A homozygous truncating mutation of FGL2 is associated with immune dysregulation - 03/02/23
, Mohammad F. Alosaimi, MD b, ∗, Anas M. Alazami, DPhil c, Abdullah Alsuliman, PhD d, Ayodele Alaiya, MBBS, PhD d, Bandar Al-Saud, MD e, Hamoud Al-Mousa, MD e, Tariq Jassim Al-Zaid, MBBS f, Emma Smith, MS a, Craig D. Platt, MD, PhD a, Hibah Alruwaili, MBS c, Sarah Albanyan, MD e, Sulaiman M. Al-Mayouf, MD g, h, §, ⁎ , Raif S. Geha, MD a, §, ⁎ Abstract |
Background |
The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2–/– mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function.
Objective |
Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies.
Methods |
Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro.
Results |
The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation.
Conclusions |
We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.
Le texte complet de cet article est disponible en PDF.Key words : FGL2, immune dysregulation, regulatory T cells
Abbreviations used : FGL2, FRED, HC, Teff, TFH, Treg, WT
Plan
| Supported by the US Public Health Service (grant AI-139633 [to R.S.G.]) and the Perkin Foundation (to R.S.G.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 2
P. 572 - février 2023 Retour au numéro
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