Inhibition of ERAP1 represses HLA-B27 free heavy chains expression on polarized macrophages and interrupts NK cells activation and function from ankylosing spondylitis

Farhad Babaie; Hamed Mohammadi; Sorayya Salimi; Alireza Ghanavatinegad; Mitra Abbasifard; Mehdi Yousefi; Mehrzad Hajaliloo; Younes Khalili; Sajjad Zamanlou; Roghaiyeh Safari; Maryam Hemmatzadeh; Alireza Rezaiemanesh; Reza Salimi; Behzad Baradaran; Zohreh Babaloo

doi:10.1016/j.clim.2023.109268

Inhibition of ERAP1 represses HLA-B27 free heavy chains expression on polarized macrophages and interrupts NK cells activation and function from ankylosing spondylitis

Clin Immunol. 2023 Mar:248:109268. doi: 10.1016/j.clim.2023.109268. Epub 2023 Feb 16.

Authors

Affiliations

¹ Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Genetic and Immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
² Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
³ Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
⁴ Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
⁵ Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Internal Medicine, Ali-Ibn Abi-Talib Hospital, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
⁶ Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
⁷ Connective Tissue Research Center, Tabriz University of Medical Science, Iran.
⁸ Iranian Social Security Organization, Emam Reza Hospital, Urmia, Iran.
⁹ Department of Infectious Disease, Imperial College London, London, UK.
¹⁰ Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
¹¹ Research and Development (R&D) Department, RS, &RS Scientific, Belgium.
¹² Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: baradaranb@tbzmed.ac.ir.
¹³ Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Connective Tissue Research Center, Tabriz University of Medical Science, Iran. Electronic address: zbabaloo@tbzmed.ac.ir.

PMID: 36804470
DOI: 10.1016/j.clim.2023.109268

Abstract

Background: We aimed to assess if Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms might impress Human leukocyte antigen (HLA)-B27-free heavy chains (FHCs) expression on macrophages and eventually NK cell activation in Ankylosing spondylitis (AS).

Methods: Blood samples were obtained from 10 HLAB27⁺ patients with protective and 10 HLAB27⁺ patients with non-protective genotype. Monocytes were isolated and polarized toward M1 and M2 macrophages. ERAP1 was inhibited in macrophages, which were then co-cultured with autologous NK cells.

Results: Expression of HLA-B27-FHCs on M1 and M2 macrophages was reduced in patients with protective ERAP1 genotype. Co-culturing ERAP1-inhibited M1 macrophages and NK cells from patients with protective genotype resulted in downmodulation of CD69 and CD107a markers on NK cells and reduced number of IFN-γ⁺ NK cells compared to that of patients with non-protective genotypes.

Conclusion: Inhibition of ERAP1 activity, by diminishing NK activation, may have therapeutic value in treating AS patients.

Keywords: Ankylosing spondylitis; Endoplasmic reticulum aminopeptidase 1; Free heavy chains; Human leukocyte antigen-B27; Macrophage; Natural killer cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopeptidases / genetics
Genetic Predisposition to Disease
Genotype
HLA-B27 Antigen / genetics
HLA-B27 Antigen / metabolism
Humans
Killer Cells, Natural
Macrophages
Minor Histocompatibility Antigens
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Spondylitis, Ankylosing* / genetics

Substances

HLA-B27 Antigen
Minor Histocompatibility Antigens
ERAP1 protein, human
Aminopeptidases