A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis

“…PBMCs were stimulated with anti-CD3. In agreement with our published data [11], the expression of PTPN22 increased approximately twofold in control PBMC but not in 1st visit PBMCs of subjects with active RA ( Figure 1B, the left panel).…”

“…While PFKFB3, ATM and IL-17F did not come out from the unbiased two-group analysis, the level of PTPN22 positively correlated with the levels of PFKFB3 and ATM, but negatively correlated with that of IL-17F ( Figure 4D). This finding is consistent with our published data showing that PTPN22 regulates the expression of PFKFB3, ATM and IL-17F in PBMC [11]. The list of genes was then analyzed with INGENUITY program to identify molecular pathways that were over-represented among the differentially regulated genes and their potential upstream regulators.…”

Genetic and environmental risk factors for rheumatoid arthritis

“…One of the strongest associations is with a polymorphism in the PTPN22 gene that is thought to lead to a lowered threshold for immune activation of T cells, as well as other cells (31–33). Recent studies have also suggested that this polymorphism may also lead to hypercitrullination because of altered PTPN22 interactions with peptidylarginine deiminase (PAD), an enzyme responsible for citrullination, although it is unknown whether this hypercitrullination is targeted by immune responses, or functionality drives other processes that lead to autoimmunity (34, 35). Other associations exist with genes that are in inflammatory pathways implicated in RA (e.g.…”

“…In particular, elevation of the cytokine MCP-1 has been identified in autoantibody negative FDRs of patients with RA from Native American populations as well as in individuals who later developed seropositive RA, although it is not clear if this is a genetic factor, or a biomarker of some response to an environmental factor (50, 51). Furthermore, detailed cellular function studies in arthritis-free FDRs of patients with RA have noted abnormalities of several inflammatory pathways as well as increased intracellular citrullination related to PTPN22 function in the absence of the known risk allele for autoimmunity associated with this protein (34). In addition, there is growing evidence that subtle genetic factors that may more indirectly influence immunity (e.g.…”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…Особое вни-мание привлечено к полиморфизму PTPN22, от которых зависят «порог активации» Т-клеток [179] и негативная се-лекция В-клеток [180], а следовательно, и формирование «аутоиммунного» репертуара Т-и В-лимфоцитов. Недавно было показано, что у пациентов, имеющих факторы риска развития РА, наблюдается нарушение функциональной активности PTPN22, ведущее к ПАД-зависимому гипер-цитруллинированию белков мононуклеарных клеток пе-риферической крови [181]. Примечательно, что аллели PTPN22, ассоциирующиеся с риском развития РА, прояв-ляют сильное взаимодействие с генами HLA-DR. Предпо-лагается, что одномоментное носительство определенных аллелей HLA-DR и PTPN22 определяет, с одной стороны, специфичность иммунного ответа к цитруллинированным белкам, а с другой -создает предпосылки для формирова-ния более разнообразного репертуара Т-клеток, реагирую-щего на факторы внешней среды, например курение [182].…”