[No Title Available]

Abstract

A critical review on the granulomatous chronic inflammation induced by Paracoccidioides brasiliensis, the agent of paracoccidioidomycosis, will be presented. The epithelioid granuloma is considered to be the most evolved tissue inflammatory host response against parasites, which consequently implicates complex and intricate molecular mechanisms and cellular modulation. An effective host granulomatous inflammatory response results in compact, pauciparasitic granulomata which are seen in the chronic, localized, "benign" , forms of the mycosis in contrast to the loose, exudative, disorganized parasite-rich granulomata seen in the acute, disseminated, "malignant" forms. During the last years, several national and international groups of research have investigated both host defense mechanisms which act to induce a protective, fungistatic, tissular response to the agent as well as how the parasite evades the host defenses in order to survive and multiply. The investigative approaches to these mechanisms can be summarized as follows: i) In vitro experiments with lymphomononuclear cells from treated or "cured" patients as well as from patients with the acute or chronic forms of the disease, or with the paracoccidioidic infection (subclinical asymptomatic form, with positive paracoccidioidin test) and ii) In vivo testing on human biopsy or on samples from experimentally infected animals. The in vitro experiments have been carried out by evaluating the fungistatic and fungicidal activity, as well as the secretion of cytokines, by circulating leukocytes stimulated with purified fungal antigens with the modulation of pro-and anti-inflammatory mediators. The in vivo studies have tested by immunohistochemistry or PCR i) the tissular expression of defensive or modulatory molecules, ii) the immunophenotyping of the infiltrating cells and iii) the cytokine network acting at and promoting the granulomatous inflammatory response. More recently, experimental models using knockout animals for anti-and proinflammatory cytokines genes have contributed significantly to the understanding of several features of the host-parasite relationship in the mycosis. Based on these results, therapeutic targets have been defined and protocols for immunotherapy and vaccination have been tested aiming at increasing the host defenses against the parasite. In summary, we will try to look critically at the amount of new information on the physiopathology of the mycosis, in order to interconnect as much as possible the available data as to be able to point out future investigative avenues which will eventually help the patients to survive with no sequelae.