Defective interferon‐gamma production by T‐lymphocytes from patients with acute brucellosis

Zapata, Manuel Rodríguez; Salmerón, I; Manzano, Luís; Salmerón, Octavio J.; Prieto, Alfredo; Álvarez‐Mon, Melchor

doi:10.1046/j.1365-2362.1996.108250.x

Cited by 37 publications

(32 citation statements)

References 11 publications

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“…The finding of enhanced intracytoplasmic IFN-␥ expression in T lymphocytes from brucellosis patients agrees with the increased serum cytokine levels observed (1,27). We previously found decreased IFN-␥ production by phytohemagglutinin (PHA)-stimulated T-lymphocyte-enriched cultures (46). PHA is a monocyte-dependent mitogen (50).…”

Section: Discussionsupporting

confidence: 79%

“…Several abnormalities in the immune system have been found in human brucellosis (27,46,49). It has been found that T and NK lymphocytes show defective functions in brucellosis patients (46,49). Since mice are naturally resistant to Brucella infections, it is possible to suggest that the immune response elicited by Brucella in humans might have different characteristics.…”

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confidence: 99%

“…Moreover, host IFN-␥ depletion results in an increase in the number of viable bacteria (17,37,52). Several abnormalities in the immune system have been found in human brucellosis (27,46,49). It has been found that T and NK lymphocytes show defective functions in brucellosis patients (46,49).…”

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confidence: 99%

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

et al. 2010

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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...

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Section: Discussionsupporting

confidence: 79%

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

et al. 2010

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“…B. abortus, as well as L-Omp19 and Pam 3 Cys, also diminished MHC-II expression and inhibited the ability of human monocytes to process and present soluble Ags (PPD) to polyclonal T cells from human donors. The finding that Brucella lipoproteins inhibited the ability of human monocytes to activate Agspecific T cells suggests that these molecules could be implicated in the down-modulation of T-cell responses reported in human brucellosis (24,33,45,46). Indeed, our results indicate that prolonged exposure to Pam 3 Cys of PBMCs from acute patients, which display a Th1-type response with cell proliferation and production of IFN-␥ and IL-2, transforms this response towards the nonresponder phenotype of chronically infected patients (24).…”

Section: Discussionmentioning

confidence: 99%

Brucella abortusInhibits Major Histocompatibility Complex Class II Expression and Antigen Processing through Interleukin-6 Secretion via Toll-Like Receptor 2

et al. 2008

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The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC- Infection with Brucella abortus has been shown to potently activate both the innate and adaptive arms of the immune system, leading to a proinflammatory response that favors the differentiation of T-cell responses toward a T-helper 1 (Th1) profile (15,(55)(56)(57). Despite this immune response, B. abortus can persist for years inside macrophages, evading host immune responses.IIMacrophages are an early barrier for defense against Brucella. They phagocytose and degrade invading microorganisms, participating actively in innate immunity. Additionally, by processing microorganisms within intracellular compartments, they present peptides in the context of the major histocompatibility complex (MHC) to T lymphocytes, promoting the adaptive immune response. Gamma interferon (IFN-␥) has a critical role in protective immunity against Brucella. This cytokine enhances both the microbicidal and antigen-presenting functions of macrophages (12,18,19,48). Thus, the virulence of B. abortus relies on the ability of this organism to survive and replicate within vacuolar phagocytic compartments of macrophages (26,30), and the macrophage-Brucella interaction is critical for the establishment of chronic Brucella infections.

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“…Some cytokines can regulate the immune system and play key roles on the outcome of brucellosis. Several studies have shown that T cell proliferation and Th1 cytokine production are reduced in brucellosis (5,6). Interferon-gamma (IFN-γ) is a well-studied cytokine (2,5,7,8).…”

Section: Brucellosis Is Endemic In Many Middlementioning

confidence: 99%

Cytokine profile and nitric oxide levels in sera from patients with brucellosis

Refik

Mehmet

Durmaz

et al. 2004

Braz J Med Biol Res

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The aims of this study were to investigate the serum levels of some cytokines [tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), IL-2R, IL-6, and IL-8] and nitric oxide (NO) levels in patients with untreated brucellosis and to test the correlation of these parameters with each other. The study was conducted on 67 subjects, 37 patients with brucellosis and 30 healthy individuals with no history of Brucella infection. Brucellosis was identified by a positive blood culture and/or increased Brucella antibodies in serological tests in addition to compatible clinical symptoms. Cytokine profile analysis was performed by the immulite chemiluminescent enzyme immunometric assay whose inter-and intra-assay coefficients of variance were 2.6-3.6 and 4.4-8.5%, respectively. The levels of nitrites/nitrates, which are representative of NO levels, were measured by the Griess method. Patients with brucellosis had significantly elevated serum levels of nitrites/ nitrates, IL-2R, IL-6 and IL-8 (mean ± SD, 102.8 ± 23.8 µmol/l, 806.1 ± 58.5 U/ml, 21.1 ± 2.3 pg/ml, and 8.8 ± 1.6 pg/ml, respectively) compared to healthy controls, whereas TNF-α and IL-1ß levels were unchanged. No statistically significant correlation was detected between any of the studied cytokine levels and nitrate/nitrite concentrations according to Pearson's linear correlation test. We conclude that only IL-6, IL-8 and IL-2R are elevated in brucellosis and the extent of elevation depends on the severity and clinical pattern of the disease. Moderate elevation in serum NO was comparable to that observed in previous studies. This explains the absence or very rare occurrence of septic shock in brucellosis.

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Defective interferon‐gamma production by T‐lymphocytes from patients with acute brucellosis

Cited by 37 publications

References 11 publications

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

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

Brucella abortusInhibits Major Histocompatibility Complex Class II Expression and Antigen Processing through Interleukin-6 Secretion via Toll-Like Receptor 2

Cytokine profile and nitric oxide levels in sera from patients with brucellosis

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