. Polyclonal low-affinity IgM RF formation is not disease-specific, but it is considered a normal physiological response that assists host defence by accelerating the ICs’ development and clearance. Though high-affinity RFs do not appear to induce RA, they are considered to contribute effectively to disease progression and chronicity by stimulating IC development. This is because RFs are produced by IC derived from disease-specific autoantibodies, which also facilitate the formation of IC and enhance the arthritogenicity of disease-specific autoantibodies, including ACPAs [34].

The development of IC between citrullinated proteins and ACPAs, advanced by complement fixation, is significant in RA synovium [39]. ACPAs are RA-specific and target epitopes focused on citrulline, a post-translationally modified arginine. The IC and citrullinated protein comprising different citrullinated antigens are more immunogenic and arthritogenic, while their existence in arthritic joints corresponds with the severity of the disease [34, 40]. Autoantibodies to type II collagen (CII) are also detected in RA and may develop IC in the joint as an essential factor in the early local onset of inflammation. The CII epitopes are found on the synovium and cartilage, while the autoantibodies to CII are released by synovial fluid cells and tissues in RA patients [41, 42] as illustrated in Figure 5. Besides, K/BxN mice, the most used autoimmune arthritis model, secrete antibodies against glucose-6-phosphate isomerase (GPI) that form ICs with GPI in the joints. These ICs also trigger arthritis in the same way as IC-mediated synovitis, considered to contribute to RA in humans [43, 44].

In chronic inflammatory arthritis, autoantibodies targeting antigens in the inflamed joint worsen inflammation by continuously producing ICs. Thus, persistent generation of ICs becomes the indicator of RA chronicity [35]. These excessively formed ICs potentially deposit in tissues, inducing inflammatory damage and the release of autoantigens and activating an autoimmune response [18].

The major histocompatibility complex (MHC), known as human leukocyte antigen (HLA) in humans, plays a crucial role in distinguishing self from foreign antigens [45]. While theories on immune responses to altered self-antigens or cross-reactivity are plausible, there is limited mechanistic and epidemiological evidence supporting them. Moreover, HLA alleles are linked to multiple immune-related diseases affecting different tissues, raising questions about the specificity of antigen presentation [18, 46].

HLA class II alleles are strongly associated with autoimmune diseases, particularly seropositive RA [47]. During T cell development, self-reactive T cells are eliminated, ensuring that CD4+ and CD8+ T cells recognise only foreign antigens presented by self-HLA molecules [48]. However, certain HLA alleles, including RA, can contribute to immune dysregulation and autoimmunity. CD4+ T cells are essential for antibody maturation in germinal centres of lymph nodes, where they interact with B cells and secrete cytokines that promote B cell proliferation, differentiation, and somatic hypermutation. B cell clones with the highest antigen-binding affinity are selected through interactions with follicular dendritic cells, leading to affinity maturation [48, 49].

Genetic factors account for approximately 60% of the risk for developing RA, with the HLA-DRβ chain containing a five-amino-acid sequence motif, known as the shared epitope (SE), a significant risk factor for ACPA-positive RA [18, 50]. A review article by Sharma et al. [51] emphasises significant HLA loci related to RA, which are the HLA class II gene (a.a. position 9 of HLA-DPβ1) and HLA class I genes (a.a. position 9 of HLA-β and position 77 of HLA-α). In addition to HLA regions, non-HLA loci, such as protein tyrosine phosphatase N22 (PTPN22), also contribute to the genetic risk of ACPA-positive RA. Up to 2024, more than 150 loci have been reported to be associated with RA risk. However, whether RA susceptibility is driven by the HLA gene or other associated genes remains unclear, necessitating further research [18, 51].

ACPA-producing germinal centre B cells may escape stringent selection due to the abundance of citrullinated antigens [52]. Activated CD4+ T cells likely support ACPA maturation. Evidence suggests the HLA class II locus is more linked to ACPA+ RA progression than initial ACPA formation, indicating its role in ACPA maturation. This is reflected in isotype expansion, increased ACPA levels, and spreading epitope, emphasising HLA class II’s importance in ACPA development [52, 53].

IC disorder is induced by the soluble antigen-antibody complexes deposition in vessel walls or the basement membrane of the kidneys or by the in-situ development of adherent IC from antibody binding to tissue antigens [41]. The factors influencing the secreted IC to lead to tissue deposition and disease remain unclear, but the properties of IC and local vascular alteration are the key influencing factors. The pathogenicity of IC by depositing on tissues depends on its antigen-antibody ratio [12, 13]. As antibody present in excess, ICs become insoluble, unable to circulate and phagocytosed by macrophages, which is considered pathogenic [10, 12, 13, 24]. Generally, ICs get concentrated and deposited in organs where blood is filtered at high pressure to form other fluids, such as synovial fluids and damage the joints [12, 13].

