Autoantibodies in Psoriatic Arthritis: Are They of Pathogenic Relevance?
Psoriatic arthritis (PsA), a chronic inflammatory disease associated with psoriasis, presents with heterogeneous clinical manifestations affecting the joints, skin, and other tissues. While autoantibodies play well-established roles in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), their relevance in PsA remains less understood. This article synthesizes current evidence on the presence, specificity, and potential pathogenic roles of autoantibodies in PsA, with a focus on emerging research that links these antibodies to disease mechanisms and clinical outcomes.
Traditional Autoantibodies in PsA: Limited Diagnostic Utility
Historically, investigations into autoantibodies in PsA focused on those associated with other rheumatic diseases. Anti-nuclear antibodies (ANAs) are frequently detected in PsA patients, with prevalence rates comparable to those in psoriasis. However, anti-double-stranded DNA (anti-dsDNA) and anti-extractable nuclear antigen (anti-ENA) antibodies, which are highly specific for SLE, are rarely identified in PsA. Consequently, ANAs have not proven diagnostically useful for distinguishing PsA from psoriasis or predicting disease progression. The pathogenic role of ANAs in PsA remains unclear, though their presence may reflect generalized immune dysregulation.
Similarly, antibodies against citrullinated proteins (ACPAs), hallmarks of RA, are detected in 5.0% to 17.5% of PsA patients. ACPA-positive PsA patients exhibit more erosive joint disease compared to ACPA-negative counterparts, mirroring observations in RA. For instance, anti-citrullinated vimentin antibodies, implicated in bone destruction in RA, are elevated in PsA and correlate with disease severity. These findings suggest that post-translationally modified proteins, such as citrullinated antigens, may drive joint inflammation and damage in a subset of PsA patients. However, the specific citrullinated targets in PsA synovium remain uncharacterized, unlike in RA, where citrullinated vimentin and fibrin are well-defined antigens.
Anti-carbamylated protein (anti-CarP) antibodies, another class associated with RA, are also detected in PsA. These antibodies target homocitrulline residues generated via carbamylation, a process distinct from citrullination. In PsA, anti-CarP antibodies correlate with disease activity, suggesting that carbamylated proteins may contribute to synovial inflammation. Notably, neither ACPA nor anti-CarP antibodies are elevated in psoriasis patients without arthritis, implying that joint-specific post-translational modifications or localized immune responses drive autoantibody production in PsA.
Emerging Autoantibodies in PsA: LL-37 and ADAMTS-L5
Recent studies have identified novel autoantibodies with potential pathogenic relevance in PsA. Among these, antibodies targeting the antimicrobial peptide LL-37 and the extracellular matrix protein ADAMTS-L5 (a disintegrin and metalloprotease domain-containing thrombospondin type 1 motif-like 5) have garnered significant interest.
LL-37: A Dual Role in Immunity and Autoimmunity
LL-37, a 37-amino acid peptide derived from the cathelicidin precursor hCAP-18, is overexpressed in psoriatic skin and synovium. It exhibits antimicrobial properties and modulates immune responses by activating plasmacytoid dendritic cells (pDCs) via complexation with self-nucleic acids. In PsA synovial fluid, autoantibodies targeting native, citrullinated, and carbamylated forms of LL-37 are significantly elevated compared to osteoarthritis controls. These antibodies correlate with synovial inflammation and disease activity, suggesting a direct role in pathogenesis.
Notably, serum anti-LL-37 antibody titers are higher in PsA patients than in those with psoriasis alone, positioning them as potential biomarkers for distinguishing PsA from cutaneous psoriasis. Anti-LL-37 antibodies are detectable in early PsA, implicating them in the initiation of autoimmunity. Mechanistically, LL-37-reactive CD4+ T cells in psoriatic lesions produce interleukin (IL)-17A, a cytokine central to PsA pathogenesis. Furthermore, LL-37 complexes with neutrophil extracellular trap (NET)-derived RNA can amplify inflammatory responses by stimulating cytokine production, a pathway potentially exacerbated by anti-LL-37 antibodies.
