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Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus

B cells and serum anti-GPI antibodies in Padi4 KO mice after the GPI immunization.(A) The number of B220+ B cells in spleens was counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 6, Padi4 KO n = 6), 14 days after the immunization (WT n = 11, Padi4 KO n = 13). (B–D) The titers of serum anti-GPI IgM, IgG antibodies and anti-CCP2 IgG antibodies were measured before and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 14 days after the immunization (WT n = 13, Padi4 KO n = 13), N.D.: not detected. *p < 0.05.
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f2: B cells and serum anti-GPI antibodies in Padi4 KO mice after the GPI immunization.(A) The number of B220+ B cells in spleens was counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 6, Padi4 KO n = 6), 14 days after the immunization (WT n = 11, Padi4 KO n = 13). (B–D) The titers of serum anti-GPI IgM, IgG antibodies and anti-CCP2 IgG antibodies were measured before and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 14 days after the immunization (WT n = 13, Padi4 KO n = 13), N.D.: not detected. *p < 0.05.

Mentions: We then examined B cell subsets and anti-GPI antibody production following the rhGPI immunization because B cells and the anti-GPI antibody were required for the development of GIA1820. After the rhGPI immunization, no significant difference was observed in the total number of B cells in the spleen or iLN cells between WT and Padi4 KO mice (Fig. 2A). Regarding serum antibodies, although rhGPI-immunized WT mice developed significant amounts of anti-GPI IgM and IgG antibodies, Padi4 KO mice only produced limited titers of anti-GPI IgM and IgG antibodies (Fig. 2B,C). Moreover, ACPA titers after rhGPI immunization were lower in Padi4 KO mice (Fig. 2D).


Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

B cells and serum anti-GPI antibodies in Padi4 KO mice after the GPI immunization.(A) The number of B220+ B cells in spleens was counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 6, Padi4 KO n = 6), 14 days after the immunization (WT n = 11, Padi4 KO n = 13). (B–D) The titers of serum anti-GPI IgM, IgG antibodies and anti-CCP2 IgG antibodies were measured before and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 14 days after the immunization (WT n = 13, Padi4 KO n = 13), N.D.: not detected. *p < 0.05.
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Related In: Results  -  Collection

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f2: B cells and serum anti-GPI antibodies in Padi4 KO mice after the GPI immunization.(A) The number of B220+ B cells in spleens was counted 0, 7, and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 7 days after the immunization (WT n = 6, Padi4 KO n = 6), 14 days after the immunization (WT n = 11, Padi4 KO n = 13). (B–D) The titers of serum anti-GPI IgM, IgG antibodies and anti-CCP2 IgG antibodies were measured before and 14 days after the immunization. Pre-immunized (WT n = 3, Padi4 KO n = 3), 14 days after the immunization (WT n = 13, Padi4 KO n = 13), N.D.: not detected. *p < 0.05.
Mentions: We then examined B cell subsets and anti-GPI antibody production following the rhGPI immunization because B cells and the anti-GPI antibody were required for the development of GIA1820. After the rhGPI immunization, no significant difference was observed in the total number of B cells in the spleen or iLN cells between WT and Padi4 KO mice (Fig. 2A). Regarding serum antibodies, although rhGPI-immunized WT mice developed significant amounts of anti-GPI IgM and IgG antibodies, Padi4 KO mice only produced limited titers of anti-GPI IgM and IgG antibodies (Fig. 2B,C). Moreover, ACPA titers after rhGPI immunization were lower in Padi4 KO mice (Fig. 2D).

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus