Brief Definitive Report
Mansouri et al. applied targeted deep sequencing to identify mutations within NF-κB core complex genes in CLL. NFKBIE, the gene encoding the inhibitory IκBε molecule, was most frequently mutated, especially in poor-prognostic subgroups of CLL. The authors show that NFKBIE mutations were associated with significantly reduced IkBε expression and p65 inhibition, ultimately leading to NF-κB activation and a more aggressive disease.
Blazek et al. demonstrate that treatment with IL-28A reduces inflammation in collagen-induced arthritis by restricting the recruitment of IL-1β+ neutrophils.
Wilson et al. show that individuals with loss-of-function mutations in STAT3 have reduced numbers of peripheral blood MAIT and NKT cells, but not γδ T cells. Residual MAIT cells had normal expression of RORγt, but displayed impaired secretion of IL-17A and IL-17F.
The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development
Yu et al. demonstrate that the transcription factor Bcl11b is specifically expressed in mouse innate lymphoid progenitors committed to the ILC2 lineage and is required for their development. Bcl11b-deficient mice exhibit a complete lack of ILC2 development, which is confirmed by immune challenges with either papain treatment or influenza virus infection.
Walker et al. demonstrate that the transcription factor Bcl11b is expressed in mouse lymphoid ILC2 precursors in the bone marrow and is required for their development. Mice deficient in Bcl11b exhibit a lack of ILC2 development and an expansion of RORγt+ ILC3s and are unable to clear Nippostrongylus brasiliensis worm infection, but can clear Citrobacter rodentium.
Jacque et al. demonstrate that B cell survival induced by B cell activating factor (BAFF) requires activation of the ERK5 MAP kinase pathway, and is independent of ERK1/2 activation. Conditional deletion of ERK5 in B cells reduces mature B2 B cell numbers in mice and impairs BAFF-induced mature B cell survival without affecting NF-κB and Akt activation.
Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance
Lin et al. generate Plasmodium berghei mutants lacking enzymes critical to hemoglobin digestion. A double gene deletion mutant lacking enzymes involved in the initial steps of hemoglobin proteolysis is able to replicate inside reticulocytes of infected mice with limited hemoglobin degradation and no hemozoin formation, and moreover, is resistant to the antimalarial drug chloroquine.
An acidic microenvironment sets the humoral pattern recognition molecule PTX3 in a tissue repair mode
Doni et al. use four tissue damage models in mice and find that the fluid phase pattern recognition molecule pentraxin 3 (PTX3) plays a role in tissue remodeling and repair. PTX3 binds fibrinogen/fibrin and plasminogen at an acidic pH within tissues. Mice deficient in PTX3 present defects in fibrin deposition, clot formation, collagen deposition, and macrophage-mediated fibrinolysis.
Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β
Kim et al. identify an autoinflammatory disease in mice that is driven by IL-18, resulting from an inactivating mutation in the actin-depolymerizing cofactor Wdr1. This alteration in actin dynamics is recognized by the pyrin inflammasome and results in exaggerated monocyte IL-18 production, whereas inflammasome activation in mature macrophages is unaltered.
Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia
Boisson et al. report a human homozygous mutation of HOIP, the gene encoding the catalytic component of the linear ubiquitination chain assembly complex, LUBAC. The missense alleles impair the expression of HOIP, destabilizing the LUBAC complex and resulting in immune cell dysfunction leading to multiorgan inflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectactasia.
DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3
Thompson et al. identify the dual specificity tyrosine-regulated kinase 1A (DYRK1A) as a new player in the control of lymphopoiesis. Loss of DYRK1A in mice results in Cyclin D3 stabilization and failure to repress E2F target genes, thus impairing cell cycle exit and proper pre–B and pre–T cell differentiation.