With increased circulating ICs concentration, the complexes are prone to deposit in tissues and trigger FcR-expressing immune cells [8, 24], initiate neutrophilic inflammation and cause host tissue damage [8, 54, 55]. Furthermore, the deposited ICs in the synovial region significantly mediate neutrophil activation and tissue inflammation [56]. Figure 6 summarises the possible mechanism of synovial inflammation observed in the early onset of RA.

Generally, ICs induce an acute inflammatory response via complement activation and interaction of leukocyte FcR once deposited in tissues [12, 24]. The tissue damage is equivalent regardless of which ICs are deposited. The resultant inflammation lesions that develop in the joints are arthritis [12, 13]. ICs formation, complement fixation, chemotactic fragments release and stimulation of the event cascade trigger innate and adaptive immune cell recruitment and facilitate stromal cell activation in RA pathogenesis [27]. Following FcR and complement receptor engagement, ICs activate various cell types, resulting in different effector actions. FcR is involved in initiating and modulating various immunological responses [61, 62]. Deposition of IC into tissues causes cleavage of complement anaphylatoxins C3a and C5a [63], which subsequently induces granule release from mast cells [64] and recruits the inflammatory cells into the tissue. The lysosomal action of inflammatory cells promotes tissue injury through phagocytosis by macrophages and polymorphonuclear neutrophils [65].

The complement systems, composed of several proteins, play crucial roles in immune processes, such as processing and clearance of circulating ICs, foreign antigen recognition, humoral and cellular immunity modulation, apoptotic and dead cells removal, and involvement in injury resolving and tissue regeneration [66]. In RA, complement system activation mediates inflammation and tissue damage [67]. Table 1 summarises the complement protein associated with RA. As an antibody to ICs in RA, RF appears to be implicated in complement system activation and the generation of chemotactic and inflammatory mediators, resulting in a state that may be maintained and reinitiated. They develop ACPA complexes or other forms of ICs in the synovial cavity, resulting in non-resolving inflammation. Upon this, RF’s second wave of IC formation occurs as an antibody reactive to the initial ICs. These processes are linked to the consumption of complement and the generation of inflammatory mediators [68, 69]. The presence of RF-IgM or RF-IgA enhances the FcR-mediated immune response, promotes complement activation (classical, alternative, and lectin cascade), and affects the functions of ACPA-ICs [68]. The ICs and ACPA activate the same complement system [66], which is remarkably observable in RA patients’ serum, synovial lining, and synovial fluid [67].

In RA events, concentrated macrophages in the synovial lining secrete cytokines and chemokines that induce inflammation, cartilage, and bone destruction [76]. Macrophages promote the progression of the RA condition by increasing the expression of cytokines such as interleukin (IL), tumour necrosis factor-α (TNF-α), chemokines, and matrix metalloproteinases. Secretion of macrophage-induced TNF-α drives most of the articular and extra-articular pathology associated with RA [77]. An article by Nascimento et al. [78], published in 2025, illustrates the role of TNF-α in intensifying inflammation in RA, suggesting the immunosuppression agent as a treatment for the disease. Secretion of macrophage-induced cytokines in RA conditions involves toll-like receptors (TLRs). These receptors identify the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [27]. In the RA synovial tissues, macrophages respond to the concentrated TLR-2 and TLR-4 [79]. Research done in 2025 by Glanville [80] suggests that microparticles carrying the ICs activate TLR-4, activate a potent DAMP stimulus that drives pro-inflammatory cytokines production and sustains synovial inflammation in RA.

Besides TRLs, cytokine production in RA conditions also involves FcR [81]. The presence of abundant ICs stimulates FcR activation and leads to persistent neutrophilic inflammation by activating the neutrophil, which causes tissue injury [8]. Activated neutrophil stimulates the secretion of IL-1β, which drives synovial cells to form chemokines, responsible for more neutrophil recruitment [56]. Neutrophil FcRs ligation effectively activates pro-inflammatory activities such as reactive oxygen species (ROS), degranulation, and cytokine secretion [82, 83]. Stimulation of ROS secretion by neutrophils leads to tissue injury, endothelial dysfunction, and immunoglobulin mutation, which further causes autoantibody secretion [82, 84]. The cytokines secreted by the neutrophils enhanced the resorption of bone in RA. Neutrophils also stimulate expression of the functionally active, membrane-bound receptor activator of nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) ligand, which leads to an upsurge of NF-κB ligand in synovial fluid of RA patients [85, 86].

IC-activated neutrophils produce a variety of inflammatory mediators, including significant neutrophil chemoattractants like IL-8 and leukotriene B4, which leads to increased neutrophil recruitment and progressive inflammation [87]. In the pathogenesis of RA, activated neutrophils are directly associated with the expression of cytotoxic capacity [86]. It includes the inhibition of chondrocyte proliferation [79] and activation of synoviocyte proliferation [88] and invasion [89], which leads to progressive joint damage. In addition, activities of the inflammatory cell that expels the produced or deposited ICs on cartilage and the IC-activated neutrophil that releases its granule enzyme into the cartilage surface create a harmful condition termed “frustrated phagocytosis” [35].