T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue.

It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D4) pathogenesis. In fact, a large proportion of islet-infiltrating B-lymphocytes in the NOD mouse model of T1D produce antibodies directed against the neuronal type III intermediate filament protein, peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B-lymphocytes express the heavy and light chain immunoglobulin molecules from the intra-islet derived anti-peripherin reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development and PerIg B-lymphocytes actively proliferate within islets and expand cognitively interactive pathogenic T-cells from a pool of naïve precursors. We now report adoptively transferred T-cells or whole splenocytes from NOD-PerIg mice expectedly induce T1D in NOD.scid recipients, but depending on the kinetics of disease development, can also elicit a peripheral neuritis (with secondary myositis). This neuritis was predominantly composed of CD4+ and CD8+ T-cells. Antibody depletion studies showed neuritis still developed in the absence of NOD-PerIg CD8+ T-cells, but required CD4+ T-cells. Surprisingly, sciatic nerve-infiltrating CD4+ cells had an expansion of IFN-γ− and TNF-α− double negative cells compared to those within both islets and spleen. Nerve and islet infiltrating CD4+ T-cells also differed by expression patterns of CD95, PD-1 and Tim-3. Further studies found transitory early B-lymphocyte depletion delayed T1D onset in a portion of NOD-PerIg mice allowing them to survive long enough to develop neuritis outside of the transfer setting. Together, this study presents a new model of peripherin-reactive B-lymphocyte dependent autoimmune neuritis.

人们越来越认识到，针对神经元成分的自身免疫反应在1型糖尿病（T1D）的发病机制中起着重要作用。事实上，在1型糖尿病的NOD小鼠模型中，很大比例的胰岛浸润性B淋巴细胞会产生针对神经元III型中间丝蛋白——外周蛋白的抗体。NOD - PerIg小鼠是一种先前开发的BCR转基因模型，其中几乎所有的B淋巴细胞都表达来自胰岛内源性抗外周蛋白反应性杂交瘤H280的重链和轻链免疫球蛋白分子。NOD - PerIg小鼠加速了1型糖尿病的发展，并且PerIg B淋巴细胞在胰岛内积极增殖，并从原始前体细胞库中扩增出具有认知相互作用的致病性T细胞。我们现在报道，从NOD - PerIg小鼠过继转移的T细胞或整个脾细胞预期会在NOD.scid受体中诱导1型糖尿病，但根据疾病发展的动力学，也可能引发周围神经炎（伴有继发性肌炎）。这种神经炎主要由CD4⁺和CD8⁺ T细胞组成。抗体耗竭研究表明，在没有NOD - PerIg CD8⁺ T细胞的情况下，神经炎仍然会发展，但需要CD4⁺ T细胞。令人惊讶的是，与胰岛和脾脏内的细胞相比，坐骨神经浸润的CD4⁺细胞中IFN - γ⁻和TNF - α⁻双阴性细胞有所扩增。神经和胰岛浸润的CD4⁺ T细胞在CD95、PD - 1和Tim - 3的表达模式上也存在差异。进一步的研究发现，暂时早期的B淋巴细胞耗竭延迟了一部分NOD - PerIg小鼠1型糖尿病的发病，使它们存活足够长的时间，在过继转移环境之外发展出神经炎。总之，这项研究提出了一种新的外周蛋白反应性B淋巴细胞依赖性自身免疫性神经炎模型。