Showing papers by "Lucy Bird published in 2013"

B cell development: a window of opportunity.

Abstract: in the bone marrow. But Fred Alt, Duane Wesemann and their colleagues now show that B cells can also develop in the mouse gut for a short time period after birth. The authors used recombination activating gene 2 (Rag2)-reporter mice, in which the Rag2 gene is fused to the gene that encodes green fluorescent protein (GFP), to mark immature B cells undergoing RAG2-mediated generation of B cell receptor repertoires. Analysis of these mice showed that approximately 3% of total CD19+ B cells in the small intestinal lamina propria expressed RAG2–GFP. The RAG2+ B lineage cells were mainly located near to the bases of the villi, whereas mature B cells were distributed throughout the lamina propria but were not found in the mesenteric lymph nodes or among intraepithelial lymphocytes and only in very low frequencies in the large intestinal lamina propria. Interestingly, the numbers of lamina propria RAG2+ B lineage cells gradually increased after birth, peaking at about 18–23 days, before decreasing to undetectable levels by postnatal day 35. The RAG+ B lineage cell populations in the bone marrow comprise pro-B cells (Igμ–Igκ–), pre-B cells (Igμ+Igκ–) and immature B cells undergoing receptor editing (Igμ+Igκ+). Similar relative levels of these three subsets were found in the gut and the bone marrow. Further investigation of repertoire diversity indicated that the immunoglobulin heavy chain (IgH) repertoires of the gut and the bone marrow cells were indistinguishable, but the immunoglobulin light chain (IgL) repertoires were distinctive. The authors proposed that the lamina propria IgL repertoires were generated by receptor editing in RAG2+ immature B cells in response to commensal microorganisms. In support of this idea, colonization of germ-free mice with commensal microorganisms led to increases in RAG1 and RAG2 expression and increased the percentages of pro-B cells relative to total B cells in the gut and the bone marrow. Moreover, there was a commensal bacteria-dependent increase in Igλ usage — a marker of receptor editing — specifically in the lamina propria. So, B cell development and diversification can occur in the intestinal mucosa in response to colonization of the intestinal microbiota at weaning. Whether this process enhances overall antibody diversity or whether it helps to eliminate antibody reactivity to commensal bacteria and self antigens will require further study. Lucy Bird B C E L L D E V E LO P M E N T

B cell tolerance: STALling B cell responses

Abstract: Journal of Clinical Investigation describes an elegant new strategy to eliminate undesired antibody responses, such as those that arise in autoimmunity, after transplantation and against biological agents. The approach uses antigenic liposomes that display ligands for the inhibitory B cell co-receptor CD22 and that effectively induce B cell tolerance to T cell-dependent antigens. CD22 — a member of the SIGLEC (sialic acid-binding immuno globulin-like lectin) family — has an inhibitory effect on B cell activation when it is localized with the B cell receptor (BCR). So, the authors forced the localization of CD22 with a BCR using liposomal nanoparticles containing a high affinity SIGLEC ligand and an antigen; these were referred to as STALs (SIGLEC-engaging toleranceinducing antigenic liposomes). In initial experiments, mice were injected with STALs bearing different antigens and this prevented the B cell response to challenge with the corresponding antigen, which occurred in mice injected with liposomes displaying the antigen alone (immunogenic liposomes). The antigen-specific inhibitory effect of STALs was shown to be CD22 dependent, as it did not occur in immunized CD22-deficient mice. Next, the authors investigated the mechanism by which STALs induced tolerance. STALs completely abrogated the activation of antigen-specific B cells in vitro, as measured by calcium influx, by the upregulation of CD86 expression and by cell proliferation. Moreover, using annexin V staining, the authors noticed a time-dependent decrease in the number of live B cells following their incubation with STALs. Indeed, antigen-specific B cells that were adoptively transferred into mice following immunization with STALs proliferated much less and their numbers were considerably reduced compared to B cells that were transferred to mice that had been immunized with control liposomes. Analysis of BCR signalling showed STALs, but not immunogenic liposomes, to strongly inhibit the phosphorylation of proximal and distal BCR signalling components. Of note forkhead box protein O1 (FOXO1) and FOXO3A, which are known to be involved in cell-cycle inhibition and apoptosis in B cells, were hypophosphorylated and localized to the nucleus. Taken together, these observations suggest that STALs induce a tolerogenic mechanism involving apoptosis. Consistent with the possible application of this approach in a therapeutic setting, the authors showed that STALs containing various T cell-dependent antigens (such as ovalbumin, factor VIII (FVIII) and myelin oligodendrocyte glycoprotein) induced tolerance to these antigens, as measured by low specific antibody responses following subsequent challenge with the corresponding antigen. Importantly, using FVIII-deficient mice, which are a mouse model of haemophilia A, the authors showed that immunization with STALs displaying FVIII prevented the formation of inhibitory antibodies against infused recombinant FVIII, which protected the mice from bleeding following a tail cut. Given that 20–30% of patients with haemophilia A develop inhibitory antibodies shortly after initiation of FVIII therapy, which renders them unresponsive to the therapy, the possible application of STALs in this setting is a promising prospect. Lucy Bird B C E L L TO L E R A N C E

