AB0192 Proof of Concept, Self-Organized Criticality Theory of Autoimmunity: Autoantibody-Inducing CD4 T Cell That Causes SLE Belongs to CD45rb-Cd122-Pd1+ Subset
Authors: Y. Miyazaki, K. Tsumiyama, S. Shiozawa
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> A critical question in elucidating the pathogenesis of SLE or autoimmunity would be how autoreactive clones emerge and expand in the host. According to the prevailing view of autoimmune disease, autoreactive clones may come from either clones that had escaped negative selection in the thymus or clones that have been reactivated from tolerance. However, clones that would emerge by either process would be restricted in their antigen specificity and apparently could not account for the broad T cell receptor (TCR) repertoire and the more than 100 distinct autoantibody specificities found in SLE (Ref 1). We have proposed an alternative novel theory, called the self-organized criticality theory, which explains that systemic autoimmunity necessarily takes place when the host9s immune system is overdriven by repeated exposure to antigen, reaching levels that surpass the immune system9s stability-limit, i.e., self-organized criticality (Ref 2). We found that a CD4 T cell subset which has passed thru TCRα but not TCRβ revision is generated at peripheral lymphoid organ spleen after heavily repeated immunization with any antigen, and we named this CD4 T cell an "autoantibody-inducing CD4 T cell" (<i>ai</i>CD4 T cell). This <i>ai</i>CD4 T cell not only induced B cells to generate a large variety of autoantibodies, but also promoted final differentiation of CD8 T cells into cytotoxic T lymphocytes (CTL) <i>via</i> antigen cross-presentation, leading to the tissue injuries identical to those seen in SLE. This <i>ai</i>CD4 T cell is functionally indispensable for the pathogenesis of SLE. <h3>Objectives</h3> We report our recent findings on the distinct cell surface markers that characterize and identify <i>ai</i>CD4 T cells to be CD45RB<sup>lo</sup>122<sup>lo</sup> and programmed cell death-1 (PD-1)-positive. <h3>Methods</h3> BALB/c mice were repeatedly immunized with OVA. To investigate gene expression profiles of <i>ai</i>CD4 T cell, we performed microarray analysis of CD45RB<sup>lo</sup>122<sup>lo</sup> CD4 T cell after immunization 12x with OVA. CD45RB<sup>lo</sup>122<sup>lo</sup> CD4 T cells were isolated referring to PD-1 expression, and these fractionated cells were adoptively transferred into naïve recipients. Autoantibodies in sera of recipient mice were measured 2 weeks after cell transfer. <h3>Results</h3> Under microarray analysis, we found that gene expression of PD-1 was increased x2 in the CD45RB<sup>lo</sup>122<sup>lo</sup> CD4 subset. Simultaneously, surface expression of PD-1 protein was also significantly increased in this subset. Adoptive cell transfer of PD-1<sup>+</sup>CD45RB<sup>lo</sup>122<sup>lo</sup> CD4 T cells from 12x immunized mice significantly increased both RF and anti-dsDNA antibody in the naïve recipients. <h3>Conclusions</h3> The <i>ai</i>CD4 T cell that induces SLE belongs to PD-1<sup>+</sup>CD45RB<sup>lo</sup>122<sup>lo</sup> CD4 subpopulation. <h3>References</h3> Shiozawa S. Joint Bone Spine 79:428, 2012. 2, Tsumiyama K et al. PLoS ONE 4(12): e8382, 2009. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3938