title: The common, autoimmunity-predisposing 620Arg > Trp variant of PTPN22 modulates macrophage function and morphology.
abstract: The C1858T single nucleotide polymorphism (SNP) in PTPN22 (protein tyrosine phosphatase nonreceptor 22) leads to the 620 Arg to Trp polymorphism in its encoded human protein LYP. This allelic variant is associated with multiple autoimmune diseases, including type 1 diabetes (T1D), Crohn's disease, rheumatoid arthritis and systemic lupus erythematosus. However, the underlying mechanisms are poorly understood. To study how this polymorphism influences the immune system, we generated a mouse strain with a knock-in of the Trp allele, imitating the human disease-associated variant. We did not find significant difference between the polymorphic and the wild type mice on the proportion of total CD4 T cell, CD8 T cell, NK cell, memory T lymphocyte, macrophage, dendritic cells in both peripheral lymph nodes and spleen. However, macrophages from Trp/Trp mice showed altered morphology and enhanced function, including higher expression of MHCII and B7 molecules and increased phagocytic ability, which further leads to a higher T-cell activation by specific antigen. Our model shows no alteration in immune cell profile by the Trp allele, but brings up macrophages as an important player to consider in explaining the PTPN22 Trp allele effect on autoimmune disease risk.
authors.affiliation: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China; Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
authors.forename: Meihang
authors.initials: M
authors.lastname: Li
authors.affiliation: Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
authors.forename: Hugues
authors.initials: H
authors.lastname: Beauchemin
authors.affiliation: Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
authors.forename: Natalija
authors.initials: N
authors.lastname: Popovic
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Peterson
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada; Translational Immunology Unit, Program in Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: d'Hennezel
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada; Translational Immunology Unit, Program in Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.affiliation: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: sunchao2775@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada. Electronic address: constantin.polychronakos@mcgill.ca.
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D060887:B7 Antigens / Q000235:genetics / Q000276:immunology; D003062:Codon; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D060887:B7 Antigens; D003062:Codon; D016207:Cytokines; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Autoimmune disease; Macrophage; PTPN22 620Arg > Trp; Phagocytosis; T cell proliferation