ADAMTS-L5: A Melanocyte-Derived Autoantigen
ADAMTS-L5, a member of the ADAMTS superfamily, binds microfibrils and regulates extracellular matrix organization. In psoriasis, ADAMTS-L5 is overexpressed in melanocytes and serves as a target for autoreactive CD8+ T cells. Autoantibodies against ADAMTS-L5 are elevated in PsA patients compared to those with psoriasis alone, paralleling findings for anti-LL-37. The heightened antibody response in PsA suggests that ectopic lymphoid structures in the synovium, which resemble germinal centers, may facilitate autoantibody production. However, ADAMTS-L5 expression in PsA synovium remains unexplored, leaving open questions about its joint-specific role.
Shared Mechanisms: Skin-to-Joint Continuity and Post-Translational Modifications
Both LL-37 and ADAMTS-L5 are upregulated in psoriatic skin and synovium, with expression modulated by tumor necrosis factor (TNF) and IL-17 inhibition. This shared regulation highlights the interplay between inflammatory cytokines and autoantigen expression. In the skin, LL-37 and ADAMTS-L5 drive T cell activation and keratinocyte hyperproliferation. In the joint, their overexpression may similarly sustain synovitis, though the triggers for synovial expression remain undefined.
Post-translational modifications, such as citrullination and carbamylation, emerge as critical processes linking autoantigen modification to autoantibody production. While these modifications occur in both RA and PsA, the factors driving them in PsA joints—but not in psoriatic skin—are unclear. Local enzymatic activity, neutrophil infiltration, or oxidative stress in the synovial microenvironment may promote antigen citrullination, fostering immune recognition and autoantibody generation.
Other Candidate Autoantigens in PsA
Antigen array studies have revealed additional autoantibodies in PsA, though their pathogenic roles are less characterized:
- PLA2G4D: A phospholipase expressed in psoriatic epidermis, PLA2G4D activates lipid-specific T cells that produce IL-17 and IL-22. While its role as a B cell antigen is unknown, PLA2G4D exemplifies how lipid metabolites may bridge innate and adaptive immunity in PsA.
- Keratin-17: Overexpressed in psoriatic keratinocytes, keratin-17 stimulates IFN-γ production by CD8+ T cells. Autoantibodies against keratin-17 are unreported, but its immunogenicity underscores the breadth of autoreactive targets in psoriasis.
- hnRNP-A1: Autoantibodies against this RNA-binding protein are detected in psoriasis, though their prevalence in PsA is unstudied.
These findings underscore the heterogeneity of autoantigens in PsA and the need for comprehensive profiling to distinguish pathogenic antibodies from epiphenomena.
Unresolved Questions and Future Directions
Despite progress, critical gaps persist in understanding autoantibody roles in PsA:
- Pathogenic vs. Epiphenomenal: Do autoantibodies directly contribute to synovitis and bone damage, or merely reflect systemic inflammation? Functional studies are needed to test whether immune complexes containing LL-37 or ADAMTS-L5 activate complement, Fc receptors, or innate immune cells in joints.
- Antigen Specificity: The precise citrullinated and carbamylated targets in PsA synovium require characterization. Comparative studies with RA could clarify disease-specific modifications.
- Biomarker Potential: Longitudinal studies must assess whether anti-LL-37 or anti-ADAMTS-L5 antibodies predict PsA development in psoriasis patients. Their utility in monitoring treatment response also warrants investigation.
- Synovial vs. Cutaneous Antigens: Why are certain autoantibodies elevated in PsA but not in psoriasis? Comparative analyses of synovial and cutaneous antigen expression, coupled with single-cell sequencing of synovial B cells, could elucidate site-specific immune responses.
Conclusion
Autoantibodies in PsA represent a promising frontier for understanding disease mechanisms and improving clinical management. While traditional autoantibodies like ACPA and anti-CarP provide clues to shared pathways with RA, novel antibodies against LL-37 and ADAMTS-L5 highlight unique aspects of PsA pathophysiology. Their association with disease activity and joint-specific inflammation positions them as potential biomarkers and therapeutic targets. However, definitive evidence of their pathogenic roles requires mechanistic studies and validation in larger cohorts. Bridging these knowledge gaps will not only clarify the autoimmunity-inflammation axis in PsA but also pave the way for personalized diagnostic and therapeutic strategies.
doi.org/10.1097/CM9.0000000000001228
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