Daifallah Omar, Farah Adham, Dawes John M
Department of Zoology, King Saud University, Riyadh, Saudi Arabia.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Front Mol Neurosci. 2023 Sep 20;16:1254854. doi: 10.3389/fnmol.2023.1254854. eCollection 2023.
The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen's syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.
免疫系统在神经性疼痛中发挥作用，其中包括自身免疫机制（例如自身抗体）。临床研究已经确定了许多神经性疼痛常见的病症，这些病症与针对神经系统内抗原的自身抗体有关。有趣的是，免疫疗法或血浆置换可以缓解感觉症状，这表明这些患者的疼痛是由抗体介导的。最近的临床前研究直接探讨了这一问题。例如，将患者的接触蛋白相关蛋白2（CASPR2）自身抗体被动转移到小鼠体内，会导致小鼠疼痛敏感性增加和感觉神经元兴奋性增强，证实了其致病性，并表明患者自身抗体是导致神经性疼痛的一种机制。小纤维神经病变（SFN）仅影响小感觉纤维（通常是伤害感受器），其特征是严重的神经性疼痛。已知病因包括糖尿病、维生素B12缺乏以及钠通道基因的罕见变异，尽管约50%的病例病因不明。SFN与自身免疫性疾病如干燥综合征、结节病和乳糜泻有关，静脉注射免疫球蛋白（IVIG）形式的免疫疗法已被证明是一种有效的治疗方法。已经鉴定出自身抗体，在某些情况下，将SFN患者的免疫球蛋白G（IgG）被动转移到小鼠体内可重现神经性疼痛样行为。在这里，我们将讨论与致病性自身抗体导致小纤维神经病变这一观点相关的临床和临床前数据。我们将讨论假定的致病性抗体、细胞靶点以及它们导致感觉神经元损伤和神经性疼痛发展的分子机制。最后，我们将对未来的研究方向进行评论，这些方向可能会为深入了解患者小纤维神经病变的潜在机制提供进一步的见解。
