Clinical Investigation| Volume 348, ISSUE 2, P156-161, August 2014

Decreased Interleukin 35 and CD4+EBI3+T cells in Patients With Active Systemic Lupus Erythematosus



      Interleukin 35 (IL-35) is likely to contribute to the development of autoimmune diseases, as the Epstein-Barr virus- induced gene protein 3 (EBI3) is the specificity subunit of IL-35. Nevertheless, until recently, no studies have evaluated its role in systemic lupus erythematosus (SLE) in humans. The objective of this study was to investigate the serum IL-35 level and the percentage of CD4+EBI3+ T cells in the peripheral blood of patients with SLE and explore the roles of double-positive T cells and IL-35 in the pathogenesis of SLE and the effects of glucocorticoid on these roles.


      Fifty-five hospitalized patients with SLE were recruited, and 20 volunteers were enrolled as healthy controls. Serum IL-35 levels were measured by enzyme-linked immunosorbent assay, and the percentage of CD4+EBI3+ T cells was analyzed by flow cytometry.


      The serum IL-35 level and the percentage of CD4+EBI3+ T cells were significantly decreased in patients with active SLE compared with healthy controls and patients with inactive SLE. The serum IL-35 level and the percentage of CD4+EBI3+ T cells were negatively correlated with the SLE disease activity index. The percentages of CD4+EBI3+ T cells and serum IL-35 levels in 10 untreated patients with active SLE were increased at days l, 3, and 7 after the treatment with methylprednisolone (0.8 mg-kg−1-d−1) compared with the percentages before the treatment.


      These results demonstrate that abnormalities in IL-35 and CD4+EBI3+ T cells may play important roles in the pathogenesis of SLE; the percentage of double-positive T cells and the level of IL-35 are parameters for the evaluation of SLE activity and severity.

      Key Indexing Terms

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of the Medical Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rahman A.
        • Isenberg D.A.
        Systemic lupus erythematosus.
        N Engl J Med. 2008; 358 (9): 929
        • Herrmann M.
        • Voll R.E.
        • Kalden J.R.
        Etiopathogenesis of systemic lupus erythematosus.
        Immunol Today. 2000; 9: 424-426
        • Pan H.F.
        • Ye D.Q.
        • Li X.P.
        Type 17 T-helper cells might be a promising therapeutic target for systemic lupus erythematosus.
        Nat Clin Pract Rheumatol. 2008; 4: 352-353
        • Li Z.J.
        • Li Y.J.
        • Huang L.H.
        • et al.
        Expression of interleukin-12 and its signaling molecules in peripheral blood mononuclear cells in systemic lupus erythematosus patients.
        Chin Med J (Engl). 2002; 115: 846-850
        • Ouyang H.
        • Shi Y.B.
        • Su N.
        • et al.
        Abnormality and significance of IL-9 and CD4+IL−9+T-cells in peripheral blood of patients with systemic lupus erythematosus [in Chinese].
        Zhonghua Yi Xue Za Zhi. 2013; 93: 99-103
        • Chen X.W.
        • Zhang Z.
        • Jiang L.M.
        • et al.
        Elevated interleukin-13 in patients with active lupus nephritis.
        Chin Med J (Engl). 2001; 114: 1022-1025
        • Devergne O.
        • Birkenbach M.
        • Kieff E.
        Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin.
        Proc Natl Acad Sci U S A. 1997; 94: 12041-12046
        • Devergne O.
        • Hummel M.
        • Koeppen H.
        • et al.
        A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes.
        J Virol. 1996; 70: 1143-1153
        • Niedobitek G.
        • Päzolt D.
        • Teichmann M.
        • et al.
        Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed-Sternberg cells.
        J Pathol. 2002; 198: 310-316
        • Niedbala W.
        • Wei X.Q.
        • Cai B.
        • et al.
        IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells.
        Eur J Immunol. 2007; 37: 3021-3029
        • Yang J.
        • Yang M.
        • Htut T.M.
        • et al.
        Epstein-Barr virus-induced gene 3 negatively regulates IL-17, IL-22 and RORgammat.
        Eur J Immunol. 2008; 38: 1204-1214
        • Nieuwenhuis E.E.
        • Neurath M.F.
        • Corazza N.
        • et al.
        Disruption of T helper 2-immune responses in Epstien-Barr virus-induced gene 3-deficient mice.
        Proc Natl Acad Sci U S A. 2002; 99: 16951-16956
        • Collison L.W.
        • Workman C.J.
        • Kuo T.T.
        • et al.
        The inhibitory cytokine IL-35 contributes to regulatory T-cell function.
        Nature. 2007; 450: 566-569
        • Whitehead G.S.
        • Wilson R.H.
        • Nakano K.
        • et al.
        IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease.
        J Allergy Clin Immunol. 2012; 129: 207-215
        • Bardel E.
        • Larousserie F.
        • Charlot-Rabiega P.
        • et al.
        Human CD4+CD25+Foxp3+ regulatory T cells do not constitutively express IL-35.
        J Immunol. 2008; 181: 6898-6905
        • Allan S.E.
        • Song-Zhao G.X.
        • Abraham T.
        • et al.
        Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3.
        Eur J Immunol. 2008; 38: 3282-3289
        • Chaturvedi V.
        • Collison L.W.
        • Guy C.S.
        • et al.
        Cutting edge. Human regulatory T cells require IL-35 to mediate suppression and infectious tolerance.
        J Immunol. 2011; 186: 6661-6666
        • Collison L.W.
        • Chaturvedi V.
        • Henderson A.L.
        • et al.
        IL-35-mediated induction of a potent regulatory T cell population.
        Nat Immunol. 2010; 11: 1093-1101
        • Kochetkova I.
        • Golden S.
        • Holderness K.
        • et al.
        IL-35 stimulation of CD39+regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10.
        J Immunol. 2010; 184: 7144-7153
        • Tan E.M.
        • Cohen A.S.
        • Fries J.F.
        • et al.
        The 1982 revisedcriteria for the classification of systemic lupus erythematosus.
        Arthritis Rheum. 1982; 25: 1271-1277
        • Bombardier C.
        • Gladman D.D.
        • Urowitz M.B.
        • et al.
        Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE.
        Arthritis Rheum. 1992; 35: 630-640
        • Zandian M.
        • Mott K.R.
        • Allen S.J.
        • et al.
        Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2.
        Gene Ther. 2011; 18: 734-742
        • Huang C.H.
        • Loo E.X.
        • Kuo I.C.
        • et al.
        Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35.
        J Immunol. 2011; 187: 462-471
        • Cai X.Y.
        • Luo M.
        • Lin X.J.
        • et al.
        Expression and significance of Th17 and Treg cells in peripheral blood of patients with systemic lupus erythematosus [in Chinese].
        Zhonghua Yi Xue Za Zhi. 2012; 92: 460-463
        • Suarez A.
        • Lopez P.
        • Comez J.
        • et al.
        Enrichment of CD4+ CD25 high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids.
        Ann Rheum Dis. 2006; 65: 1512-1517