October 2014 | Volume 211, No. 11
- Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies
Casanova and colleagues discuss the importance of single-patient genetic studies in the discovery of novel primary immunodeficiencies and offer insight into the standards and criteria that should accompany these studies.
Brief Definitive Reports
- Progressive replacement of embryo-derived cardiac macrophages with age
Molawi et al. examine the origin and cellular dynamics of macrophages in the heart during postnatal development. Cardiac macrophages derived from CX3CR1+ embryonic progenitors persist into adulthood, but the contribution of these cells to resident macrophages declines after birth with diminished self-renewal as the mice age. Over time, the heart is progressively reconstituted with bone marrow–derived macrophages, even in the absence of inflammation.
- Immunoglobulin E plays an immunoregulatory role in lupus
Dema et al. show evidence that deficiency of IgE delays lupuslike disease development and severity, as demonstrated by reduced autoantibody production and amelioration of organ pathologies. Loss of IgE causes a striking decrease in innate immune cell infiltration in secondary lymphoid organs and decreased activation of T cells and basophils.
- The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation
Carotta et al. show that the interaction between IRF8 and PU.1 controls the propensity of B cells to undergo class-switch recombination and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1.
- The miR-155–PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation
Lu et al. disrupt the interaction between miR-155 and the transcription factor PU.1 by specifically removing miR-155–binding site from PU.1 mRNA in mice. They show that this interaction is required for plasma cell formation and extrafollicular response to immunization in vivo.
- The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells
Grötsch et al. find that the AP-1 transcription factor Fra-1 limits the generation of antibody-producing plasma cells. Absence of Fra1 in B cells results in abnormally high numbers of plasma cells and increased antibody responses after vaccination.
- Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F
Lundberg et al. show that a single hematopoietic stem cell carrying a mutation in JAK2 is able to initiate cancer in mice by promoting cell division and maintaining self-renewal.
- Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity
Srivastava et al. define a new and improved way to predict immunoprotective cancer neoepitopes based in part on the difference in MHC-binding scores between the mutant epitope and its wild-type counterpart. Remarkably, all neoepitopes that elicited tumor regression bound to class I MHC molecules with very low affinity.
- Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
Liang et al. find that the tumor suppressors TSC1 and TSC2, defects in which underlie the genetic disease Tuberous Sclerosis Complex (TSC), drive the mTOR-dependent autophagosomal destruction of the transcriptional activator YAP. Blocking YAP inhibited the abnormal proliferation of TSC1/2-deficient human cells and reversed TSC-like disease symptoms in mosaic Tsc1 mutant mice.
- Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses
Fasnacht et al. now show that fibroblasts in secondary lymphoid organs are responsible for the production of Notch ligands regulating the differentiation of immune cells
- microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells
Using Dicer-deficient CD4 T cells, Marcais et al. show that microRNAs regulate the expression of mTOR components that are needed to discriminate between activating and anergy-inducing stimuli.
- Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo–activated cells
Maul et al. show that proteins associated with variable gene hypermutation, such as Spt5 and AID, are recruited to the initiating form of RNA polymerase II specifically in cells activated in germinal centers but not in culture.
- CARD9 mediates Dectin-1–induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity
CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands in mice. However, Dectin-1–induced H-Ras activation is mediated by a complex with CARD9, which leads to ERK activation for host innate immune responses to Candida albicans infection.