Oligoarticular JIA (oJIA) is the most common JIA subtype. It is defined as asymmetric arthritis affecting up to four joints, mainly large joints such as the knee, ankle, wrist, and/ or elbow, during the first 6 months after disease onset (23). oJIA can be subcategorized in two types of arthritis: persistent oJIA (no more than four joints are affected during the course of the disease) and extended oJIA (more than four joints are affected after the first 6 months of disease). oJIA usually begins before 4 years of age and female gender is predominantly affected (24). ANA are present in up to 60–80% of patients with oJIA. Importantly, oJIA is associated with a high risk of uveitis (24, 25), particularly in ANA positive (ANA+) patients (26–28).

Polyarticular JIA (pJIA) is the second most common JIA subtype, defined as arthritis in which 5 or more joints are affected during the first 6 months of the disease. There are two forms of pJIA: polyarticular RF negative (pJIA RF-) and polyarticular RF positive (pJIA RF+) (23). Female gender is predominant in both types of pJIA.

Systemic JIA (sJIA) is a disease subtype defined by the presence of arthritis in one or more joints and concomitant systemic manifestations that include fever persisting for more than 2 weeks, generalized lymphadenopathy, rash, hepatosplenomegaly, and/ or serositis (23). Disease onset may occur at any time during childhood and both female and male genders are equally affected. Autoantibodies are usually absent (25, 29). A dysregulation of the innate immune system has been associated to the systemic inflammation present in sJIA, suggesting that this JIA subtype may rather be part of the spectrum of autoinflammatory disorders (29–33). Nevertheless, alterations in adaptive immunity have also been described in sJIA (34–38).

Enthesitis-related arthritis (ERA) is a subtype of JIA that affects the joints of the lower limbs (hip, knee, ankle, and foot) in association with enthesitis. In addition, axial involvement and arthritis of the sacroiliac joints and upper limbs, particularly the shoulders, can also occur (23). ERA is more frequent in male gender. Disease onset usually occurs in late childhood or adolescence. Acute anterior uveitis and gut inflammation can also be present in ERA patients. The diagnosis of this JIA subtype is strongly associated to the major histocompatibility complex (MHC) class I antigen human leukocyte antigen (HLA)-B27 (25).

Juvenile psoriatic arthritis (JPsA) is characterized by an asymmetric arthritis of small and large joints and the presence either of a psoriatic rash or, in the absence of rash, at least two of the following criteria: first-degree relative with psoriasis, nail pitting or onycholysis, and dactylitis (23). Clinical symptoms may also include uveitis. JPsA is composed of two subgroups, differentiated by age at onset. Children with early-onset JPsA (<6 years old) are predominantly female, ANA+, more predisposed to uveitis, with arthritis of the wrists and small joints of the hands and feet. In contrast, children with later-onset JPsA are more associated to male gender, axial disease, enthesitis, and HLA-B27 positivity (39, 40).

Undifferentiated juvenile idiopathic arthritis includes patients who do not fulfill the criteria for any JIA category above described, or who meet the criteria for more than one (23, 41).

The main clinical features of all JIA categories are summarized in Table 1. Notably, the complexity and heterogeneity of JIA diagnosis is still controversial and subject to new classification proposals (42, 43).

