Systems approach to understand the immune response in tuberculosis: an iterative process between mouse models and human disease.

Tuberculosis remains a disease of considerable mortality and morbidity. The immune response determining whether individuals infected with the pathogen Mycobacterium tuberculosis control the infection, and remain latent, or go on to develop active tuberculosis disease is poorly understood. Our studies used microarray technology to derive blood transcriptional profiles of the host response during tuberculosis, which, combined with data from experimental systems, highlighted a potentially detrimental role for Type I interferons during infection, with important implications for vaccine and therapeutic development.

ATPase mechanism of the 5'-3' DNA helicase, RecD2: evidence for a pre-hydrolysis conformation change.

The superfamily 1 helicase, RecD2, is a monomeric, bacterial enzyme with a role in DNA repair, but with 5'-3' activity unlike most enzymes from this superfamily. Rate constants were determined for steps within the ATPase cycle of RecD2 in the presence of ssDNA. The fluorescent ATP analog, mantATP (2'(3')-O-(N-methylanthraniloyl)ATP), was used throughout to provide a complete set of rate constants and determine the mechanism of the cycle for a single nucleotide species.

Contribution of cytokines to pathology and protection in virus infection.

Acute and chronic viral infections greatly contribute to global health burden. While concerted action of multiple elements of the immune system help the host cope with most viruses, some infections lead to host damage or death. Cytokines are central drivers and controllers of both immune-mediated virus elimination and of immunopathology.

The role of IL-10 in immune regulation during M. tuberculosis infection.

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.

Using non-homogeneous models of nucleotide substitution to identify host shift events: application to the origin of the 1918 'Spanish' influenza pandemic virus.

Nonhomogeneous Markov models of nucleotide substitution have received scant attention. Here we explore the possibility of using nonhomogeneous models to identify host shift nodes along phylogenetic trees of pathogens evolving in different hosts. It has been noticed that influenza viruses show marked differences in nucleotide composition in human and avian hosts.

The role of T helper subsets in autoimmunity and allergy.

The classification of T helper (T(H)) cells in subsets has progressively expanded and more effector subsets, besides T(H)1 and T(H)2, have been documented. These include follicular helper T cells (T(FH)), and the more recent T(H)17, 'T(H)9', and 'T(H)22'. In addition, T(H) are no longer thought of as terminally committed effector cells, with plasticity now recognized.

Retrovirus-specificity of regulatory T cells is neither present nor required in preventing retrovirus-induced bone marrow immune pathology.

Chronic viral infections of the hematopoietic system are associated with bone marrow dysfunction, to which both virus-mediated and immune-mediated effects may contribute. Using unresolving noncytopathic Friend virus (FV) infection in mice, we showed that unregulated CD4(+) T cell response to FV caused IFN-gamma-mediated bone marrow pathology and anemia. Importantly, bone marrow pathology was triggered by relative insufficiency in regulatory T (Treg) cells and was prevented by added Treg cells, which suppressed the local IFN-gamma production by FV-specific CD4(+) T cells.

The influence of CD4 T-cell subsets on control of CD4 T-cell-mediated graft-versus-host disease.

In this study, we tested the effect of different T-cell subpopulations on antigen driven effector cell expansion in lymphopenic hosts, making use of an experimental model of graft-versus-host disease (GVHD). Fluorescence-activated cell sorted (FACS) naïve CD4 T cells from C57BL/6 mice, transferred into lymphopenic F1 (C57BL/6 x BALB/c) Rag-deficient hosts, proliferated extensively and migrated systemically causing acute GVHD within 4 weeks after transfer. Adoptive hosts of CD4 memory T cells on the other hand developed milder symptoms of GVHD with later onset.

Th17 T cells: linking innate and adaptive immunity.

While the cytokine IL-17 has been cloned and described more than 10 years ago [Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3(6):811-21; Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, et al.

Differentiation and function of Th17 T cells.

IL-17-producing T cells have recently been classified as a new effector T-cell subset, termed Th17, which is distinct from Th1, Th2 and Treg subsets. There has been much progress in the past year, leading to identification of the molecular mechanisms that drive differentiation of Th17 T cells. This has helped to clarify many aspects of their role in host defense as well as in autoimmunity.

Good for Goose, but not for Gander: IL-2 interferes with Th17 differentiation.

In this issue of Immunity, Laurence et al. (2007) examined the effects of interleukin-2 on differentiation of the T helper 17 (Th17) cells and found that this essential growth factor for all other T cell subsets blocks the development of Th17 T cells.