Evidence from Human and Animal Studies: Pathological Roles of CD8+ T Cells in Autoimmune Peripheral Neuropathies

Abstract

Autoimmune peripheral neuropathies such as Guillain-Barre Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) affect millions of people worldwide. Despite significant advances in understanding the pathology, the molecular and cellular mechanisms of immune-mediated neuropathies remain elusive. T lymphocytes definitely play an important role in disease pathogenesis and CD4+ T cells have been the main area of research for decades. This is partly due to the fact that the most frequent animal model to study autoimmune peripheral neuropathy is experimental allergic neuritis (EAN). As it is induced commonly by immunization with peripheral nerve proteins, EAN is driven mainly by CD4+ T cells. However, similarly to what has been reported for patients suffering from multiple sclerosis, a significant body of evidence indicates that CD8+ T cells may play a pathogenic role in GBS and CIDP disease development and/or progression. Here, we summarize clinical studies pertaining to the presence and potential role of CD8+ T cells in autoimmune peripheral neuropathies. We also discuss the findings from our most recent studies using a transgenic mouse line (L31 mice) in which the T cell co-stimulator molecule B7.2 (CD86) is constitutively expressed in antigen presenting cells of the nervous tissues. L31 mice spontaneously develop peripheral neuropathy, and CD8+ T cells are found accumulating in peripheral nerves of symptomatic animals. Interestingly, depletion of CD4+ T cells accelerates disease onset and increases disease prevalence. Finally, we point out some unanswered questions for future research to dissect the critical roles of CD8+ T cells in autoimmune peripheral neuropathies.

Animal models of chronic inflammatory demyelinating polyneuropathy

“…The pathogenesis of inflammatory demyelination might be caused not only by CD4+ T cells and macrophages, but possibly also B cells, plasmablasts and autoantibodies . Future studies should confirm the Th1/Th2 balance and verify the role of CD8+ T cells …”

“…In addition to NOD mice, B7‐2 constitutively expressed mice with the C57/B6 background (line 31, L31) have also been reported to develop chronic spontaneous peripheral polyneuropathy (Table ) . In L31 mice, CD8+ T cells accumulate in the peripheral nerves of symptomatic mice.…”

“…42,43,45,46 Future studies should confirm the Th1/ Th2 balance and verify the role of CD8+ T cells. 47,48 NOD with HLA/H2 g7 haplotype are a common background for other similar models that lead to spontaneous autoimmune polyneuropathies by modifying costimulatory factors and adhesion molecules. For example, NOD mice with a partial loss of Aire gene function (NOD Aire GW/+ ) also spontaneously develop autoimmune neuritis.…”

“…52,56 In addition to NOD mice, B7-2 constitutively expressed mice with the C57/B6 background (line 31, L31) have also been reported to develop chronic spontaneous peripheral polyneuropathy (Table 2). 47,57 In L31 mice, CD8+ T cells accumulate in the peripheral nerves of symptomatic mice. Although the molecular targets for L31 mice have not been fully elucidated, major histocompatibility complex class I-expressing cells including Schwann cells are a potential candidate.…”

Pain in autoimmune disorders

“…The involvement of T cells in various autoimmune disorders has been well established. Both CD4 + and CD8 + T‐cell subtypes have been implicated in several autoimmune diseases, such as multiple sclerosis, type 1 diabetes, and Guillain‐Barré syndrome (Ferretti and La Cava, 2015; Salou et al ; Yang et al, ). An imbalance in T‐helper 1 (Th1)/Th2 immunity has traditionally been thought to contribute to autoimmune disease development (O'Shea et al, ; Coffman, ; Moudgil, ).…”