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Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis
Author(s) -
Kempen Tessa S.,
Leijten Emmerik F.A.,
Lindenbergh Marthe F.S.,
Nordkamp Michel Olde,
Driessen Christoph,
Lebbink RobertJan,
Baerlecken Niklas,
Witte Torsten,
Radstake Timothy R.D.J.,
Boes Marianne
Publication year - 2020
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201948502
Subject(s) - cd74 , autoantibody , immunology , ankylosing spondylitis , rheumatoid arthritis , mhc class ii , autoimmunity , mhc class i , biology , antigen processing , major histocompatibility complex , medicine , endocrinology , antigen , antibody
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.