Background/Purpose: One of the biggest obstacle we face in elucidating the pathogenesis of autoimmunity today is the mechanism how autoreactive lymphocyte clones could survive or emerge beyond the firewall called ‘forbidden clone’ of Burnet. We have proposed that autoreactive clones emerge via de novo T cell receptor (TCR) revision from thymus-passed non-autoreactive clones at periphery, and we named this T cell as autoantibody-inducing CD4 (aiCD4) T cell (Tsumiyama K et al. PLoS ONE 4(12):e8382, 2009). Our novel ‘self-organized criticality theory’ explains that systemic autoimmunity or systemic lupus erytematosus (SLE) necessarily takes place when host’s immune system is overdriven by repeated exposure to antigen to levels that surpass the immune system’s stability-limit, i.e., self-organized criticality. This aiCD4 T cells not only induced varieties of autoantibodies but also helped final maturation of CD8 T cell into cytotoxic T lymphocyte (CTL) via antigen cross-presentation to induce tissue injuries identical to SLE. We here examine the role of interferon α (IFNα) in relation to the aiCD4 T cell.  

Methods:  BALB/c mice were repeatedly immunized with ovalbumin (OVA), keyhole limpet hemocyanin (KLH) or staphylococcal enterotoxin B (SEB), and sera and tissues were examined using ELISA, immunohistopathogy, PCR, southern blotting and flow cytometry. Because IFNα transgenic (Tg) mice are basically infertile, we adopted a Tet-off expression system. Mouse IFNa1 (mIFNα)  cDNA integrated under TetOp promoter (TetOp-mIFNα) was microinjected into fertilized eggs of C57BL/6 to obtain TetOp-mIFNα Tg mice. They were mated with EµSR-tTA Tg mice under the control of IgH chain enhancer/SRα promoter (EµSR-tTA) to obtain double Tg TetOp-mIFNα/EµSR-tTA mice. IFNα was inducible 12 weeks after doxycycline cessation.

Results: Repeated immunization with antigen caused lesions identical to SLE including anti-dsDNA and anti-Sm autoantibodies in the mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4 T cells led to the development of aiCD4 T cell which had undergone TCR revision and was capable of inducing autoantibodies and overdriving CD8 T cell to become CTL via antigen cross-presentation leading to tissue injuries identical to SLE. However, in the IFNα Tg mice, the lesions identical to SLE just except for anti-Sm antibody were induced by solely increasing IFNα. Pathological lesions included IC-deposited glomerulonephritis, alopecia, epidermal liquefaction and positive skin lupus-band test and splenic onion-skin lesion. The IFNγ⁺ activated CD4 and CD8 T cells with effector phenotype (CTL) and activated CD3⁺CD4^–CD8^– double negative (DN) T cell pathognomonic for SLE were increased. This DN T cell not only infiltrated to glomeruli, but also induced de novo glomerulonephritis and alopecia upon transfer to naïve mice.

Conclusion:  IFNα causes SLE. However, IFNα does not represent the whole picture of SLE and thus, antigen induced mechanism, i.e., ‘self-organized criticality theory’, was discussed in relation to aiCD4 T cell and a classical DN T cell.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-%ce%b1-and-self-organized-criticality-theory/