Yonsei Med J.  2014 Sep;55(5):1354-1358. 10.3349/ymj.2014.55.5.1354.

Regulatory B Cells Are Inversely Associated with Disease Activity in Rheumatoid Arthritis

• Kim J
• Lee HJ
• Yoo IS
• Kang SW
• Lee JH

• KMID: 1799502
• DOI: http://doi.org/10.3349/ymj.2014.55.5.1354

Abstract

PURPOSE
The function of regulatory B lymphocytes is known to be abnormal in inflammatory diseases. However, a recent study indicates that IL-10+ B cells seem to be expanded in rheumatoid arthritis (RA). Therefore, the state of IL-10+ B cells in the peripheral blood from RA patients and healthy controls were investigated.
MATERIALS AND METHODS
CD19+ cells in peripheral blood mononuclear cells were purified from blood samples of RA patients and age and gender-matched healthy controls, and stimulated with CD40 ligand and CpG for 48 hours. Then, intracellular IL-10 in CD19+ cells was analyzed using flow cytometry.
RESULTS
There was no significant difference in the proportion of IL-10+ B cells between 10 RA patients and 10 healthy controls (RA, 0.300+/-0.07 vs. healthy control 0.459+/-0.07, p=0.114). The proportion of induced IL-10+ B cells to total B cells in RA patients was significantly higher than those in controls (RA, 4.44+/-3.44% vs. healthy control 2.44+/-1.64%, p=0.033). However, the proportion of IL-10+ B cells to total B cells correlated negatively with disease activity in RA patients (r=-0.398, p=0.040). Erythrocyte sedimentation rate or C-reactive protein or medication was not associated with the proportion of IL-10+ B cells.
CONCLUSION
The proportion of induced IL-10+ B cell increased in RA patients compared to healthy control, however, negatively correlated with disease activity in RA.

Keyword

Regulatory B lymphocytes; rheumatoid arthritis; interleukin-10

MeSH Terms

Adult
Aged
Antigens, CD19/metabolism
Arthritis, Rheumatoid/blood/*immunology/pathology
B-Lymphocytes, Regulatory/metabolism/*physiology
Biological Markers/blood
Female
Humans
Interleukin-10/metabolism
Male
Middle Aged
Severity of Illness Index
Antigens, CD19
Biological Markers
Interleukin-10

Figure

• 

  Fig. 1 The IL-10+ B cell was increased in RA patients compared to control patients. B cells from patients and controls were stimulated with CD40L and CpG for 48 hours and IL-10 intracellular staining was performed. (A) The representative plot of IL-10+ B cell in RA patients and healthy control. (B) The proportion of IL-10+ B cells among B cells was elevated in RA patients compared to normal control (p=0.033, by t-test). RA, rheumatoid arthritis; IL-10, interleukin-10.

• 

  Fig. 2 The correlation of IL-10+ B cell and DAS28-CRP. The proportion of IL-10+ B cells was negatively correlated with RA disease activity measured using DAS28-CRP (r=-0.398, p=0.040, by correlation analysis). DAS28-CRP, 28-joint disease activity score calculated using C-reactive protein; RA, rheumatoid arthritis; IL-10, interleukin-10.

Reference

1. Nakken B, Munthe LA, Konttinen YT, Sandberg AK, Szekanecz Z, Alex P, et al. B-cells and their targeting in rheumatoid arthritis--current concepts and future perspectives. Autoimmun Rev. 2011; 11:28–34.

2. Moura RA, Graca L, Fonseca JE. To B or not to B the conductor of rheumatoid arthritis orchestra. Clin Rev Allergy Immunol. 2012; 43:281–291.

3. Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St Clair EW, Tedder TF. B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol. 2007; 179:1369–1380.

4. Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996; 184:2271–2278.

5. Watanabe R, Fujimoto M, Ishiura N, Kuwano Y, Nakashima H, Yazawa N, et al. CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol. 2007; 171:560–570.

6. Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med. 2003; 197:489–501.

7. Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol. 2007; 178:7868–7878.

8. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002; 3:944–950.

9. DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci. 2010; 1183:38–57.

10. Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011; 117:530–541.

11. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19⁺CD24^hiCD38^hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010; 32:129–140.

12. Lee JH, Noh J, Noh G, Choi WS, Lee SS. IL-10 is predominantly produced by CD19(low)CD5(+) regulatory B cell subpopulation: characterisation of CD19 (high) and CD19(low) subpopulations of CD5(+) B cells. Yonsei Med J. 2011; 52:851–855.

13. Noh G, Lee JH. Regulatory B cells and allergic diseases. Allergy Asthma Immunol Res. 2011; 3:168–177.

14. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1d^hiCD5⁺ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008; 28:639–650.

15. Yang M, Deng J, Liu Y, Ko KH, Wang X, Jiao Z, et al. IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. Am J Pathol. 2012; 180:2375–2385.

16. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315–324.

17. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62:2569–2581.

18. Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995; 38:44–48.

19. van Riel PL, van Gestel AM. Clinical outcome measures in rheumatoid arthritis. Ann Rheum Dis. 2000; 59:Suppl 1. i28–i31.

20. Calvo-Alén J, Corrales A, Sánchez-Andrada S, Fernández-Echevarría MA, Peña JL, Rodríguez-Valverde V. Outcome of late-onset rheumatoid arthritis. Clin Rheumatol. 2005; 24:485–489.

21. Tamas MM, Felea I, Rednic S. How much difference does the age at onset make in early arthritis patients? Comparison between the ACR 1987 and the ACR/EULAR 2010 classification criteria for rheumatoid arthritis at the time of diagnosis. Rheumatol Int. 2013; 33:2881–2884.

22. Ma L, Liu B, Jiang Z, Jiang Y. Reduced numbers of regulatory B cells are negatively correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Rheumatol. 2014; 33:187–195.

23. Jeong YI, Hong SH, Cho SH, Lee WJ, Lee SE. Induction of IL-10-producing CD1d^highCD5⁺ regulatory B cells following Babesia microti-infection. PLoS One. 2012; 7:e46553.

24. Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 2011; 121:3645–3656.

25. MacDonald KP, Nishioka Y, Lipsky PE, Thomas R. Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J Clin Invest. 1997; 100:2404–2414.

26. Liu MF, Chao SC, Wang CR, Lei HY. Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity. 2001; 34:107–113.

27. Yang M, Sun L, Wang S, Ko KH, Xu H, Zheng BJ, et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol. 2010; 184:3321–3325.

28. Yehudai D, Snir A, Peri R, Halasz K, Haj T, Odeh M, et al. B cell-activating factor enhances interleukin-6 and interleukin-10 production by ODN-activated human B cells. Scand J Immunol. 2012; 76:371–377.