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1、BACKGROUND,Within the lymph node environment, there is a heterogeneous population of stromal cells that are characterized, in part, by their differential expression of CD31 (also known as PECAM1) and podoplanin (also known as gp38 in mice and gp36 in humans). The five major stromal cell types that c
2、an be distinguished on the basis of their morphology and function are fibroblastic reticular cells (FRCs), marginal reticular cells (MRCs), lymphatic endothelial cells (LECs), blood endothelial cells (BECs) and FDCs.,FDCs have received little attention and in vitro studies are challenging because FD
3、Cs are rare and fragile. an understanding of FDCs is critical to an understanding of GCs, B lymphocyte maturation, and optimal Ab responses that are critical to effective vaccination. GCs are a fundamental feature of the immune system and presentation of FDC-Ags to B cells has potential applications
4、. Rapid responses may be crucial for protecting people traveling in areas with endemic infections, from biological warfare, or rapidly spreading epidemics. The ability of FDCs to productively present Ag to B cells should advance the development of new mAbs including human mAbs. On the other hand, FD
5、C-ICs probably promote autoimmune diseases.,Timeline of major discoveries in the FDC field,Basic overview of lymph node and FDC,Follicular dendritic cells (FDCs) are a unique population of cells that is essential for efficient germinal centre (GC) formation and for the production of high-affinity an
6、tibodies1 . They are centrally located within B cell follicles in secondary lymphoid organs and, they develop from perivascular precursors of stromal cell origin that are seeded throughout the body. FDC maturation requires lymphotoxin and tumour necrosis factor (TNF) signalling through B cells, and
7、the disruption of these pathways leads to the loss of FDCs.,In the spleen and lymph nodes, FDCs are just one stromal cell type within a network of stromal cells. Although incompletely defined, the interplay between these different stromal cell populations may have substantial effects on the generati
8、on of protective immunity.,FDCs are localized to the follicles of all secondary lymphoid tissues, where they retain antigens for months in the form of ICs The origin of FDCs remains unclear. There are data supporting a hematopoietic origin but even more supporting a stromal cell origin Morphological
9、ly, FDCs are slightly larger than lymphocytes and possess fine dendritic processes that intimately interact with neighboring cells. They have irregular, sometimes bilobed, euchromatic nuclei (sometimes there are multiple nuclei) containing distinct nucleoli. FDCs possess a scanty cytoplasm with few
10、mitochondria, a rough endoplasmic reticulum, a Golgi apparatus and vesicles Morphological types include one with filiform or finger-like processes, and one with beaded dendrites. The released beads are called “iccosomes”, which are immune complex-coated bodies or somes,Monoclonal Abs useful for iden
11、tifying FDCs include: FDC-M1 & FDC-M2 for murine FDCs and DRC-1, HJ2 & KI-M4 for human FDCs Other phenotypic markers include: fcriib/cd32, FcRII/CD23, CR1/2/CD21/35,ICAM-1/CD54, VCAM-1/CD106, MadCAM-1, 8D6/CD320, CD40, TLR(2, 3 and 4), & lymphotoxin receptor FDC-cytokines and chemokines include: CXC
12、L13, IL-6, IL-7, IL-15, BAFF, and TNF- FDCs are critically involved in germinal center development, immunoglobulin class switching, memory B cell generation, selection of somatically mutated B cells with high affinity receptors, affinity maturation, induction of recall responses, and regulation of s
13、erum IgG & IgE levels In addition to their role in humoral immunity, FDCs are associated with certain diseases including HIV/AIDS, prion diseases, follicular lymphomas, and chronic inflammatory autoimmune diseases,The germinal centre reaction,FDCs have the unique ability to retain intact antigen for
14、 extended periods. Indeed, this is required for GC maintenance, robust B cell somatic hypermutation (SHM) and the promotion of long-term immune memory. Activated B cells that participate in a GC reaction interact with antigen on the surface of FDCs in order to receive survival signals and undergo af
