In Brief

Infectious disease

Mycobacterium tuberculosis infection induces Il12rb1 splicing to generate a novel IL-12Rβ1 isoform that enhances DC migration Robinson, R. T. et al. J. Exp. Med. 8 Mar 2010 (doi:10.1084/jem.20091085)

The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans Tobin, D. M. et al. Cell 140, 717–730 (2010)

The immune response to infection with Mycobacterium tuberculosis requires interleukin-12 (IL-12), which promotes both T helper 1 cell differentiation and dendritic cell (DC) migration to the lung-draining lymph nodes for T cell priming. Robinson et al. show that M. tuberculosis infection in mice increases the splicing of mRNA encoding IL-12 receptor-β1 (IL-12Rβ1) in lung DCs to generate IL-12Rβ1 protein lacking the transmembrane domain. The IL-12Rβ1 splice variant associates with the DC membrane by an unknown mechanism and, although it lacks signalling capacity of its own, it enhances signalling through full-length IL-12Rβ1, leading to increased activation of M. tuberculosis-specific T cells. DC stimulation with Mycobacterium avium, but not lipopolysaccharide or Yersinia pestis, also increased production of the IL-12Rβ1 splice variant, which indicates that this mechanism might be unique to mycobacteria. IL12RB1 deficiency is associated with mycobacterial susceptibility in humans, and preliminary data suggest that human DCs also respond to mycobacteria by increasing IL12RB1 mRNA splicing.

Another factor that influences susceptibility to mycobacterial disease is described by Tobin et al. By screening zebrafish larvae for hypersusceptibility to Mycobacterium marinum, they identified lta4h as a susceptibility gene. lta4h encodes leukotriene A₄ hydrolase — the enzyme responsible for converting leukotriene A₄ into pro-inflammatory leukotriene B₄. Deficiency of this enzyme in infected or uninfected mutant larvae led instead to the conversion of leukotriene A₄ into anti-inflammatory lipoxins. Excess lipoxins were associated with decreased levels of tumour necrosis factor and a subsequent failure to control mycobacterial proliferation. Finally, the finding that protection from tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms supports an important role for balanced eicosanoid production in resistance to mycobacterial infection in humans.

Autoimmunity

CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis Liu, L. et al. Nature Neurosci. 13, 319–327 (2010)

In a subset of patients with multiple sclerosis, actively demyelinating lesions are characterized by widespread death of the oligodendrocytes that produce protective myelin sheaths. Cuprizone-induced demyelination is characterized by oligodendrocyte loss, but the exact mechanisms involved are not known. This study has shown that CXC-chemokine receptor 2 (CXCR2)-expressing neutrophils promote oligodendrocyte death and demyelination in this model. Cuprizone promotes metabolic stress in oligodendrocytes, and initial cuprizone feeding led to similarly decreased myelin levels in both wild-type and CXCR2-deficient mice. However, long term toxicity and oligodendrocyte loss was only observed in wild-type mice. Bone marrow chimaera studies revealed that a CXCR2⁺ bone marrow-derived cell population (later shown to be neutrophils) was necessary for disease. CXCR2 signalling might potentiate neutrophil effector functions that can promote oligodendrocyte death.