Autoantibody production is a hallmark function of B cells in autoimmunity. In JIA, autoantibodies such as ANA, RF and ACPA can be detected in the serum of these patients (8, 108–114), which supports a breakdown in B cell tolerance. ANA are autoantibodies that can target several autoantigens within cell nucleus structures including nucleic acids, nucleosomes, phospholipids, and several nuclear and nucleolar proteins (115). These autoantigens, which are normally “hidden,” are exposed to antigen presenting cells during cell death, particularly during apoptosis. ANA can be detected in several autoimmune diseases such as systemic lupus erythematosus (SLE), RA, Sjögren's syndrome, idiopathic thrombocytopenic purpura, mixed connective tissue disease, juvenile dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, ulcerative colitis, and autoimmune thyroiditis (116–125). In JIA patients, the overall seroprevalence of ANA among all subtypes of JIA combined is < 50% (126). ANA are more commonly detected in oJIA and pJIA (mostly in pJIA RF-) patients and are particularly more prevalent in young, female oJIA patients (127). In JPsA patients, ANA positivity is also more strongly associated with early-onset disease and female predominance (39). ANA are less commonly detected in sJIA and undifferentiated JIA (126). Although the exact contribution of ANA to JIA pathology remains unclear, previous reports have suggested that ANA positivity is associated with the development of ectopic lymphoid structures in synovial tissue (16). Interestingly, the presence of a lymphoid organization in synovial tissue from ANA+ JIA patients was strongly related to the concomitant degree of plasma cells infiltration (16). Thus, the development of these lymphoid structures could contribute to the interactions between autoreactive B and T cells, which could directly support the production of these autoantibodies and the inflammatory process in the joint. Furthermore, it has been demonstrated that ANA are associated to a higher risk of uveitis (119, 128). RF is an immunoglobulin of any isotype (predominantly IgM) that specifically recognizes the Fc portion of IgG molecules, which was first described in RA patients (129, 130) and is currently included in the classification criteria for RA (131). RF can be detected in other autoimmune disorders such as SLE, Sjögren's syndrome, systemic sclerosis, mixed connective tissue disease, polymyositis, dermatomyositis, as well as in healthy individuals (132, 133). RF have also been identified in JIA patients (8, 134) and, despite being present in a small subgroup of pJIA patients (only 5% of total JIA patients), RF positivity is associated with a worse disease prognosis (113, 135). Indeed, patients with pJIA RF+ are at higher risk of a more aggressive disease course with cartilage and bone erosions than JIA patients without RF (113, 136–138). Notably, pJIA RF+ is considered the pediatric version of adult RA (139, 140). In fact, it has been demonstrated that the majority of pJIA patients, particularly pJIA RF+, evolve to RA in adulthood (21). Of note, these observations reinforce that pJIA RF+ and RA are likely to have similar underlying pathological mechanisms and that current treatment strategies applied in RA are directly relevant to pJIA RF+. RF can have important physiological roles in the normal immune system such as promoting phagocytosis and the removal of antigen-antibody complexes in the course of infection; fixation of complement; and enhancing B cell antigen uptake and presentation to CD4+ T cells (141). Nevertheless, these naturally-occurring RF are generally low-affinity and polyreactive, whereas pathogenic RF tend to have undergone affinity maturation (133, 142). Although the mechanisms of RF production are not entirely understood, previous reports have described to be dependent on immune-complex recognition by B cell receptors in the context of toll-like receptor stimulation, as well as T cell help (143–145). ACPA are autoantibodies that recognize citrullinated peptides and proteins and, similarly to RF, are included in the classification criteria for RA (131). Although ACPA are highly specific to RA diagnosis, these antibodies can also be detected in JIA patients, particularly in pJIA RF+ (111, 112, 114, 146–148). In fact, it has been demonstrated that ACPA detected in pJIA RF+ patients express the inherently autoreactive 9G4 idiotope, which supports an activation of autoreactive 9G4+ B cells in JIA (148), similarly to what has been described in RA patients (149). Importantly, ACPA detection in JIA patients is associated to more severe and erosive disease progression, which might implicate an earlier and more intensive treatment (8, 112–114, 146, 150, 151). During inflammation, ACPA might be produced in a process called citrullination, a post-translational modification catalyzed by peptidylarginine deiminases (PAD) enzymes in which arginine amino acid residues are enzymatically converted into citrulline residues in a wide range of proteins (152, 153). These structural changes in proteins can form new epitopes that trigger ACPA production by autoreactive B cells. Of note, both ACPA and RF autoantibodies are able to form immune complexes that deposit in the joints. These immune complexes can activate complement and macrophages through Fc-gamma receptors (FcγR) and induce cytokine release that contribute to the inflammatory process in JIA (Figure 3A) (8, 154, 155). Importantly, evidence of hypergammaglobulinaemia correlated with clinical disease activity has been described in JIA patients (mainly in oJIA and pJIA), which is consistent with B cell hyperactivity (14).

