Pichler Werner J, Beeler Andreas, Keller Monika, Lerch Marianne, Posadas Sinforiano, Schmid Daphné, Spanou Zoi, Zawodniak Anna, Gerber Basil
Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspitel, Berne, Switzerland.
Allergol Int. 2006 Mar;55(1):17-25. doi: 10.2332/allergolint.55.17.
Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an endogenous protein the immune system reacts to this so called hapten-carrier complex, as the larger molecule (protein) is modified, and thus immunogenic for B and T cells. Consequently, a B and T cell immune response might develop to the drug with very heterogeneous clinical manifestations. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept. While the exact mechanism is still a matter of debate, non-covalent drug presentation clearly leads to the activation of drug-specific T cells as documented for various drugs (lidocaine, sulfamethoxazole (SMX), lamotrigine, carbamazepine, p-phenylendiamine, etc.). In some patients with drug hypersensitivity, such a response may occur within hours even upon the first exposure to the drug. Thus, the reaction to the drug may not be due to a classical, primary response, but rather be mediated by stimulating existing, pre-activated, peptide-specific T cells that are cross specific for the drug. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the peculiar nature of many drug hypersensitivity reactions.
药物诱导的超敏反应已通过半抗原概念进行解释，根据该概念，一种小的化合物因其太小而无法被免疫系统识别。只有在与内源性蛋白质共价结合后，免疫系统才会对这种所谓的半抗原 - 载体复合物产生反应，因为较大的分子（蛋白质）被修饰，从而对B细胞和T细胞具有免疫原性。因此，可能会对该药物产生具有非常异质性临床表现的B细胞和T细胞免疫反应。然而，近年来，越来越多的证据表明，并非所有药物都需要与MHC - 肽复合物共价结合才能触发免疫反应。相反，一些药物可能直接且可逆地与免疫受体如主要组织相容性复合体（MHC）或T细胞受体（TCR）结合，从而类似于其他受体的药理学激活来刺激细胞。这一概念被称为与免疫受体的药理学相互作用（p - i）概念。虽然确切机制仍存在争议，但非共价药物呈递显然会导致药物特异性T细胞的激活，这已在多种药物（利多卡因、磺胺甲恶唑（SMX）、拉莫三嗪、卡马西平、对苯二胺等）中得到证实。在一些药物超敏患者中，即使在首次接触药物后数小时内也可能发生这种反应。因此，对药物的反应可能不是由于经典的初次反应，而是由刺激现有的、预激活的、对药物具有交叉特异性的肽特异性T细胞介导的。通过这种方式，某些药物可能绕过经典抗原加工和呈递机制施加的免疫激活检查点，这可能有助于解释许多药物超敏反应的特殊性质。
