Calich V L, Kashino S S
Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brasil.
Braz J Med Biol Res. 1998 May;31(5):615-23. doi: 10.1590/s0100-879x1998000500003.
Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-alpha and TGF-beta) and type-1 (IL-2 and IFN-gamma) and type-2 (IL-4,5,10) cytokines. Total lymph node cells from resistant mice infected i.p. with P. brasiliensis produced early and sustained levels of IFN-gamma and IL-2; type-2 cytokines (IL-4 and IL-5) started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-gamma concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-beta and low levels of TNF-alpha. In contrast, macrophages from A/Sn animals released high levels of TNF-alpha associated with a small production of TGF-beta. The in vivo depletion of IFN-gamma not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-alpha and IFN-gamma followed by a sustained secretion of IL-2 and IFN-gamma plays a dominant role in the resistance mechanisms to P. brasiliensis infection. In contrast, an early and ephemeral secretion of low levels of TNF-alpha and IFN-gamma associated with production of IL-5, IL-10 and TGF-beta characterizes the progressive disease of susceptible animals.
副球孢子菌病（PCM）是拉丁美洲最常见的深部真菌病，临床表现多样。我们建立了一种基因控制的PCM小鼠模型，其中A/Sn小鼠发生的感染模拟良性疾病（有利于细胞免疫的免疫反应），而B10.A动物则呈现PCM的进行性播散形式（B细胞优先激活和细胞免疫反应受损）。为了解实验性PCM中与抗性和易感性相关的免疫调节现象，对A/Sn和B10.A小鼠进行了研究，观察其抗原诱导的单核因子（TNF-α和TGF-β）以及1型（IL-2和IFN-γ）和2型（IL-4、5、10）细胞因子的分泌情况。经腹腔感染巴西副球孢子菌的抗性小鼠的总淋巴结细胞早期分泌并持续产生高水平的IFN-γ和IL-2；2型细胞因子（IL-4和IL-5）在感染8周后开始出现。相比之下，易感小鼠在感染早期产生低水平的IFN-γ，同时伴有高水平的IL-5和IL-10。在疾病的慢性期，易感动物出现IL-2和IL-4的短暂分泌。在肺部感染中，在易感动物的肺细胞冲洗液中优先检测到IL-4、IL-5和IL-10。用真菌抗原进行体外刺激后，来自B10.A小鼠的正常腹膜巨噬细胞分泌高水平的TGF-β和低水平的TNF-α。相比之下，来自A/Sn动物的巨噬细胞释放高水平的TNF-α，同时产生少量的TGF-β。体内IFN-γ的消耗不仅消除了A/Sn小鼠的抗性，还降低了B10.A动物的相对抗性。体内IL-4的消耗并未改变疾病结局，而给予重组IL-12可显著增强易感动物的抗性。综上所述，这些结果表明，早期高水平分泌TNF-α和IFN-γ，随后持续分泌IL-2和IFN-γ，在抵抗巴西副球孢子菌感染的机制中起主导作用。相比之下，早期短暂分泌低水平的TNF-α和IFN-γ，并伴有IL-5、IL-10和TGF-β的产生，是易感动物进行性疾病的特征。