During the inflammatory process in JIA, B cells can function as efficient antigen presenting cells and, once activated, can release cytokines and stimulate T cell activation, thus contributing to the exacerbation of inflammation (Figure 3B). A distinctive feature of chronic inflammatory arthritis is the presence of synovial lymphocytic infiltrates that play a role in disease pathogenesis by secretion of pro-inflammatory cytokines and other soluble mediators (156–166). Indeed, both B and T cells are detected in synovial infiltrates from JIA and RA patients (17, 18, 69, 79, 156, 163–165, 167–172). In particular, high levels of plasma cells infiltration have been detected in the synovial membrane of JIA patients (69, 173). Furthermore, it has been shown that lymphoid neogenesis in JIA is correlated to ANA positivity and plasma cells infiltration not only in synovia, but also in iris tissue, which further supports a dysregulated B cell activation in JIA patients (16, 174, 175). Notably, it was shown that JIA patients with ANA+ anterior uveitis often show an infiltrate of plasma cells in iris (174). In addition, it has been demonstrated that activated memory B cells accumulate in the inflamed joints of patients with JIA (17, 18, 171, 176). Of note, it was shown that class-switched CD27+ and CD27- memory B cells expressed up-regulated levels of the costimulatory molecules CD80 and CD86 and could activate allogenic CD4+ T cells in vitro more effectively when compared to peripheral blood B cells (18). Additionally, it was observed that synovial B cells could not only induce the activation and polarization of T helper (Th)-1 cells, but also secrete Th1-polarizing cytokines (18). Overall, the accumulation of memory B cells in the synovia of JIA patients suggests antigen-driven activation of B cells within the inflamed tissues potentially triggered by local antigens (18). Changes in B cell subpopulations have also been documented in peripheral blood and synovial fluid from JIA patients (12–14, 17, 18, 92, 177–179). Indeed, expansions of CD5+ B cells and transitional (CD24^highCD38^high) B cells have been reported in oJIA and pJIA patients (12–14, 17), which suggest that defects in B cell differentiation and homeostasis may occur in JIA. Of note, CD5+ B cells might be involved in autoantibody production and have the ability to function as antigen presenting cells (180–182). Moreover, it has been demonstrated that transitional B cells (CD24^highCD38^high) can secrete interleukin (IL)-10 and regulate CD4+ T cell proliferation and differentiation toward T helper effector cells (183–186). Furthermore, transitional B cells can also secrete pro-inflammatory cytokines such as IL-6 and tumor necrosis factor (TNF) that contribute to disease pathogenesis (187–189). In addition, alterations in regulatory B cells (Bregs) have also been described in JIA patients that might contribute to disease development (178, 190). Indeed, it was shown that the frequency of CD19⁺CD24^highCD38^high Bregs was significantly decreased in peripheral blood and synovial fluid from JIA patients (178). Interestingly, patients with pJIA RF+ had reduced levels of CD19⁺CD24^highCD38^high Bregs when compared to patients with pJIA RF- (178). Moreover, the frequency of IL-10-producing Bregs (B10 cells) was significantly lower in active JIA patients in comparison to inactive patients (178). In fact, alterations in regulatory B cell numbers and/ or functions have been described in several autoimmune diseases (183, 191–195). Previous studies have shown that RA patients have decreased frequencies of CD19⁺CD24^highCD38^high Bregs in circulation and that these cells fail to suppress Th17 cells differentiation (183). Furthermore, RA patients with active disease have reduced levels of CD19⁺CD24^highCD38^high Bregs in peripheral blood when compared to patients with inactive disease, similarly to what has been described in JIA (183). Taken together, these observations suggest that patients with JIA might have altered regulatory B cell functions, with defective suppression of T helper cell subsets (Th1 and Th17) and/ or impaired regulatory T cells activation, as previously described in other autoimmune diseases (Figure 3C) (183, 191–195). In addition, increased levels of cytokines relevant for B cell activation, maturation, differentiation and survival such as B cell activating factor (BAFF), A proliferation-inducing ligand (APRIL), IL-6 or IL-21, have been detected in serum and/ or synovial fluid from JIA patients (76, 89, 196–201). Of note, BAFF and APRIL serum levels from JIA patients were significantly correlated with disease activity (199). Furthermore, elevated peripheral blood BAFF mRNA levels have been described in JIA patients (202). Also, increased levels of IL-6 and IL-21, cytokines relevant for B cell maturation and plasma cell differentiation, respectively, have been found in synovial fluid from JIA patients (76). Interestingly, IL-21 synovial fluid concentration was particularly increased in pJIA patients (76). Moreover, it was observed that a worse disease severity at baseline in JIA patients was associated with increased IL-6 plasma levels (201). Overall, these observations support the occurrence of B cell triggering mechanisms in JIA that contribute to disease progression. B cells can also act as major producers of receptor activator of nuclear factor kappa-B ligand (RANKL), a key cytokine in osteoclastogenesis, and bone erosion (167, 169, 203). Interestingly, it has been shown that JIA patients have significantly increased levels of RANKL not only in serum, but also in synovial fluid (99, 204–206). Importantly, higher levels of RANKL were associated with a more serious disease, particularly in pJIA patients (99, 205, 206). Thus, these observations suggest that B cells might have a critical role in bone damage and joint destruction in JIA (Figure 3D).