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Key Points The production of IgE and its clearance from the blood are tightly regulated, which results in transient IgE antibody responses and the maintenance of low steady-state levels of IgE. IgE can be generated by a direct class-switch recombination pathway from Sμ to Sε, by a sequential class-switch pathway from Sμ to Sγ1 followed by Sε, as well as by a recently described alternative sequential class-switch pathway from Sγ1 to Sε, which then joins to Sμ. Additional work is needed to better understand the contribution of each class-switch pathway to IgE production in health and disease. Early IgE antibody responses arise from extrafollicular sources, whereas later IgE responses are derived from germinal centres. IgE germinal centre responses are transient, which may limit IgE production. IgE plasma cells that are derived from germinal centres are predisposed to be short-lived in contrast to IgG1 plasma cells that are derived from germinal centres, and are primarily long-lived. IgE memory responses can arise from both IgE memory B cells and IgG1 memory B cells, but the contribution of each memory B cell subset to total IgE memory responses remains to be clarified. The high-affinity Fc receptor for IgE (FcεRI) on dendritic cells and macrophages, but not on mast cells or basophils, contributes to the clearance of serum IgE. By contrast, the low-affinity Fc receptor for IgE (FcεRII; also known as CD23) on B cells does not contribute to the clearance of serum IgE, but modulates total serum IgE levels by providing a sink that binds a substantial portion of the total IgE pool. A better understanding of IgE biology may lead to new approaches to treat IgE-driven allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. IgE provides protective immunity against helminths, but is also involved in the pathogenesis of allergic diseases. In this Review, Wu and Zarrin discuss recent studies using different IgE reporter mice, as well as other genetically modified mice, that have provided new insights on the cells and pathways involved in the production and regulation of IgE, and highlight the areas in need of additional studies. IgE not only provides protective immunity against helminth parasites but can also mediate the type I hypersensitivity reactions that contribute to the pathogenesis of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Despite the importance of IgE in immune biology and allergic pathogenesis, the cells and the pathways that produce and regulate IgE are poorly understood. In this Review, we summarize recent advances in our understanding of the production and the regulation of IgE in vivo , as revealed by studies in mice, and we discuss how these findings compare to what is known about human IgE biology.

Microglia are specialized brain macrophages that play numerous roles in tissue homeostasis and response to injury. Colony stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase required for the development, maintenance, and proliferation of microglia. Here we show that in adult mice peripheral dosing of function-blocking antibodies to the two known ligands of CSF1R, CSF1, and IL-34, can deplete microglia differentially in white and gray matter regions of the brain, respectively. The regional patterns of depletion correspond to the differential expression of CSF1 and IL-34. In addition, we show that while CSF1 is required to establish microglia in the developing embryo, both CSF1 and IL-34 are required beginning in early postnatal development. These results not only clarify the roles of CSF1 and IL-34 in microglia maintenance, but also suggest that signaling through these two ligands might support distinct sub-populations of microglia, an insight that may impact drug development for neurodegenerative and other diseases.

Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer's disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer's disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.Unmet medical needs in the treatment of autoimmune and inflammatory diseases still exist. This Review discusses the activity of kinases that regulate production of inflammatory mediators and the recent advances in developing inhibitors to target such kinases.

Programmed DNA breaks are made and repaired at two points during the development of antibody-producing B cells. While the breaks occurring during V(D)J recombination utilize factors that promote non-homologous end joining, this study finds that breaks that happen during class switch recombination require only a subset of these factors, suggesting that there are other as-yet-unrecognized proteins that function in this process. Immunoglobulin variable region exons are assembled in developing B cells by V(D)J recombination. Once mature, these cells undergo class-switch recombination (CSR) when activated by antigen. CSR changes the heavy chain constant region exons (C h ) expressed with a given variable region exon from Cμ to a downstream C h (for example, Cγ, Cε or Cα), thereby switching expression from IgM to IgG, IgE or IgA. Both V(D)J recombination and CSR involve the introduction of DNA double-strand breaks and their repair by means of end joining 1 , 2 . For CSR, double-strand breaks are introduced into switch regions that flank Cμ and a downstream C h , followed by fusion of the broken switch regions 1 . In mammalian cells, the ‘classical’ non-homologous end joining (C-NHEJ) pathway repairs both general DNA double-strand breaks and programmed double-strand breaks generated by V(D)J recombination 2 , 3 . C-NHEJ, as observed during V(D)J recombination, joins ends that lack homology to form ‘direct’ joins, and also joins ends with several base-pair homologies to form microhomology joins 3 , 4 . CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ 5 , 6 , 7 , 8 . Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they are absolutely required for V(D)J recombination and have no known functions other than C-NHEJ 2 . Here we assess whether C-NHEJ is also critical for CSR by assaying CSR in Xrcc4- or Lig4-deficient mouse B cells. C-NHEJ indeed catalyses CSR joins, because C-NHEJ-deficient B cells had decreased CSR and substantial levels of IgH locus (immunoglobulin heavy chain, encoded by Igh ) chromosomal breaks. However, an alternative end-joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in C-NHEJ-deficient B cells. In the absence of C-NHEJ, this alternative end-joining pathway also frequently joins Igh locus breaks to other chromosomes to generate translocations.

