title: Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis.
abstract: Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.
authors.affiliation: Autoimmunity Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gianchecchi
authors.affiliation: Division of Endocrinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Crinò
authors.affiliation: B cell Development Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Giorda
authors.affiliation: Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Luciano
authors.affiliation: Autoimmunity Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Perri
authors.affiliation: Autoimmunity Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Anna Lo
authors.initials: AL
authors.lastname: Russo
authors.affiliation: Division of Endocrinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cappa
authors.affiliation: B cell Development Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: M Manuela
authors.initials: MM
authors.lastname: Rosado
authors.affiliation: Autoimmunity Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fierabracci
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D018899:CpG Islands / Q000235:genetics; D004269:DNA, Bacterial / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000276:immunology
chemical_list: D004269:DNA, Bacterial; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22