PMID- 31569504 OWN - NLM STAT- MEDLINE DCOM- 20200212 LR - 20200212 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 19 DP - 2019 Sep 29 TI - Human Cysteine Cathepsins Degrade Immunoglobulin G In Vitro in a Predictable Manner. LID - 10.3390/ijms20194843 [doi] LID - 4843 AB - Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology. FAU - Hoglund, Rune Alexander AU - Hoglund RA AUID- ORCID: 0000-0002-5801-3360 AD - Department of Neurology, Akershus University Hospital, 1478 Lorenskog, Norway. r.a.hoglund@medisin.uio.no. AD - Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital and University of Oslo, 1478 Lorenskog, Norway. r.a.hoglund@medisin.uio.no. AD - Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway. r.a.hoglund@medisin.uio.no. FAU - Torsetnes, Silje Boen AU - Torsetnes SB AUID- ORCID: 0000-0002-2788-1237 AD - Department of Neurology, Akershus University Hospital, 1478 Lorenskog, Norway. silje.torsetnes@medisin.uio.no. AD - Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital and University of Oslo, 1478 Lorenskog, Norway. silje.torsetnes@medisin.uio.no. FAU - Lossius, Andreas AU - Lossius A AUID- ORCID: 0000-0002-9640-1954 AD - Department of Neurology, Akershus University Hospital, 1478 Lorenskog, Norway. andreas.lossius@medisin.uio.no. AD - Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital and University of Oslo, 1478 Lorenskog, Norway. andreas.lossius@medisin.uio.no. AD - Department of Immunology and Transfusion Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway. andreas.lossius@medisin.uio.no. FAU - Bogen, Bjarne AU - Bogen B AUID- ORCID: 0000-0001-5387-7461 AD - Department of Immunology and Transfusion Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway. bjarne.bogen@medisin.uio.no. FAU - Homan, E Jane AU - Homan EJ AD - ioGenetics LLC, Madison, WI 53704, USA. jane_homan@iogenetics.com. FAU - Bremel, Robert AU - Bremel R AD - ioGenetics LLC, Madison, WI 53704, USA. robert_bremel@iogenetics.com. FAU - Holmoy, Trygve AU - Holmoy T AD - Department of Neurology, Akershus University Hospital, 1478 Lorenskog, Norway. trygve.holmoy@medisin.uio.no. AD - Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway. trygve.holmoy@medisin.uio.no. LA - eng GR - 250864/F20/Norges Forskningsrad/ GR - Internal strategic funds/Akershus Universitetssykehus/ GR - Unrestricted research award (Norway)/Novartis/ PT - Journal Article DEP - 20190929 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Immunoglobulin G) RN - 0 (Immunoglobulin Heavy Chains) RN - EC 3.4.- (Cathepsins) RN - K848JZ4886 (Cysteine) SB - IM MH - Cathepsins/*chemistry/*metabolism MH - Cysteine/*metabolism MH - Humans MH - Hydrogen-Ion Concentration MH - Immunoglobulin G/*chemistry/genetics/*metabolism MH - Immunoglobulin Heavy Chains/chemistry/genetics/metabolism MH - Molecular Conformation MH - Protein Binding MH - Proteolysis MH - Reproducibility of Results MH - Structure-Activity Relationship PMC - PMC6801702 OTO - NOTNLM OT - B cell OT - antigen presenting cell OT - bioinformatics OT - cathepsin OT - endolysosome OT - endosome OT - in silico model OT - protease OT - protease cleavage prediction COIS- R.B. and E.J.H. hold equity in ioGenetics LLC, the company responsible for designing the bioinformatics models used in this project. RAH, AL, TH have all received speakers' honoraria, unrestricted research grants and/or participated in advisory boards for Biogen, Merck, Novartis, Roche and Sanofi Genzyme. SBT and BB declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/10/02 06:00 MHDA- 2020/02/13 06:00 PMCR- 2019/10/01 CRDT- 2019/10/02 06:00 PHST- 2019/09/09 00:00 [received] PHST- 2019/09/26 00:00 [revised] PHST- 2019/09/27 00:00 [accepted] PHST- 2019/10/02 06:00 [entrez] PHST- 2019/10/02 06:00 [pubmed] PHST- 2020/02/13 06:00 [medline] PHST- 2019/10/01 00:00 [pmc-release] AID - ijms20194843 [pii] AID - ijms-20-04843 [pii] AID - 10.3390/ijms20194843 [doi] PST - epublish SO - Int J Mol Sci. 2019 Sep 29;20(19):4843. doi: 10.3390/ijms20194843.