MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

Abstract

Nerve injury-induced chronic pain has been an urgent problem for both public health and clinical practice. While transition to chronic pain is not an inevitable consequence of nerve injuries, the susceptibility/resilience factors and mechanisms for chronic neuropathic pain after nerve injuries still remain unknown. Current preclinical and clinical studies, with certain notable limitations, have shown that major histocompatibility complex class II-restricted T helper (Th) cells is an important trigger for nerve injury-induced chronic tactile allodynia, one of the most prevalent and intractable clinical symptoms of neuropathic pain. Moreover, the precise pathogenic neuroimmune interfaces for Th cells remain controversial, not to mention the detailed pathogenic mechanisms. In this review, depending on the biology of Th cells in a neuroimmunological perspective, we summarize what is currently known about Th cells as a trigger for chronic tactile allodynia after nerve injuries, with a focus on identifying what inconsistencies are evident. Then, we discuss how an interdisciplinary perspective would improve the understanding of Th cells as a trigger for chronic tactile allodynia after nerve injuries. Finally, we hope that the expected new findings in the near future would translate into new therapeutic strategies via targeting Th cells in the context of precision medicine to either prevent or reverse chronic neuropathic tactile allodynia.

Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain

“…The importance of MHC class II genes for CNP development indicates that, similar to the animal models, CD4 + Th cells contribute to CNP development in human patients. The relevance of MHCII-restricted T helper cells as an important trigger for chronic hypersensitivity after nerve injuries has been recently discussed by Ding et al ( 28 ), where they indicate that there is a growing body of clinical evidences showing that increased blood Th cell numbers and changes in subset patterns are correlated with neuropathic pain intensities after nerve injuries. Other clinical data indicate that an emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain ( 29 ).…”

Sensory root demyelination: Transforming touch into pain

“…In recent years, we have seen remarkable progress in our understanding of the neural circuits for painful touch in the dorsal horns of the spinal cord or medulla, with an increasing emphasis on the upstream roles of local non-neuronal cells (summarized in Figure 1; detailed in our and other recent reviews) (Ding et al, 2020;Moehring et al, 2018).…”

“…In recent years, we have seen remarkable progress in our understanding of the neural circuits for painful touch in the dorsal horns of the spinal cord or medulla, with an increasing emphasis on the upstream roles of local non‐neuronal cells (summarized in Figure 1; detailed in our and other recent reviews) (Ding et al, 2020; Moehring et al, 2018). After a parallel and intermingle journey through peripheral nerves/sensory ganglia/sensory roots, Aδ/C nociceptors and Aβ touch receptors (also known as low‐threshold mechanoreceptors; LTMRs) are separately engaged into the superficial pain neurocircuits and the deep touch neurocircuits in the dorsal horns (Figure 1a).…”

“…Therefore, touch is not felt as pain under physiological conditions. Under neuropathic or inflammatory conditions, aberrant inputs from hyper‐excitable primary sensory neurons and/or altered descending supraspinal inputs collectively drive or strengthen the enhancement of excitatory synaptic transmission and the degeneration of inhibitory synaptic transmission (e.g., inhibitory interneuron death or inhibitory synapse pruning) in local touch‐to‐pain transforming neurocircuits (Figure 1b) (Ding et al, 2020). Moreover, local non‐neuronal cells, including microglia and astrocytes, are abnormally activated to induce or maintain these facilitation and disinhibition processes that open or overcome the feed‐forward inhibitory neuronal gates for painful touch (Ding et al, 2020; Ji et al, 2016).…”

“…Under neuropathic or inflammatory conditions, aberrant inputs from hyper‐excitable primary sensory neurons and/or altered descending supraspinal inputs collectively drive or strengthen the enhancement of excitatory synaptic transmission and the degeneration of inhibitory synaptic transmission (e.g., inhibitory interneuron death or inhibitory synapse pruning) in local touch‐to‐pain transforming neurocircuits (Figure 1b) (Ding et al, 2020). Moreover, local non‐neuronal cells, including microglia and astrocytes, are abnormally activated to induce or maintain these facilitation and disinhibition processes that open or overcome the feed‐forward inhibitory neuronal gates for painful touch (Ding et al, 2020; Ji et al, 2016). As a result, touch inputs from myelinated LTMRs (Maksimovic et al, 2014; Neubarth et al, 2020; Zimmerman et al, 2014) are allowed to abnormally enter into the pain neurocircuits in the superficial dorsal horns and ultimately turns touch into pain (Moehring et al, 2018; Peirs et al, 2020).…”