Hofmann B, Bass H, Nishanian P, Faisal M, Figlin R A, Sarna G P, Fahey J L
Center for Interdisciplinary Research in Immunology and Disease, University of California, Los Angeles 90024-1747.
Clin Exp Immunol. 1992 Jun;88(3):548-54. doi: 10.1111/j.1365-2249.1992.tb06485.x.
Immune activation is central to many immune disorders. Clinical investigations have shown that immune activation can be quantified by measurements of soluble immune activation products in serum. Most in vitro studies of these immune activation products have focused on single products. In this study the specific cell sources and the major lymphokines inducing multiple activation products were investigated. In vitro addition of interferon-gamma (IFN-gamma) or IL-2 stimulated peripheral blood mononuclear cells to produce neopterin, beta 2-microglobulin (beta 2-M) and soluble IL-2 receptor (sIL-2R). These two lymphokines can act independently, because neutralizing antibodies to one of the lymphokines did not block the inducing activity of the other. Tumour necrosis factor-alpha (TNF-alpha) was also investigated and shown to be a less powerful inducer than IL-2 or INF-gamma. Separated lymphoid subpopulations responded differently to specific lymphokines. Monocytes produced only neopterin and only in response to INF-gamma. T cells released beta 2-M and sIL-2R in response to IL-2. B cells, however, were capable of producing all three immune activation products. Neopterin production in B cells was induced by either INF-gamma of IL-2, indicating that B cells have additional mechanisms for responding to lymphokines. To investigate whether these in vitro findings also occur in vivo, sera from patients who had received either rIL-2 or INF-gamma treatment were tested. INF-gamma administration led to substantial increases in serum neopterin but only a moderate beta 2-M increase and no increase in the serum sIL-2R levels. rIL-2 administration caused a substantial increase of all three serum immune activation products, consistent with our in vitro findings. The results confirm that increased serum levels of soluble immune activation products are indicators of increased cytokine production by lymphocytes and monocytes and also that B cells can be a prominent source of immune activation products.
免疫激活是许多免疫紊乱的核心。临床研究表明，免疫激活可通过测量血清中可溶性免疫激活产物来量化。这些免疫激活产物的大多数体外研究都集中在单一产物上。在本研究中，对诱导多种激活产物的特定细胞来源和主要淋巴因子进行了研究。体外添加干扰素-γ（IFN-γ）或白细胞介素-2（IL-2）刺激外周血单个核细胞产生新蝶呤、β2-微球蛋白（β2-M）和可溶性IL-2受体（sIL-2R）。这两种淋巴因子可独立发挥作用，因为针对其中一种淋巴因子的中和抗体不会阻断另一种淋巴因子的诱导活性。还对肿瘤坏死因子-α（TNF-α）进行了研究，结果表明它作为诱导剂的作用不如IL-2或INF-γ强。分离的淋巴细胞亚群对特定淋巴因子的反应不同。单核细胞仅产生新蝶呤，且仅对INF-γ有反应。T细胞对IL-2有反应时释放β2-M和sIL-2R。然而，B细胞能够产生所有三种免疫激活产物。B细胞中新蝶呤的产生可由INF-γ或IL-2诱导，这表明B细胞具有对淋巴因子作出反应的额外机制。为了研究这些体外研究结果在体内是否也会出现，对接受rIL-2或INF-γ治疗的患者的血清进行了检测。给予INF-γ导致血清新蝶呤大幅增加，但β2-M仅适度增加，血清sIL-2R水平未增加。给予rIL-2导致所有三种血清免疫激活产物大幅增加，这与我们的体外研究结果一致。这些结果证实，血清中可溶性免疫激活产物水平的升高是淋巴细胞和单核细胞细胞因子产生增加的指标，也证实B细胞可能是免疫激活产物的主要来源。
