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IGF1R signalling is a guardian of self-tolerance restricting autoantibody production

Erlandsson, Malin C ; Erdogan, Seval ; Wasén, Caroline ; Andersson, Karin M E LU ; Silfverswärd, Sofia T ; Pullerits, Rille ; Bemark, Mats LU orcid and Bokarewa, Maria I (2022) In Frontiers in Immunology 13.
Abstract

OBJECTIVE: Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14 + APCs, we investigated the role that IGF1R plays during adaptive immune responses.

METHODS: The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of... (More)

OBJECTIVE: Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14 + APCs, we investigated the role that IGF1R plays during adaptive immune responses.

METHODS: The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14 + cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing.

RESULTS: Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S 256-phosphorylated FoxO1 + APCs, and an increased frequency of IgM +CD21 + B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII +CD11b + APCs ensured favourable conditions for their communication with IgM + B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14 + APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14 + APCs.

CONCLUSIONS: In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Humans, Immune Tolerance, Immunoglobulin M, Mice, Neoplasms, Receptor, IGF Type 1, Self Tolerance, Signal Transduction
in
Frontiers in Immunology
volume
13
article number
958206
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85137915358
  • pmid:36105797
ISSN
1664-3224
DOI
10.3389/fimmu.2022.958206
language
English
LU publication?
no
additional info
Copyright © 2022 Erlandsson, Erdogan, Wasén, Andersson, Silfverswärd, Pullerits, Bemark and Bokarewa.
id
daef62dc-fb3e-4ce4-a0ea-3ef30ba62f02
date added to LUP
2023-11-16 12:32:38
date last changed
2024-04-14 16:58:38
@article{daef62dc-fb3e-4ce4-a0ea-3ef30ba62f02,
  abstract     = {{<p>OBJECTIVE: Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14 + APCs, we investigated the role that IGF1R plays during adaptive immune responses. </p><p>METHODS: The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14 + cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing. </p><p>RESULTS: Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S 256-phosphorylated FoxO1 + APCs, and an increased frequency of IgM +CD21 + B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII +CD11b + APCs ensured favourable conditions for their communication with IgM + B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14 + APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14 + APCs. </p><p>CONCLUSIONS: In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.</p>}},
  author       = {{Erlandsson, Malin C and Erdogan, Seval and Wasén, Caroline and Andersson, Karin M E and Silfverswärd, Sofia T and Pullerits, Rille and Bemark, Mats and Bokarewa, Maria I}},
  issn         = {{1664-3224}},
  keywords     = {{Animals; Humans; Immune Tolerance; Immunoglobulin M; Mice; Neoplasms; Receptor, IGF Type 1; Self Tolerance; Signal Transduction}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{IGF1R signalling is a guardian of self-tolerance restricting autoantibody production}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.958206}},
  doi          = {{10.3389/fimmu.2022.958206}},
  volume       = {{13}},
  year         = {{2022}},
}