Signalling

RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Tam, S. Y. et al. Nature Immunol. 5, 844–852 (2004).

Ras signalling is required for the optimal release of lipid mediators and cytokines following IgE and antigen-induced mast-cell activation. In this study, RabGEF1 — previously identified as having guanine-nucleotide exchange factor (GEF) activity — was shown to bind Ras. Reducing RabGEF1 expression in vitro increased Ras activity and cytokine and lipid-mediator production on FcεRI aggregation, indicating that RabGEF1 negatively regulates these functions in mast cells. Further support for this hypothesis comes from similar results that were obtained using bone-marrow-cultured mast cells derived from RabGEF1-deficient mice. RabGEF1 mRNA is widely expressed, and RabGEF1-deficient mice have many phenotypic abnormalities; therefore, RabGEF1 might function as a negative regulator of Ras signalling in other cells as well as mast cells.

Infectious disease

An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Traggiai, E. et al. Nature Med. 10, 871–875 (2004).

Although monoclonal antibodies could be used to prevent and treat infectious diseases, inherent difficulties in their development mean that they have had little impact. In this study, an improved method for immortalization of B cells was used to transform IgG+ memory B cells isolated from a patient who recovered from infection with severe acute respiratory syndrome coronavirus (SARS-CoV). B-cell clones were screened for the production of SARS-CoV-specific antibodies, and 35 antibodies capable of neutralizing the virus in vitro were identified. One of these inhibited viral replication in the lower respiratory tract (in a mouse model of acute SARS-CoV), indicating that this improved technique of memory B-cell transformation can be used to rapidly isolate effective candidate therapeutic monoclonal antibodies.

Immune evasion

Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor. Foster-Cuevas, M. et al. J. Virol. 78, 7667–7676 (2004).

Many viruses hijack host proteins to evade immune defences. This paper describes a viral homologue of CD200 — a widely expressed host cell-surface glycoprotein — encoded by the K14 open reading frame of human herpesvirus 8. Although K14 has only 40% sequence identity with CD200, they showed that the K14 protein interacts with the CD200 receptor, which is mainly expressed by myeloid cells, with the same kinetics and low affinity as the host protein. Cells expressing CD200 or K14 inhibited the secretion of pro-inflammatory cytokines by activated macrophages, indicating that infected cells might deliver downmodulatory signals to host myeloid cells through the CD200 receptor to evade elimination.

Cytokines

High mobility group box protein 1: an endogenous signal for dendritic cell maturation and TH1 polarization. Messmer, D. et al. J. Immunol. 173, 307–313 (2004).

HMGB1 was originally identified as a nuclear factor involved in chromatin organization, but it has recently been shown to also function as a cytokine, mediating local inflammation and macrophage activation. Now, this study extends the known pro-inflammatory actions of HMGB1 to dendritic-cell (DC) activation. HMGB1 induced the phenotypic maturation of DCs in vitro and their secretion of inflammatory cytokines and chemokines. DCs matured by exposure to HMGB1 activated resting allogeneic T cells and led to a T-helper-1-cell-polarized response. The authors therefore suggest that environments that are rich in HMGB1 — for example, those containing necrotic cells — might facilitate the breaking of tolerance and lead to autoimmune responses.

Reproductive immunology

Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system. Erlebacher, A. et al. J. Clin. Invest. 114, 39–48 (2004).

This study indicates that links between the immune system and the reproductive endocrine system might partly explain pregnancy loss associated with an inflammatory response. The hormone progesterone is essential for pregnancy maintenance, and in mice, it is produced by the ovaries in response to pituitary-derived prolactin, which signals through a JAK2–STAT5 pathway. Laurie Glimcher and colleagues show that ligation of the immune co-stimulatory molecule CD40 in pregnant mice leads to decreased progesterone synthesis and embryo resorption. The mechanism involves tumour-necrosis factor (TNF) production by natural killer cells in response to the inflammatory environment produced by CD40 ligation on dendritic cells. Increased levels of TNF then upregulate expression of the STAT5 inhibitors SOCS1 and SOCS3 in the ovaries, which in turn inhibit prolactin-receptor signalling.

Transplantation

Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Chen, L. et al. Nature Med. 10, 814–815 (2004).

This is the first study to link regulation of lymphangiogenesis with the induction of adaptive immunity. Chen et al. report that signalling through vascular endothelial growth factor receptor 3 (VEGFR3) has a key role in corneal immunity. They observed increased expression of VEGFR3 on both stromal dendritic cells (DCs) and newly developed lymphatics in inflamed mouse corneas. VEGFR3 expression by DCs enabled their migration in vitro in response to the ligand VEGF-C. Moreover, blockade of VEGFR3 reduced the trafficking of DCs from corneal transplants to the draining lymph nodes and also significantly inhibited donor-specific delayed-type hypersensitivity responses. As VEGFR3 blockade improved corneal transplant survival, this could be used as a specific therapy for transplant rejection.