Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3

Abstract

In this study, we explored the local cytokine/chemokine profiles in patients with active pulmonary or pleural tuberculosis (TB) using multiplex protein analysis of bronchoalveolar lavage and pleural fluid samples. Despite increased pro-inflammation compared to the uninfected controls; there was no up-regulation of IFN-γ or the T cell chemoattractant CCL5 in the lung of patients with pulmonary TB. Instead, elevated levels of IL-4 and CCL4 were associated with high mycobacteria-specific IgG titres as well as SOCS3 (suppressors of cytokine signaling) mRNA and progression of moderate-to-severe disease. Contrary, IL-4, CCL4 and SOCS3 remained low in patients with extrapulmonary pleural TB, while IFN-γ, CCL5 and SOCS1 were up-regulated. Both SOCS molecules were induced in human macrophages infected with Mycobacterium tuberculosis in vitro. The Th2 immune response signature found in patients with progressive pulmonary TB could result from inappropriate cytokine/chemokine responses and excessive SOCS3 expression that may represent potential targets for clinical TB management.

Structural identification and immunostimulating activity of a Laminaria japonica polysaccharide

“…Up to date, several types of immunomodulators have been developed, including mammalian proteins and chemical synthetic drugs [7]. Although these drugs have beneficial effects on the enhancement of immunity, the side effect of high toxicity is still presented in clinical trials [8,9]. Thus, development of novel immunomodulators to enhance the innate immune response has been considered to be a more efficient and possibly more effective long-term healthcare strategy [10].…”

Antibodies and tuberculosis

“…Antibodies are present in the sputum of patients with active pulmonary TB as shown by mass spectroscopy [25]. This polarization towards a humoral immune response has previously been hypothesized to represent immune evasion by the skewing of host responses away from a protective Th1-mediated response [23]. Despite the variable AMI response in individual patients and the association of antibody responses with the clinical state of active disease, there are multiple clinical scenarios in which AMI may be protective against M.tb .…”

“…Humoral immunity is also stimulated at the site of disease: pulmonary TB is associated with an increase in the Th2 cytokines IL-4, CCL-4 and SOCS3 in bronchoalveolar lavage (BAL) fluid taken from patients with active pulmonary TB [23]. IL-4 levels in sputum correspond to increased bacterial load and antibody levels in serum [24].…”

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

“…Further, in IL-4 + IL-10-polarized MFs, the use of L-citrulline as a source of L-arginine may bypass arginase-mediated inhibition of iNOS function and elicit better antimycobacterial immunity. This method of polarization is likely relevant in vivo, because M. tuberculosis-infected patients with elevated type 2 cytokines have increased prevalence of TB (27)(28)(29). To test this, PDMs were stimulated with IL-4 + IL-10 for 24 h prior to infection to further induce Arg1 activity.…”