Impaired Dendritic Cell Function in a Spontaneous Autoimmune Polyneuropathy

Abstract

Spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout non-obese diabetic (NOD) mice mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and is mediated by myelin P0-reactive Th1 cells. In this study, we focused on the effect of B7-2 deletion on the function of dendritic cells (DCs) within the context of SAP. We found that development of SAP was associated with a preponderance or increase of CD11b+ DCs in peripheral lymph nodes and sciatic nerves. B7-2 deletion led to altered immunophenotypic properties that differ between CD11b+ DCs and CD8α+ DCs. Both DC subsets from B7-2 knockout (KO) NOD mice exhibited impaired capacity to capture fluorophore-labeled myelin P0, but diminished antigen-presenting function was observed only in CD11b+ DCs. Clinical assessment, electrophysiologic studies and splenocyte proliferation studies revealed that absence of B7-2 on DCs was sufficient to cause impaired ability to induce tolerance to P0, which could be overcome by pre-conditioning with interleukin-10 (IL-10). Tolerance induction by antigen-pulsed WT NOD DCs was dependent on IL-10 and was associated with increased CD4+ regulatory T cells (Tregs), whereas tolerance induction by IL-10-conditioned B7-2 deficient DCs was associated with increased percentages of both Tregs and B10 cells in the spleen. We conclude that B7-2 deletion has an impact on the distribution of DC subsets in lymphoid organs, and alters the expression of co-stimulatory molecules, but functional consequences are not uniform across DC subsets. Defective tolerance induction in the absence of B7-2 can be restored by preconditioning of DCs with IL-10.

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies

“…In another model, Tregs also ameliorated neuritis induced by transfer of T cells from NOD.ICAM1 tm1Jcgr mice (28). Interestingly, the absence of B7-2 costimulatory molecules on DCs may prevent peripheral tolerance induction to P0 antigen and may occur through decreased Treg generation (29). Together, these findings suggest that Tregs normally play an important role in preventing PNS autoimmunity.…”

IL-10 Paradoxically Promotes Autoimmune Neuropathy through S1PR1-Dependent CD4+ T Cell Migration

“…On the surface, our findings may seem to contradict a recent report that IL-10 protected NOD. B7-2 −/− mice from SAPP (57). Quan et al, 2015 show that transfer of dendritic cells (DCs) pretreated with IL-10 protects from neuropathy.…”

Regulatory T and B lymphocytes in a spontaneous autoimmune polyneuropathy

“…Results of two trials were averaged for each mouse per session. After the last grip strength measurement, electrophysiological studies of sciatic nerves were performed as described in our previous publications . Latencies, conduction velocities and peak to peak amplitudes were measured.…”

“…Approximately 1 × 10 6 sorted cells were injected via tail vein into 6‐month‐old female B7‐2 –/– NOD mice for suppression studies and 5‐month‐old female B7‐2 –/– NOD mice for prevention studies. Serial clinical assessments, grip strength measurements and electrophysiology were performed as described previously . Animals were euthanized at the end of study duration for immunological studies.…”

“…More recently, we have demonstrated that absence of B7‐2 on DCs leads to impaired capacity to induce tolerance to P0, which can be restored by preconditioning with IL‐10. Adoptive transfer (AT) of IL‐10‐conditioned DCs leads to increased CD4 + T regs and B10 cells in vivo . Whether CD4 + T regs and B regs /B10 cells share overlapping or distinct functions in SAP has not been investigated.…”