How Follicular Dendritic Cells Shape the B-Cell Antigenome

Follicular dendritic cells (FDCs) are stromal cells residing in primary follicles and in germinal centers of secondary and tertiary lymphoid organs (SLOs and TLOs). There, they play a crucial role in B-cell activation and affinity maturation of antibodies. FDCs have the unique capacity to bind and retain native antigen in B-cell follicles for long periods of time. Therefore, FDCs shape the B-cell antigenome (the sum of all B-cell antigens) in SLOs and TLOs. In this review, we discuss recent findings that explain how this stromal cell type can arise in almost any tissue during TLO formation and, furthermore, focus on the mechanisms of antigen capture and retention involved in the generation of long-lasting antigen depots displayed on FDCs

Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner

Progressive accumulation of PrPSc, a hallmark of prion diseases, occurs when conversion of PrPC into PrPSc is faster than PrPSc clearance. Engulfment of apoptotic bodies by phagocytes is mediated by Mfge8 (milk fat globule epidermal growth factor 8). In this study, we show that brain Mfge8 is primarily produced by astrocytes. Mfge8 ablation induced accelerated prion disease and reduced clearance of cerebellar apoptotic bodies in vivo, as well as excessive PrPSc accumulation and increased prion titers in prion-infected C57BL/6 × 129Sv mice and organotypic cerebellar slices derived therefrom. These phenotypes correlated with the presence of 129Sv genomic markers in hybrid mice and were not observed in inbred C57BL/6 Mfge8−/− mice, suggesting the existence of additional strain-specific genetic modifiers. Because Mfge8 receptors are expressed by microglia and depletion of microglia increases PrPSc accumulation in organotypic cerebellar slices, we conclude that engulfment of apoptotic bodies by microglia may be an important pathway of prion clearance controlled by astrocyte-borne Mfge8

Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMφs). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8−/− mice, all splenic Mfge8 was derived from FDCs rather than TBMφs. However, Mfge8−/− TBMφs acquired and displayed Mfge8 only when embedded in Mfge8+/+ stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMφ-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8−/− mice. Hence, FDCs facilitate TBMφ-mediated corpse removal, and their malfunction may be involved in autoimmunity

Repetitive Immunization Enhances the Susceptibility of Mice to Peripherally Administered Prions

The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease

Follicular dendritic cells: origin, phenotype, and function in health and disease

Follicular dendritic cells (FDCs) were originally identified by their specific morphology and by their ability to trap immune-complexed antigen in B cell follicles. By virtue of the latter as well as the provision of chemokines, adhesion molecules, and trophic factors, FDCs participate in the shaping of B cell responses. Importantly, FDCs also supply tingible body macrophages (TBMs) with the eat-me-signaling molecule milk fat globule-EGF factor 8 (Mfge8), thereby enabling the disposal of apoptotic B cells. Recent studies have provided fundamental insights into the multiple functions of FDCs in both physiological and pathophysiological contexts and into their origin. Here we review these findings, and discuss current concepts related to FDC histogenesis both in lymphoid organs and in inflammatory lymphoneogenesis

Comparison of methods for phylogenetic B-cell lineage inference using time-resolved antibody repertoire simulations (AbSim)

Abstract Motivation The evolution of antibody repertoires represents a hallmark feature of adaptive B-cell immunity. Recent advancements in high-throughput sequencing have dramatically increased the resolution to which we can measure the molecular diversity of antibody repertoires, thereby offering for the first time the possibility to capture the antigen-driven evolution of B cells. However, there does not exist a repertoire simulation framework yet that enables the comparison of commonly utilized phylogenetic methods with regard to their accuracy in inferring antibody evolution. Results Here, we developed AbSim, a time-resolved antibody repertoire simulation framework, which we exploited for testing the accuracy of methods for the phylogenetic reconstruction of B-cell lineages and antibody molecular evolution. AbSim enables the (i) simulation of intermediate stages of antibody sequence evolution and (ii) the modeling of immunologically relevant parameters such as duration of repertoire evolution, and the method and frequency of mutations. First, we validated that our repertoire simulation framework recreates replicates topological similarities observed in experimental sequencing data. Second, we leveraged Absim to show that current methods fail to a certain extent to predict the true phylogenetic tree correctly. Finally, we formulated simulation-validated guidelines for antibody evolution, which in the future will enable the development of accurate phylogenetic methods. Availability and implementation https://cran.r-project.org/web/packages/AbSim/index.html Supplementary information Supplementary data are available at Bioinformatics online

(A) Apoptotic cells, TBMφs, and GCs were visualized by TUNEL, anti-CD68, and PNA, respectively, on splenic cryosections 9 wk after BM reconstitution and after immunization

(right) Each datapoint represents the mean number of TUNEL cells per TBMφ in one individual GC. → and WT→ mice showed increased numbers of TUNEL cells per TBMφ. Horizontal bars represent means. White circles (left) indicate GCs. Bars, 100 μm. (B) Ultrastructural features of TBMφs of aged BM-chimeric mice 41 wk after reconstitution. Apoptotic cells in various degradation stages were observed inside TBMφs of all chimeric mice. (C) Engulfment of apoptotic cells by TBMφs in WT, , , , and mice was analyzed by TUNEL (green) and CD68 (red) staining. WT TBMφs contained copious TUNEL material. The latter was also observed in mice, but most TUNEL cells were large and intact. , , and macrophages were small and only contained intact TUNEL cells. At least three mice per genotype and ≥10 follicles per mouse were analyzed. Bars, 20 μm.<p><b>Copyright information:</b></p><p>Taken from "Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8"</p><p></p><p>The Journal of Experimental Medicine 2008;205(6):1293-1302.</p><p>Published online 9 Jun 2008</p><p>PMCID:PMC2413028.</p><p></p

Follicular dendritic cells emerge from ubiquitous perivascular precursors

The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation. PAPERFLICK