Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis

Abstract

Ankylosing spondylitis (AS) is associated with autoantibody production to class II MHC‐associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti‐CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase‐like 2A (SPPL2a). We analyzed monocytes from healthy controls ( n = 42), psoriatic arthritis ( n = 25), rheumatoid arthritis ( n = 16), and AS patients ( n = 15) for SPPL2a enzyme activity and complemented the experiments using SPPL2a‐sufficient and ‐deficient THP‐1 cells. We found defects in SPPL2a function and CD74 processing in a subset of AS patients, which culminated in CD74 and HLA class II display at the cell surface. These findings were verified in SPPL2a‐deficient THP‐1 cells, which showed expedited expression of MHC class II, total CD74 and CD74 N‐terminal degradation products at the plasma membrane upon receipt of an inflammatory trigger. Furthermore, we observed that IgG anti‐CD74/CLIP autoantibodies recognize CD74 N‐terminal degradation products that accumulate upon SPPL2a defect. In conclusion, reduced activity of SPPL2a protease in monocytes from AS predisposes to endosomal accumulation of CD74 and CD74 N‐terminal fragments, which, upon IFN‐γ‐exposure, is deposited at the plasma membrane and can be recognized by anti‐CD74/CLIP autoantibodies.

Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation

“…Although these data associate the humoral immune response against CD74 to pathogenic T-cell responses, the exact trigger for increased anti-CD74 antibody production in SpA patients remains to be determined. Alternatively, anti-CD74 antibodies could recognize CD74 degradation products, which accumulate at the cell surface following impaired proteolysis of its transmembrane portion, as shown in monocytes from ankylosing spondylitis patients (26). There are currently no studies directly supporting the role of anti-CD74 IgA in SpA pathogenesis, although it is crucial to understand whether these antibodies are mechanistically involved or merely mirror Th1-and Th17-skewed T-cell responses in SpA patients.…”

Uncovering the Underworld of Axial Spondyloarthritis

“…CD74 also represents the surface cellular receptor for the cytokine MIF [ 129 ]. Formation of these autoantibodies could be linked to the reduced activity of the enzyme signal peptide peptidase-like 2A (SPPL2A), which in turn may cause the accumulation of CD74 and its degradation products, thus inducing antibody production [ 130 ]. The role of these autoantibodies in axial-SpA is currently unknown, but those directed towards the CLIP part of the molecule could be used as serum biomarkers to disclose the disease in these patients.…”

B Cell Involvement in the Pathogenesis of Ankylosing Spondylitis

“…However, recently, van Kempen et al found that monocytes in a subset of AS patients exhibit a defect in the enzyme signal peptide peptidase-like 2A (SPPL2A) [121]. Reduced SPPL2A activity causes the accumulation of CD74 and CD74 degradation products, which are deposited on the surface membrane upon exposure to IFNγ stimulation [121]. These degradation products can be recognized by the anti-CD74 antibodies in patients' sera.…”