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Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis
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 t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496470/ https://www.ncbi.nlm.nih.gov/pubmed/32198923 http://dx.doi.org/10.1002/eji.201948502 |
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author | 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 |
author_facet | 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 |
author_sort | van Kempen, Tessa S. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7496470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74964702020-09-25 Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis 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 Eur J Immunol Immunodeficiencies and autoimmunity 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. John Wiley and Sons Inc. 2020-04-14 2020-08 /pmc/articles/PMC7496470/ /pubmed/32198923 http://dx.doi.org/10.1002/eji.201948502 Text en © 2020 The Authors. European Journal of Immunology published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Immunodeficiencies and autoimmunity 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 Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title | Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title_full | Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title_fullStr | Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title_full_unstemmed | Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title_short | Impaired proteolysis by SPPL2a causes CD74 fragment accumulation that can be recognized by anti‐CD74 autoantibodies in human ankylosing spondylitis |
title_sort | impaired proteolysis by sppl2a causes cd74 fragment accumulation that can be recognized by anti‐cd74 autoantibodies in human ankylosing spondylitis |
topic | Immunodeficiencies and autoimmunity |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496470/ https://www.ncbi.nlm.nih.gov/pubmed/32198923 http://dx.doi.org/10.1002/eji.201948502 |
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