Innate Immunity

Antagonistic antibody prevents Toll-like receptor 2-driven lethal shock-like syndromes. Meng, G. et al. J. Clin. Invest. 113, 1473–1481 (2004).

Infection with Gram-positive bacteria, such as Bacteroides subtilis, elicits inflammatory responses through the stimulation of Toll-like receptor 2 (TLR2) on host cells. The induction of hyper-inflammation through this pathway can cause septic shock, so the authors looked at whether targeting TLR2 might be an effective treatment. They raised an antibody against TLR2 that prevented the activation of TLR2-expressing cells through this pathway. When mice were pretreated with the antibody then challenged with a synthetic TLR2 agonist, levels of pro-inflammatory cytokines and chemokines were reduced compared with untreated mice. Pre-treated mice were also less susceptible to lethal toxaemia induced by infection with B. subtilis.

Asthma and Allergy

Acidic mammalian chitinase in asthmatic TH2 inflammation and IL-13 pathway activation. Zhu, Z. et al. Science 304, 1678–1682 (2004).

Lower life forms produce chitinases as a protective mechanism in response to infection with parasites that have chitin coats. Recently, humans have also been shown to express a chitinase known as acidic mammalian chitinase (AMCase). Given the link between antiparasite and allergic responses, which both have a Thelper 2 (TH2)-cell bias, the authors looked at whether AMCase might be involved in asthma pathogenesis. They showed in a mouse model of lung inflammation that lung epithelial cells and macrophages both express AMCase and that this depends on IL-13 production by TH2 cells. Administration of an antibody specific for AMCase reduced lung inflammation by inhibiting the ability of IL-13 to induce chemokine responses. AMCase expression could also be detected in human lung tissue from patients with asthma. This study indicates that chitinases might be mediators of TH2-cell responses and therefore potential therapeutic targets to control these responses.

Signalling

Rac1 and Toll–IL-1 receptor domain-containing adapter protein mediate Toll-like receptor 4 induction of HIV-long terminal repeat. Equils, O. et al. J. Immunol. 172, 7642–7646 (2004).

Patients infected with HIV commonly suffer microbial infections that cause increased HIV-1 replication. Previous studies indicate that lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 (TLR4) induces transcription of the HIV long-terminal repeat (HIV-LTR). In this paper, Equils et al. show that LPS induces RAC1 activation and that RAC1 stimulates HIV-LTR trans-activation. RAC1-induced HIV-LTR activation depends on Toll/IL-1-receptor-domain-containing adaptor protein (TIRAP), but RAC1 activation is probably downstream of MyD88. This study therefore provides insight into the signalling pathways likely to be important in microbial-induced HIV-1 replication.

Innate Immunity

Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin–immunoglobulin G complexes. Boulé, M. W. et al. J. Exp. Med. 14 June 2004 (doi:10.1084/jem20031942).

B-cell-receptor-mediated uptake of immune complexes containing chromatin and chromatin-specific IgG (chromatin-ICs) enables chromatin to trigger Toll-like receptor 9 (TLR9) and activate autoreactive B cells. Boulé et al. show that a similar two-receptor process can activate bone-marrow-derived dendritic cells (BMDCs): the production of tumour-necrosis factor in response to chromatin-ICs was impaired in TLR9- and MyD88-deficient BMDCs and was abolished in the absence of FcγRIII. By contrast, production of the B-cell survival factor BAFF was TLR9 independent. This identification of two distinct chromatin-IC activation pathways in BMDCs might provide insight into the mechanisms of systemic lupus erythematosus pathogenesis.

Lymphocyte Signalling

Requirement for Tec kinases in chemokine-induced migration and activation of Cdc42 and Rac. Takesono, A. et al. Curr. Biol. 14, 917–922 (2004).

The tyrosine kinases that regulate chemokine-induced signalling pathways were ill-defined until this report identified a role for the TEC kinases ITK and RLK. Stromal-cell-derived factor 1α (SDF1α) induced tyrosine phosphorylation of ITK and RLK, and a dominant-negative ITK mutant decreased migration in response to this chemokine. Impaired migration was associated with decreased actin polymerization and decreased activation of the actin-cytoskeleton regulators CDC42 and RAC. T cells from Itk−/−Rlk−/− mice also showed decreased migration in response to SDF1α. These TEC kinases also regulate actin polymerization induced by T-cell receptor (TCR) stimulation, so the authors suggest that chemokine-receptor and TCR-signalling pathways converge to induce actin-cytoskeleton reorganization.

Haematopoiesis

Stepwise reprogramming of B cells into macrophages. Xie, H. et al. Cell 117, 663–676 (2004).

This study looked at the transcription-factor networks that determine whether a multipotent haematopoietic progenitor will enter the lymphoid or myeloid lineages. When the myeloid transcription factors C/EBP-α or C/EBP-β are expressed in B-cell precursors or mature splenic B cells, these cells are reprogrammed to become functional macrophages. This was the result of both downregulation of the late B-cell-specific marker CD19, through inhibition of the B-cell commitment factor PAX5, and upregulation of Mac1 and other myeloid markers in synergy with endogenous PU.1. This antagonism between C/EBP and PAX5 is a novel mechanism of lineage commitment, and the authors suggest that the decision to become a B cell or macrophage depends on which becomes dominant. This ties in with the fact that the B-cell to macrophage conversion frequency depended on the dose of C/EBP.