Human Brucellosis Is Characterized by an Intense Th1 Profile Associated with a Defective Monocyte Function

Abstract

In animal models, a defective Th1 response appears to be critical in the pathogenesis of brucellosis, but the Th1 response in human brucellosis patients remains partially undefined. Peripheral blood from 24 brucellosis patients was studied before and 45 days after antibiotherapy. Twenty-four sex-and age-matched healthy donors were analyzed in parallel. Significantly increased levels of interleukin 1␤ (IL-1␤), IL-2, IL-4, IL-6, IL-12p40, gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣), but not of IL-10, in serum and/or significantly increased percentages of samples with detectable levels of these cytokines, measured by enzymelinked immunosorbent assays (ELISA), were found for untreated brucellosis patients, but these levels were reduced and/or normalized after treatment. Flow cytometry studies showed that the intracytoplasmic expression of IFN-␥, IL-2, and TNF-␣, but not that of IL-4, by phorbol myristate-activated CD4 ؉ CD3 ؉ and CD8 ؉ CD3 ؉ T lymphocytes was significantly increased in untreated brucellosis patients and was also partially normalized after antibiotherapy. The percentage of phagocytic cells, the mean phagocytic activity per cell, and the phagocytic indices for monocytes at baseline were defective and had only partially reverted at follow-up. T lymphocytes from untreated brucellosis patients are activated in vivo and show Th1 cytokine production polarization, with strikingly high serum IFN-␥ levels. In spite of this Th1 environment, we found deficient effector phagocytic activity in peripheral blood monocytes.Brucellosis is a zoonotic disease of worldwide distribution. Despite its control in many countries, it remains endemic in the Mediterranean and Middle Eastern regions (20,28,41,42). Brucella melitensis is the most frequent cause of human brucellosis in these geographical areas (19). In Spain, it has been reported that the majority (more than 97.5%) of isolates were identified as Brucella melitensis (13,44,45).Brucella organisms are facultatively intracellular Gram-negative coccobacilli that reside and replicate in a vacuolar compartment within myelomonocytic cells of the infected host (14,15,47). The response to Brucella involves the whole gamut of the immune system, from innate to adaptive immunity (21). In murine models, passive transfer of immune cells resulted in an effective antiBrucella defensive response mediated by CD4 ϩ and CD8 ϩ T lymphocytes (5, 6, 32, 37, 51, 52). Furthermore, the pattern of T-lymphocyte cytokine secretion is considered to be critical for the effectiveness of the protective anti-Brucella immune response (3, 7). It has been postulated that Th1 cytokines confer resistance, while Th2 cytokines facilitate the development of brucellosis (2,3,24,25,40,43,52). In animal models, gamma interferon (IFN-␥) induces macrophage activation and control of Brucella infection (16,18,43). In Brucella-infected mice, administration of recombinant IFN-␥ enhances host resistance, resulting in a deep decrease in the number of viable bacteria (51). Moreover, host IFN-␥ de...

Acute Brucella melitensis M16 infection model in mice treated with tumor necrosis factor-alpha inhibitors

“…That study also showed that high TNFα levels were decreased by brucellosis treatment. A recently published study reported results similar to those of Demirdag et al [6].…”

“…are intracellular bacteria that release cytokines such as IFN-gamma, IL-2, and TNFα. Activated macrophages and dendritic cells are required for the immune response against Brucella infection [4][5][6]. TNFα has a critical role in macrophage activation, apoptosis, proinflammatory cytokine release, and granuloma formation.…”

Study the Impact of T-helper 1 Cytokine (TNF-α) Polymorphisms on Susceptibility/Resistance to Brucellosis in Makkah Region

“…This involves mainly activated antigen-presenting cells (dendritic cells, macrophages) and CD4+, CD8+ T lymphocytes. This is mediated by a Th1 immune response and is considered to be critical for the efficiency of the protective anti-Brucella immune response (Zhan et al, 1993;Rodriguez-Zapata et al, 2010). The activated host antigen-presenting cells release interleukin-12 (IL-12), which causes the differentiation of Th0 cells into Th1 cells that secrete gamma interferon (IFN-γ) and up-regulates macrophage killing mechanisms.…”

The IL4-VNTR P1 Allele, IL4-VNTR P2P2 Genotype, and IL4-VNTR_IL6-174CG P2P1-GG Genotype Are Associated with an Increased Risk of Brucellosis

“…Acute human brucellosis also raises IL-8 levels (19). Significantly increased levels of IL-4 and IL-6 have been found in untreated brucellosis patients (20).…”