Variable, diversity and joining gene segment (V(D)J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D)J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus ( Igh ) to c-myc (also known as Myc ) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D)J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D)J-recombination-associated breaks at the lambda IgL locus ( Igl ), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and Igh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh–Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh–c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours. B cell DNA breaks late The development of B cells in the immune system proceeds through several developmentalstages and in different compartments. Wang et al . show that two processes — editing and class switch recombination — widely thought to be separated temporally and spatially in the bone marrow and spleen respectively, can both occur in peripheral mature B cells. As these processes involve the formation of DNA double-strand breaks at different loci, rejoining of these breaks offers insight into the origin of chromosomal translocations observed in certain B cell lymphomas. Editing and class switch recombination, two processes in the development of B cells, are thought to be separated in the bone marrow and spleen, respectively. Errors in either of these processes can initiate chromosomal translocations, including those of B cell lymphomas, but collaboration between them may also initiate translocations. Here it is shown that both editing and class switch recombination can occur in peripheral B cells, offering insights into the origin of the translocations observed in certain B cell lymphomas.

Antibody class switch recombination (CSR) in B lymphocytes joins two DNA double-strand breaks (DSBs) lying 100–200 kb apart within switch (S) regions in the immunoglobulin heavy-chain locus (IgH). CSR-activated B lymphocytes generate multiple S-region DSBs in the donor Sμ and in a downstream acceptor S region, with a DSB in Sμ being joined to a DSB in the acceptor S region at sufficient frequency to drive CSR in a large fraction of activated B cells. Such frequent joining of widely separated CSR DSBs could be promoted by IgH -specific or B-cell–specific processes or by general aspects of chromosome architecture and DSB repair. Previously, we found that B cells with two yeast I-SceI endonuclease targets in place of Sγ1 undergo I-SceI–dependent class switching from IgM to IgG1 at 5–10% of normal levels. Now, we report that B cells in which Sγ1 is replaced with a 28 I-SceI target array, designed to increase I-SceI DSB frequency, undergo I-SceI–dependent class switching at almost normal levels. High-throughput genome-wide translocation sequencing revealed that I-SceI–generated DSBs introduced in cis at Sμ and Sγ1 sites are joined together in T cells at levels similar to those of B cells. Such high joining levels also occurred between I-SceI–generated DSBs within c- myc and I-SceI– or CRISPR/Cas9-generated DSBs 100 kb downstream within Pvt1 in B cells or fibroblasts, respectively. We suggest that CSR exploits a general propensity of intrachromosomal DSBs separated by several hundred kilobases to be frequently joined together and discuss the relevance of this finding for recurrent interstitial deletions in cancer.

Immunoglobulin H class-switch recombination (CSR) occurs between switch regions and requires transcription and activation-induced cytidine deaminase (AID). Transcription through mammalian switch regions, because of their GC-rich composition, generates stable R-loops, which provide single-stranded DNA substrates for AID. However, we show here that the Xenopus laevis switch region S μ , which is rich in AT and not prone to form R-loops, can functionally replace a mouse switch region to mediate CSR in vivo . X. laevis S μ –mediated CSR occurred mostly in a region of AGCT repeats targeted by the AID–replication protein A complex when transcribed in vitro . We propose that AGCT is a primordial CSR motif that targets AID through a non-R-loop mechanism involving an AID–replication protein A complex.