Immunometabolism: Mef2 in sickness and in health

Abstract: Phosphorylation of Mef2 controls immune versus metabolic gene expression in infected Drosophila melanogaster.

Want to neutralize HIV? Get help!

Abstract: The presence of memory TFH cells in the blood correlates with the development of broadly neutralizing antibodies against HIV.

Macrophages: BACH2 normal

Abstract: Bisphosphonates are clinically used inhibitors of bone resorption. Previous studies have noted an increase in humoral immune responses in bisphosphonate-treated mice. Investigating this phenomenon in vesicular stomatitis virus-infected mice, the authors found that bisphosphonates increased neutralizing antibody levels (both IgM and IgG) by 100-fold compared with controls. Similarly, bisphosphonates increased antibody responses to proteins, haptens and existing commercial vaccine formulations. Bisphosphonates were shown to directly target B cells, and although the mechanism of this adjuvanticity remains to be determined it was independent of the Toll-like receptor and inflammasome pathways. Of note, patients with skeletal disease had a transient but significant increase in total IgG levels following a single intravenous infusion of bisphosphonates. Thus, bisphosphonates are B cell-targeting adjuvants that could be readily combined with vaccines, given that bisphosphonates are already widely used in the clinic.

Autoimmunity: SCARF1 helps clean up the dead

Abstract: SCARF1 helps clean up the dead A failure of the immune system to remove apoptotic cells can lead to autoimmune disease, such as systemic lupus erythematosus (SLE). This study identifies a key scavenger receptor that is used by phagocytes to recognize and to engulf apoptotic cells. Similar to the Caenorhabditis elegans homologue CED-1, SCARF1 (scavenger receptor class F member 1) was found to bind to apoptotic cells but not to live cells. This interaction did not involve direct binding to known ‘eat-me’ signals such as phosphatidylserine, but rather involved specific recognition of the complement component C1q, which bound phosphatidylserine on dying cells. Dendritic cells, and to a lesser extent macrophages and endothelial cells, from Scarf1 mice had impaired uptake of apoptotic cells. Consequently, dying cells accumulated in Scarf1 mice and the mice developed a lupus-like disease, which was associated with autoantibody production, nephritis and dermatitis.

NK cell responses: A dietary boost for NK cells

Abstract: The monocyte family tree Monocytes and dendritic cells (DCs) originate from a common macrophage and DC progenitor (MDP) and classical and plasmacytoid DCs develop from an intermediate stage, the common DC progenitor (CDP). Now, Hettinger et al. identify a progenitor for monocytes and monocyte-derived macrophages downstream of the MDP, which they termed the common monocyte progenitor. Common monocyte progenitors had a lineage-negative CD117CD115CD135LY6CCD11b phenotype and showed high proliferative and clonogenic activity. In mice, common monocyte progenitors gave rise to LY6C and LY6C monocytes, and to macrophages following macrophage deletion or inflammation, but they did not give rise to DCs. These observations, together with the results of proteomic analyses, indicate that common monocyte progenitors are committed to monocyte differentiation but that they lack any monocyte functionality.

HIV: advancing the antibody approach.

Abstract: Antibodies come to the fore in therapeutic and prophylactic approaches to suppress SHIV in macaques.