Relationship between Circulating Levels of IFN‐γ, IL‐10, CXCL9 and CCL2 in Pulmonary and Extrapulmonary Tuberculosis is Dependent on Disease Severity

Abstract

Protection against Mycobacterium tuberculosis infection is dependent on T cell and macrophage activation regulated by cytokines. Cytokines and chemokines produced at disease sites may be released into circulation. Data available on circulating cytokines in tuberculosis (TB) is mostly on pulmonary TB (PTB) with limited information on extrapulmonary disease (EPul‐TB). We measured interferon‐gamma (IFN‐γ), interkeukin‐10 (IL‐10), CXCL9 and CCL2 in sera of patients (n = 80) including; PTB (n = 42), EPul‐TB (n = 38) and BCG vaccinated healthy endemic controls (EC, n = 42). EPul‐TB patients comprised those with less severe (LNTB) or severe (SevTB) disease. Serum IFN‐γ, IL‐10 and CXCL9 levels were significantly greater while CCL2 was reduced in TB patients as compared with EC. IFN‐γ was significantly greater in PTB as compared with LNTB (P = 0.002) and SevTB (P = 0.029). CXCL9 was greater in PTB as compared with LNTB (P = 0.009). In contrast, CCL2 levels were reduced in PTB as compared with LNTB (P = 0.021) and SevTB (P = 0.024). A Spearman’s rank correlation analysis determined a positive association between IFN‐γ and IL‐10 (rho = 0.473, P = 0.002) and IFN‐γ and CXCL9 (rho = 0.403, P = 0.008) in the PTB group. However, in SevTB, only IFN‐γ and CXCL9 were positively associated (rho = 0.529, P = 0.016). Systemic levels of cytokines are reflective of local responses at disease sites. Therefore, our data suggests that in PTB increased IFN‐γ and CXCL9 balanced by IL‐10 may result in a more effective cell mediated response in the host. However, elevated inflammatory chemokines CXCL9 and CCL2 in severe EPul‐TB without concomitant down modulatory cytokines may exacerbate disease related pathology and hamper restriction of M. tuberculosis infection.

Differential Early Secreted Antigen Target (ESAT) 6 kDa–induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis

“…Concordant with the raised levels of ESAT6 induced IFN-γ secretion observed [23], ESAT6-induced IFN-γ mRNA expression levels were increased in the EC ESAT6 IFN-γ (+),as compared with EC ESAT6 IFN-γ (-) cases (p = 0.019), Figure 2A. Also, ESAT6-induced IFN-γ expression levels were raised in PTB (p = 0.039) and ETB (p = 0.010) as compared with EC ESAT6-induced IFN-γ(-) cases .…”

“…Cells were lysed with Trizol reagent (Invitrogen, USA) and total RNA isolated as described previously [22,23]. RNA (1µg) was reverse transcribed using MulV reverse transcriptase (Invitrogen, Grand Island, New York USA) as described [24].…”

Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis

“…Some have found similar cytokine levels in sera from persons with various TB manifestations (40), while others such as Hasan et al found that circulating levels of cytokines such as IFN-␥ and CXCL9 differ based on the site of TB disease (19,40). Other groups have stimulated whole blood or PBMCs from persons with various forms of TB and measured cytokine levels and T lymphocyte proliferation (20,21,36,41,42).…”

Mycobacterium tuberculosis Culture Filtrate Proteins plus CpG Oligodeoxynucleotides Confer Protection to Mycobacterium bovis BCG-Primed Mice by Inhibiting Interleukin-4 Secretion

“…We suggest that IFN-␥ plays a key role in exacerbating inflammation in the presence of IL-4 and IL-5. Indeed, IFN-␥ has also been associated with the development of mycobacterium-induced caseous necrosis, with excessive amounts of this cytokine contributing to the pathology observed in tuberculous patients (2,13,15,22,43).…”