The immune response in tuberculosis O'Garra, Anne; Redford, Paul S; McNab, Finlay W ...
Annual review of immunology,
01/2013, Letnik:
31
Journal Article
Recenzirano
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of ...these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
During gaseous exchange the lungs are exposed to a vast variety of pathogens, allergens, and innocuous particles. A feature of the lung immune response to lung-tropic aerosol-transmitted bacteria ...such as Mycobacterium tuberculosis (Mtb) is a balanced immune response that serves to restrict pathogen growth while not leading to host-mediated collateral damage of the delicate lung tissues. One immune-limiting mechanism is the inhibitory and anti-inflammatory cytokine interleukin (IL)-10. IL-10 is made by many hematopoietic cells and a major role is to suppress macrophage and dendritic cell (DC) functions, which are required for the capture, control, and initiation of immune responses to pathogens such as Mtb. Here, we review the role of IL-10 on bacterial control during the course of Mtb infection, from early innate to adaptive immune responses. We propose that IL-10 is linked with the ability of Mtb to evade immune responses and mediate long-term infections in the lung.
Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and ...disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
IL-10 regulates the balance of an immune response between pathogen clearance and immunopathology. We show here that Mycobacterium tuberculosis (Mtb) infection in the absence of IL-10 (IL-10⁻/⁻ mice) ...results in reduced bacterial loads in the lung. This reduction was preceded by an accelerated and enhanced IFN-γ response in the lung, an increased influx of CD4⁺ T cells into the lung, and enhanced production of chemokines and cytokines, including CXCL10 and IL-17, in both the lung and the serum. Neutralization of IL-17 affected neither the enhanced production of CXCL10 nor the accumulation of IFN-γ-producing T cells in the lungs, but led to reduced numbers of granulocytes in the lung and reduced bacterial loads in the spleens of Mtb-infected mice. This suggests that IL-17 may contribute to dissemination of Mtb.
In future measurements of the dilepton (
Z
/
γ
∗
) transverse momentum,
Q
T
, at both the Tevatron and LHC, the achievable bin widths and the ultimate precision of the measurements will be limited by ...experimental resolution rather than by the available event statistics. In a recent paper the variable
a
T
, which corresponds to the component of
Q
T
that is transverse to the dilepton thrust axis, has been studied in this regard. In the region,
Q
T
< 30 GeV,
a
T
has been shown to be less susceptible to experimental resolution and efficiency effects than the
Q
T
. Extending over all
Q
T
, we now demonstrate that dividing
a
T
(or
Q
T
) by the measured dilepton invariant mass further improves the resolution. In addition, we propose a new variable,
, that is determined exclusively from the measured lepton directions; this is even more precisely determined experimentally than the above variables and is similarly sensitive to the
Q
T
. The greater precision achievable using such variables will enable more stringent tests of QCD and tighter constraints on Monte Carlo event generator tunes.
Reliable sample delivery and efficient use of limited beam time have remained bottlenecks for serial crystallography (SX). Using a high-intensity polychromatic X-ray beam in combination with a newly ...developed charge-integrating JUNGFRAU detector, we have applied the method of fixed-target SX to collect data at a rate of 1 kHz at a synchrotron-radiation facility. According to our data analysis for the given experimental conditions, only about 3 000 diffraction patterns are required for a high-quality diffraction dataset. With indexing rates of up to 25%, recording of such a dataset takes less than 30 s.
Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. Whether neutrophils can kill mycobacteria in vivo probably depends on the tissue ...microenvironment, stage of infection, individual host, and infecting organism. The interaction of neutrophils with macrophages, as well as the downstream effects on T cell activity, could result in a range of outcomes from early clearance of infection to dissemination of viable bacteria together with an attenuated acquired immune response. In established disease, neutrophils accumulate in situations of high pathogen load or immunological dysfunction, and are likely to contribute to pathology. These activities may have clinical importance in terms of new treatments, targeted interventions and vaccine strategies.
Although researchers are exploring animals' capacity for monitoring their states of uncertainty, the use of some paradigms allows the criticism that animals map avoidance responses to error-causing ...stimuli not because of uncertainty monitored but because of feedback signals and stimulus aversion. The authors addressed this criticism with an uncertainty-monitoring task in which participants completed blocks of trials with feedback deferred so that they could not associate reinforcement signals to particular stimuli or stimulus-response pairs. Humans and 1 of 2 monkeys were able to make cognitive, decisional uncertainty responses that were independent of feedback or reinforcement history within a task. This finding unifies the comparative literature on uncertainty monitoring. The dissociation of performance from reinforcement has theoretical implications, and the deferred-feedback technique has many applications.
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