Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Interferon Causes SLE by Expanding CD3 CD4 CD8 Double Negative T Cell (DN T Cell).

Akiyama1,  Chieri, Honda1,  Eriko, Hashiramoto2,  Akira, Felsher3,  Dean W., Shiozawa2,  Shunichi

Department of Biophysics, Graduate School of Health Science, Kobe University, Kobe, Hyogo, Japan
Department of Biophysics, Graduate School of Health Science, Kobe University/Department of Medicine, Graduate School of Medicine, Kobe University/The Center for Rheumatic Disease, Kobe University Hospital, Kobe, Japan
Stanford University, School of Medicine, Division of Oncology, Department of Medicine and Pathology, Stanford, CA

Objective:

Interferon alpha (IFNa) has been suggested to cause systemic lupus erythematosus (SLE), however, the direct proof for this is lacking. We showed by solely increasing IFNa in doxycycline-inducible transgenic mice (IFNa Tg mice) that IFNa induces autoantibodies including serum anti-dsDNA antibody, serum immune complex (IC) and lupus-like tissue injuries (Uchimura C et al. Arthritis Rheum 56 (suppl.9):S200).

We now show that IFNa causes SLE by expanding CD3+ CD4- CD8- double negative T cell (DN T cell) to induce lupus glomerulonephritis.

Methods:

Mouse IFNa (mIFNa) cDNA, amplified by RT-PCR, was subcloned into pTet Splice vector under the control of TetOp promoter to generate TetOp-mIFNa. This was microinjected into fertilized eggs of C57BL/6 to generate TetOp-mIFNa Tg mice. The EmSR-tTA Tg mice of FVB/N background was mated with TetOp-mIFNa Tg mice to obtain double Tg mice (IFNa Tg mice). Serum IFNa was measured using Mu-IFN-a ELISA kit. Serum autoantibodies and IC were measured with ELISA, referring to pooled sera of MRL/lpr female adult mice (arbitrary units).Proteinuria were measured semiquantitatively using urine dipsticks. Frozen kidney sections were stained for C3 and IgG using immunofluorescent antibodies. To detect intracellular IFNa, splenocytes (1×106/ml) were stimulated with ionomycin and phorbol 12-myristate 13-acetate for 4 h in the presence of blefeldin A. Cells were then stained with anti-CD4 and anti-CD8 antibodies, followed by fixation, permeabilization with saponin and treatment with anti-IFNa antibody. The CD3+ (5×106), CD4+(5×106), CD8+ (5×106), and DN(3×105) subsets derived from the IFNa Tg mice of 30 weeks after cessation of Dox were transferred twice into naÏve recipients, and renal histopathology was studied 21 days after transfer.

Results:

In IFNa Tg mice, pathological lesion consisted of IC-deposited glomerulonephritis, interstitial lung disease, liquefaction and positive lupus band test in the skin epidermis, onion skin lesion in the spleen and inflammatory infiltrates to salivary gland and bile duct. Activated effector CD4+ and CD8+ T cells producing IFNa were increased, in which IFNa+CD8+ T cell with effector phenotype, i.e., full-matured CTL, and in particular, activated CD3+CD4-CD8- double negative T cell (DN T cell) was increased. The DN T cells not only infiltrated to the glomerular lesions of IFNa Tg mice but also induced de novo glomerulonephritis when transferred into naÏve recipients. Thus, IFNa is responsible for the core manifestation of SLE except for anti-Sm autoantibody.

Conclusion:

IFNa causes SLE by expanding CD3+ CD4- CD8- double negative T cell (DN T cell) to induce lupus glomerulonephritis.

To cite this abstract, please use the following information:
Akiyama, Chieri, Honda, Eriko, Hashiramoto, Akira, Felsher, Dean W., Shiozawa, Shunichi; Interferon Causes SLE by Expanding CD3 CD4 CD8 Double Negative T Cell (DN T Cell). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :434
DOI: 10.1002/art.28203

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