Kitching A Richard, Turner Amanda L, Semple Timothy, Li Ming, Edgtton Kristy L, Wilson Gabrielle R, Timoshanko Jennifer R, Hudson Billy G, Holdsworth Stephen R
Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
J Am Soc Nephrol. 2004 Jul;15(7):1764-74. doi: 10.1097/01.asn.0000128968.27705.5e.
IL-12 and IFN-gamma play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ-specific autoimmunity are unknown. To establish the roles of endogenous IFN-gamma and IL-12 in experimental autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40-deficient (IL-12p40-/-) mice, and IFN-gamma-deficient (IFN-gamma-/-) mice by immunization with alpha3-alpha5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40-/- mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-gamma-/- mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40-/- mice, IFN-gamma-/- mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti-alpha3-alpha5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-gamma-/- mice had decreased anti-alpha3-alpha5(IV)NC1 IgG2a. Therefore, IFN-gamma-/- mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in alpha3-alpha5(IV)NC1 immunized IFN-gamma-/- mice and was suppressed by recombinant murine IFN-gamma. CD4+ cells from draining nodes of immunized IFN-gamma-/- mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ-specific autoimmunity, IL-12 is pathogenetic but IFN-gamma is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN-gamma has different effects.
白细胞介素 -12（IL -12）和干扰素 -γ（IFN -γ）在小鼠狼疮及肾小球肾炎的植入抗原模型中发挥关键作用。然而，它们在肾脏器官特异性自身免疫中的作用尚不清楚。为了确定内源性IFN -γ和IL -12在实验性自身免疫性抗肾小球基底膜（GBM）肾小球肾炎（EAG）中的作用，通过用α3 -α5（IV）NC1异二聚体免疫，在正常C57BL / 6小鼠（野生型，WT）、IL -12p40缺陷型（IL -12p40 -/-）小鼠和IFN -γ缺陷型（IFN -γ-/-）小鼠中诱导出EAG。在13周时，WT小鼠出现了伴有线性小鼠抗GBM抗体沉积、组织学损伤、蛋白尿和轻度肾小管间质疾病的EAG。与WT小鼠相比，IL -12p40 -/-小鼠的组织学损伤减轻，白细胞浸润有减少趋势。相比之下，40%（10只中的4只）的IFN -γ-/-小鼠出现了显著的新月体形成以及局灶性或弥漫性间质浸润（WT，8只中0只）。与WT和/或IL -12p40 -/-小鼠相比，IFN -γ-/-小鼠的损伤增加：组织学损伤、肾小球细胞总数、肾小球内白细胞以及P -选择素和细胞间黏附分子1的肾脏表达。所有组均产生了相似的血清抗α3 -α5（IV）NC1抗体和肾小球Ig沉积，但IFN -γ-/-小鼠的抗α3 -α5（IV）NC1 IgG2a减少。因此，尽管抗体反应的潜在损伤可能较小，但IFN -γ-/-小鼠的细胞反应性增强。在α3 -α5（IV）NC1免疫的IFN -γ-/-小鼠中，皮肤迟发型超敏反应增强，并且被重组鼠IFN -γ抑制。来自免疫的IFN -γ-/-小鼠引流淋巴结的CD4 +细胞显示增殖性CD4 +细胞比例增加，但凋亡细胞数量相似。这些研究表明，在肾脏器官特异性自身免疫中，IL -12具有致病作用，而IFN -γ具有保护作用。它们支持了这样一种假说，即根据致肾炎性免疫反应的背景/严重程度，IFN -γ具有不同的作用。