15、finity maturation, which leads to the formation of memory B cell populations.,Antigen acquisition by FDCs.,FDCs and B cell,FDCs: beyond the necessity of T-cell help,Follicular dendritic cells (FDCs) are potent accessory cells for B cells,。 The engagement of CD21 in the B-cell coreceptor complex by c
16、omplement-derived CD21 ligand on FDCs delivers a crucial signal that dramatically augments the stimulation delivered by the binding of antigen to the B-cell receptor (BCR). FDCs minimize a negative B-cell signal. In short, these ligandreceptor interactions help to signal to B cells and meet a requir
17、ement for B-cell stimulation that goes beyond the necessity of T-cell help.,Activation of B cells by antigens on follicular dendritic cells,A need for antigen-processing and presentation to B cells is not widely appreciated. However, cross-linking of multiple B cell receptors (BCRs) by T-independent
18、 antigens delivers a potent signal that induces antibody responses. Such BCR cross-linking also occurs in germinal centers where follicular dendritic cells (FDCs) present multimerized antigens as periodically arranged antigen-antibody complexes (ICs). Certain antigens (Ag) can engage B cells such th
19、at specific antibodies (Abs) are induced in the absence of T cell help. These so-called T cell-independent (TI) Ags are further classified into TI type 1 and 2. FDCs trap immune complexes (ICs), and Ag in FDC-ICs are intact and persist in a form that can be recognized by specific antibodies for mont
20、hs or even years,Model of FDC-dependent but T-independent B cell activation and Ig production,T independent B cell activation by IC-bearing FDCs,Robust GCs and plasmablast responses induced in 48 h in nude mice by OVA-ICs in association with IC-retaining FDC-reticula,IL-21-dependent B cell death dri
21、ven by prostaglandin E2, a product secreted from follicular dendritic cells, In germinal centers (GCs), B cells are selected through interaction with follicular dendritic cells bearing immune complexes and follicular helper T (Tfh) cells secreting Tfh cytokines, including IL-21. FL-YB cells efficien
22、tly enhanced viability of cocultured mouse B cells in a BAFF-dependent fashion. Addition of IL-21, a major Tfh cytokine, readily induced death of B cells that were cocultured with FL-YB cells, whereas IL-21 alone sustained viability of B cells in the absence of FL-YB cells. The IL-21induced death wa
23、s dependent on a low m.w. soluble factor that was released from FL-YB cells, which was finally identified as PGE2. Treatment of B cells with IL-21 plus PGE2, but not either alone, resulted in enhanced expression of a proapoptotic protein Bim and the upstream transcription factor Foxo1. A PGE2 recept
24、or isoform, EP4, was responsible for IL-21/PGE2induced B cell death.,IL-21 induces B cell death in the presence of FDCs,Identification of the FL-YBderived factor responsible for IL-21induced B cell death,Mechanism of action of PGE2 in inducing death of IL-21stimulated B cells,Follicular Dendritic Ce
25、ll Activation by TLR Ligands Promotes Autoreactive B Cell Responses Human follicular dendritic cells promote the APC capability of B cells by enhancing CD86 expression levels Immune regulation by Fc/ receptor (CD351) on marginal zone B cells and follicular dendritic cells Co-stimulatory function in
26、primary germinal center responses: CD40 and B7 are required on distinct antigen-presenting cells,FDCs and HIV,Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes, Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged p
27、eriods. Despite the success of ART, it does not cure HIV and discontinuation results in viral rebound. Follicular dendritic cells (FDC), located central to the B cell follicle, are also in direct contact with T cells. FDCs retain intact antigen for prolonged periods. We found that human FDCs isolate
28、d from patients on ART retain infectious HIV and can transmit virus to uninfected T cells in vitro. Treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission to T cells in vitro.,Human FDCs recycle immune complexes in a transferrin (
29、Tf) positive non-degradative endosomal compartment.,Human FDCs isolated from HIV positive subjects on ART treatment retain HIV in a Tf positive compartment.,FDCs are a source of HIV infection for T cells.,sCD21-Ig can purge HIV from the FDC and prevent infection of CD4 T cells.,odel of FDC HIV retention, transfer to T cells and sCD21-Ig purging.,DISCUSSION,THANK YOU,