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

Gianchecchi, Elena; Crinò, Antonino; Giorda, Ezio; Luciano, Rosa; Perri, Valentina; Russo, Anna Lo; Cappa, Marco; Rosado, Maria Manuela; Fierabracci, Alessandra

doi:10.1371/journal.pone.0110755

Cited by 24 publications

(41 citation statements)

References 48 publications

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“…Gianchecchi et al (2014) investigated the effect of the C1858T (Lyn) polymorphism in the protein tyrosine phosphatase non-receptor type 22 ( PTPN22 ) on innate and adaptive immunity in patients with T1D and healthy control subjects [91]. The authors found that the presence of the Lyn variant was associated with a significant increase in the percentage of transitional B cells in C/T carriers of patients with T1D and control subjects compared to patients and control subjects carrying the C/C polymorphism [91]. Further stimulation with CpG resulted in a significant increase of IgM + memory B cells in C/T carrier patients, suggesting that altered B cell homeostasis mediated by increased TLR9 signaling could contribute to the pathogenesis of T1D.…”

Section: Tlrs and T1dmentioning

confidence: 99%

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Tai

Wong

2016

Journal of Autoimmunity

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Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cells mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or NOD-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease.

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Section: Tlrs and T1dmentioning

confidence: 99%

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Tai

Wong

2016

Journal of Autoimmunity

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“…Taken together, these data may suggest that ACPA towards some cit-Fib antigens might not arise via classical T cell help to autoreactive B cells, but instead in a more innate or T cell independent fashion. In this context it has been demonstrated that the autoimmune risk allele PTPN22 promotes survival of autoreactive B cells in both RA and type-1 diabetes mellitus by evading the tolerance checkpoints [31, 41, 42]. …”

Section: Discussionmentioning

confidence: 99%

Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells

et al. 2016

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BackgroundAntibodies against citrullinated proteins (ACPA) are common in patients with rheumatoid arthritis (RA). ACPA can appear before disease onset and target many self-antigens. Citrullinated fibrin/fibrinogen represents a classical ACPA target antigen, and mass spectrometry of RA synovial fluid reveals elevated citrullinated (cit) fibrinogen (Fib) peptides compared to non-RA controls. We investigated the extent to which these less-studied peptides represent autoantibody targets and sought to visualize the corresponding cit-Fib-reactive B cells in RA patients.MethodsAn in-house ELISA was established against four cit-Fib α-subunit peptides (cit-Fib α-35; cit-Fib α-216,218; cit-Fib α-263,271 and cit-Fib α-425,426) and serum from patients with established RA (n = 347) and disease controls with psoriatic arthritis (PsA) or ankylosing spondylitis (AS) (n = 236) were analyzed. RA patients were genotyped for HLA-DR alleles, PTPN22 R620W and screened for anti-CCP2 and cit-Fib protein antibodies. The cit-Fib peptides were also used to assemble antigen tetramers to identify cit-Fib-reactive B cells in peripheral blood by flow cytometry.ResultsThe frequencies of autoantibodies against different cit-Fib epitopes in RA patients compared to PsA/AS patients were: cit-Fib α-35 (RA 20%, vs PsA/AS 1%); cit-Fib α-216,218 (13% vs 0.5%); cit-Fib α-263,271 (21% vs 0.5%) and cit-Fib α-425,426 (17% vs 1%). The presence of autoantibodies against these peptides was associated with presence of anti-CCP2 and anti-cit-Fib protein antibodies. No association was found between HLA-DR shared epitope and antibodies to the different cit-Fib peptides. However, association was observed between the PTPN22 risk allele and positivity to cit-Fib α-35 and cit-Fib α-263,271. B cells carrying surface Ig reactive to these cit-Fib peptides were found in RA peripheral blood and these tend to be more common in PTPN22 risk allele carriers.ConclusionsOur data show that several cit-Fib peptides are targeted by autoantibodies in RA, but not in PsA/AS, implicating that these are not due to arthritis but more specific for RA etiology. The RA-associated anti-cit protein response is broad with many parallel immune responses. The association between cit-Fib autoantibodies and the PTPN22 R620W risk allele supports the hypothesis of altered B cell regulation, such as autoreactive B cells evading tolerance checkpoints.

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“…100 PTPN22 promotes the survival of B-cells in RA and other inflammatory conditions, such as type 2 diabetes, by evading tolerance checkpoints. [105][106][107] Fibrinogen and Fibrin Are Endogenous Sources of RA Autoantigens…”

Section: Fibrinogen In Rheumatoid Arthritismentioning

confidence: 99%

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

Bezuidenhout

Pretorius

2020

Semin Thromb Hemost

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Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

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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

Cited by 24 publications

References 48 publications

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

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