Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis. Issue 8 (14th April 2020)

• Record Type: Journal Article
• Authors: van Kempen, Tessa S.; Leijten, Emmerik F.A.; Lindenbergh, Marthe F.S.; Nordkamp, Michel Olde; Driessen, Christoph; Lebbink, Robert‐Jan; Baerlecken, Niklas; Witte, Torsten; Radstake, Timothy R.D.J.; Boes, Marianne
• Is Part Of: European journal of immunology. Volume 50:Issue 8(2020)
• Page Start: 1209
• Page End: 1219
• Publication Date: 2020-04-14
• Subjects: Ankylosing spondylitis -- Autoimmunity -- CD74 -- Monocytes -- SPPL2a; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201948502
• Languages: English
• ISSNs: 0014-2980

Abstract

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. Abstract : Ankylosing spondylitis (AS) patient sera contain anti‐CD74 autoantibodies. Signal peptide peptidase‐like 2a (SPPL2a) is involved in CD74 processing. These results show that a subset of AS patients have impaired SPPL2a enzyme function. SPPL2a dysfunction leads to CD74 fragment accumulation on the plasma membrane, which can be recognized by anti‐CD74 autoantibodies.