Elkoshi Zeev
Research and Development Department, Taro Pharmaceutical Industries Ltd, Haifa, Israel.
J Inflamm Res. 2021 Mar 18;14:929-947. doi: 10.2147/JIR.S303750. eCollection 2021.
In an earlier publication a binary model for chronic diseases classification has been proposed. According to the model, chronic diseases were classified as "high Treg" or "low Treg" diseases, depending on whether the immune response is anti- or pro-inflammatory and assuming that regulatory T cells are major determinants of the response. It turned out that most cancers are "high Treg" diseases, while autoimmune diseases are "low Treg". This paper proposes a molecular cause for this binary response. The mechanism proposed depends on the effect of protein kinases on the immune system. Thus, protein kinases are classified as anti- or pro-inflammatory kinases depending on whether they drive "high Treg" or "low Treg" diseases. Observations reported in the earlier publication can be described in terms of anti-inflammatory kinase (AIK) or pro-inflammatory kinase (PIK) activity. Analysis of literature data reveals that the two classes of kinases display distinctive properties relating to their interactions with pathogens and environmental factors. Pathogens that promote Treg activity ("high Treg" pathogens) activate AIKs, while pathogens that suppress Treg activity ("low Treg" pathogens) activate PIKs. Diseases driven by AIKs are associated with "high Treg" pathogens while those diseases driven by PIKs are associated with "low Treg" pathogens. By promoting the activity of AIKs, alcohol consumption increases the risk of "high Treg" cancers but decreases the risk of some "low Treg" autoimmune diseases. JAK1 gain-of-function mutations are observed at high frequencies in autoimmune diseases while JAK1 loss-of-function mutations are observed at high frequencies in cancers with high tumor-infiltrating Tregs. It should also be noted that the corresponding two classes of protein kinase inhibitors are mutually exclusive in terms of their approved therapeutic indications. There is no protein kinase inhibitor that is approved for the treatment of both autoimmune diseases and "high Treg" cancers. Although there are exceptions to the conclusions presented above, these conclusions are supported by the great bulk of published data. It therefore seems that the binary division of protein kinases is a useful tool for elucidating (at the molecular level) many distinctive properties of cancers and autoimmune diseases.
在早期的一篇出版物中，有人提出了一种用于慢性疾病分类的二元模型。根据该模型，慢性疾病被分为“高调节性T细胞（Treg）”或“低调节性T细胞（Treg）”疾病，这取决于免疫反应是抗炎还是促炎，并假设调节性T细胞是反应的主要决定因素。结果发现，大多数癌症是“高Treg”疾病，而自身免疫性疾病是“低Treg”疾病。本文提出了这种二元反应的分子原因。所提出的机制取决于蛋白激酶对免疫系统的作用。因此，根据蛋白激酶是驱动“高Treg”还是“低Treg”疾病，将其分为抗炎激酶或促炎激酶。早期出版物中报道的观察结果可以用抗炎激酶（AIK）或促炎激酶（PIK）活性来描述。对文献数据的分析表明，这两类激酶在与病原体和环境因素的相互作用方面表现出独特的特性。促进Treg活性的病原体（“高Treg”病原体）激活AIK，而抑制Treg活性的病原体（“低Treg”病原体）激活PIK。由AIK驱动的疾病与“高Treg”病原体相关，而由PIK驱动的疾病与“低Treg”病原体相关。通过促进AIK的活性，饮酒会增加“高Treg”癌症的风险，但会降低一些“低Treg”自身免疫性疾病的风险。在自身免疫性疾病中，JAK1功能获得性突变的发生率很高，而在肿瘤浸润性Treg高的癌症中，JAK1功能丧失性突变的发生率很高。还应注意的是，相应的两类蛋白激酶抑制剂在其批准的治疗适应症方面是相互排斥的。没有一种蛋白激酶抑制剂被批准用于治疗自身免疫性疾病和“高Treg”癌症。尽管上述结论存在例外情况，但这些结论得到了大量已发表数据的支持。因此，蛋白激酶的二元划分似乎是在分子水平上阐明癌症和自身免疫性疾病许多独特特性的有用工具。
