Brucellosis is a febrile illness with various and nonspecific signs and symptoms, including high fever, night sweats, and joint pain that can make its diagnosis difficult (13). Also, skeletal system involvement is common in brucellosis and its incidence is altered from 11% to 85% in different reports (14).
Brucellosis is a disease with a complex immunopathogenesis and the pathogen mechanisms of brucella and other features remain unclear. It has been suggested that the balance between Th 1 and Th 2 cytokines plays an important role in brucellosis and TNF-α, INF-γ, and IL-12 are considered as key cytokines in this respect (3). Brucella infection in mice provokes a type 1 (Th1) immune response, that leads to elimination of the microorganism and termination of the infection that is mediated by major cytokines, including TNF-a, IFN-γ, and IL-12 (8).
Interleukin-12, a key cytokine, promoting Th 1 differentiation and resultant immune responses, is produced and secreted by B cells and macrophages and stimulates T cells to synthesize and secrete IFN-γ and increase cytotoxic activity. This cytokine is also required for the stimulation of Natural Killer cells (NK), to produce IFN-γ (15). The enhanced activation of T and NK cells by IL-12 has been shown to contribute to the control of infection. Besides, IFN-γ activates bactericidal function of macrophages, and limits brucella infection both in vitro and in vivo (4, 16). It was previously demonstrated that Leishmania major-susceptible BALB/c mice, which received recombinant IL-12, had the ability to control the infection. This protective effect of IL-12 is reversible by the neutralization of IFN-γ (17).
According to Zhan et al.’s study, reduction in IL-12 in mice with Brucella abortus significantly intensifies brucella infection. Also, administration of anti-IL-12 before infection significantly exacerbated the infection, and numbers of brucella in the spleen and liver cells were 20- to 40-fold higher in mice treated with anti-IL-12 than those in isotype control globulin-treated mice (4). Consistent with previous studies, the serum levels of IL-12 increased in the patients with brucellosis, compared with the levels in the controls (12, 18).
In addition, the serum level of IFN-γ increased in patients with active brucellosis. Furthermore, IFN-γ, the main cytokine responsible for activating macrophages, is produced mainly by CD4 and NK cells or in response to IL-12. Its role is particularly imperative in killing phagocytized intracellular microbes, thus, it also plays a critical role in the pathogenesis of brucellosis (19, 20). Once produced, it leaves remarkable effects on the immune system, including activating the macrophages, inducing the synthesis of reactive oxygen species, and nitrogen intermediates. It also increases apoptosis, cell differentiation, and cytokine production.
Typically, serum levels of IFN-γ are reported to increase in patients with brucellosis (1, 2, 18, 19). In a study by Demirdag, mean IFN-γ values appeared to be significantly higher in acute brucellosis compared to that in control group.
In response to inflammation and infection, TNF-α is produced mainly from macrophages and probably plays an important role in resistance to infection with intracellular bacteria. This cytokine could act as a stimulator of IFN-γ secretion by NK cells from severe combined immunodeficiency (SCID) splenocytes in vitro (15). Even though the exact role of the cytokine, regarding Th 1 is not clear, an in vitro research with ovalbumin-specific T-cell receptor transgenic mice concluded that TNF-α had no direct effect on the induction of Th 1 responses (21).
The important role of TNF-α in immunity against brucella was confirmed when in a research on TNF-α depleted mice with the polyclonal antibody, the numbers of brucella per gram of the spleen or liver were more than 10 folds higher than those in control infected mice (10). Two weeks after infection in this TNF-α depleted mice, the infection aggravated, yet it recovered in 6 weeks after infection in the controls. Interestingly, IL-12 depleted mice did not show any significant improvement 6 weeks after infection with brucella (P, 0.001) (10).
According to a few published articles, there are conflicting results about changes in the serum levels of TNF-α in brucellosis. Ahmed K et al. reported undetectable levels of TNF-α in the serum of patients with acute brucellosis. In a research performed on 67 cases, 37 patients with brucellosis and 30 healthy individuals with no history of brucella infection, serum TNF-α levels were unchanged compared to healthy controls (12). In another study on humans, brucella infected macrophages produced IL-1, IL-6, IL-10 and other chemokines like IL-8 yet did not secrete TNF-α (16, 22).
In contrast to the aforementioned study and in agreement with the present study, serum TNF-α levels were significantly higher in the acute phase of brucellosis compared with levels in the post-treatment and the control group in a study from Turkey. This increased level of TNF-α was also correlated with increased levels of IFN-γ in the acute phase of the disease (2). Akbulutet al. also reported that TNF-α levels after treatment were significantly lower than that in pre-treatment (P < 0.001) (23).
Although the definite role of IL-4 in human brucellosis is not understood clearly (2), as the main cytokine of the Th 2 system and the key stimulant of the production of Ig E antibodies, it deserves more investigations in brucellosis. Furthermore, CD4 T lymphocytes of the Th 2 subset and activated mast cells are the main cellular producers of IL-4. According to Galanakis et al., serum IL-4 levels increased in the acute phase of brucellosis in children. Deterioration of the disease process was attributed to increased levels of this cytokine causing a reduction in brucella immunity through extreme Th 2 response. In Rafeie et al.’s study, IL-4 were not secreted in response to heat-inactivated Rev-1 bacteria (24). In another research by Demirdag et al., (2) serumIL-4 levels were relatively low and did not significantly differ from that of the control group, consistent with the current study.
As shown by previous studies, the Th1 response was dominant in patients with acute brucellosis (18). In this study, serum levels of Th1 system cytokines significantly increased in acute brucellosis, yet the serum level of IL-4 showed no surge in this setting. It is notable that the brucellosis patients were compared with those with febrile issues.
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