Singh R R, Hahn B H, Sercarz E E
Department of Medicine/Rheumatology, University of California at Los Angeles 90095, USA.
J Exp Med. 1996 Apr 1;183(4):1613-21. doi: 10.1084/jem.183.4.1613.
Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.
新生儿暴露于抗原被认为会导致T细胞克隆失活或缺失。在此我们报告，与这一观念相反，以假定的“致耐受性”剂量给新生BALB/c小鼠注射鸡卵溶菌酶肽106 - 116，可诱导T细胞增殖以及T辅助细胞1（Th1）依赖性（IgG2a、IgG2b和IgG3）和Th2依赖性（IgG1）同种型的免疫球蛋白G（IgG）抗体（Ab）反应。在成年后用该肽与完全弗氏佐剂再次攻击时，尽管这种新生期方案抑制了增殖以及Th1细胞因子（白细胞介素[IL]-2和干扰素γ）的产生，但Th2细胞因子（IL-5、IL-4和IL-10）的分泌增加，且肽特异性Ab的Th1和Th2依赖性同种型的血清水平仍保持升高。Th1细胞中体外增殖无反应性可被抗Th2细胞因子（IL-4和IL-10）的抗体逆转。因此，用肽抗原进行新生期治疗可诱导T细胞致敏，包括产生Th1和Th2依赖性同种型的IgG Ab。在随后接触该肽后，肽特异性T细胞反应会朝着Th2方向发生有效的类别转换，导致T细胞增殖无反应性。因此，这种向自身抗原抗体产生增加的转变对于易患抗体介导疾病的个体可能是有害的。实际上，用来自抗DNA单克隆抗体（A6H 58 - 69）的自身自身抗原肽对新生狼疮易感NZB/NZW F1小鼠进行治疗，尽管抑制了肽特异性T细胞增殖，但显著提高了IgG抗双链DNA Ab水平。这种不良的临床反应与其他人报道的在Th1介导的自身免疫性疾病（如自身免疫性脑脊髓炎）中用自身抗原进行新生期治疗的有益结果形成鲜明对比。Th1向Th2的免疫偏离可以解释在自身抗体介导与Th1介导的自身免疫性疾病中假定诱导新生期耐受性后出现的不一致的生物学反应。
