9 research outputs found
Follicular dendritic cells in health and disease
No full textFollicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerise Ags and present them polyvalently to B cells in periodically arranged arrays that extensively crosslink the B cell receptors for Ag (BCRs). FDC-Fc-gamma-RIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6 and -C4bBP, are essential for the induction of the germinal centre (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses
Isolation and Characterization of Mouse and Human Follicular Dendritic Cells.
No full textFollicular dendritic cells (FDCs) reside in the B cell follicles of secondary and tertiary lymphoid tissues where they play key roles in the development and maintenance of lymphoid tissue architecture and function. FDCs trap native antigens for extended periods of time in the form of immune complexes which critcally regulate germinal center reactions in health and disease. Here, we describe how to isolate and characterize FDCs from murine and human lymphoid tissues
O001 Lymphoid tissue macrophages express peptidylarginine deiminase 2 and 4: new implications in citrullination and anti-citrulline antibodies production in autoimmune arthritis
No full textMast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production
No full textThe research leading to these results has received funding from the
People Programme (Marie Curie Actions) of the European Union’s Seventh
Framework Programme (FP7/2007 2013) under REA grant agreement n° 608765.
This work was supported in part by grants from the Ministero dell’Istruzione,
Università e Ricerca (MIUR) and Regione Campania CISILab Project, CRÈME
Project, and TIMING Project. The Pathobiology of Early Arthritis Cohort (PEAC) was
funded by the MRC grant 36661. Additional funding from MRC funded Maximising
Therapeutic Utility for Rheumatoid Arthritis using genetic and genomic tissue
responses to stratify medicines (MATURA) Grant Ref: MR/K015346/1 and ARUK
funded Experimental Arthritis Treatment Centre (EATC) Grant Ref: 20022. The
animal work was supported by Arthritis Research UK Grants Reference 20305 and
20770
LLT1 and CD161 expression in human germinal centers promotes B cell activation and CXCR4 downregulation
No full textGerminal centers (GC) are microanatomical structures critical for the development of high-affinity antibodies and B-cell memory. They are organised into two zones, light and dark, with coordinated roles, controlled by local signalling. The innate Lectin-like transcript 1 (LLT1) is known to be expressed on B-cells, but its functional role in the GC reaction has not been explored. Here we report high expression of LLT1 on GC-associated B-cells, early plasmablasts and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40 and CpG stimulation on B-cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on Follicular dendritic cells (FDCs). Triggering of LLT1 supported B-cell activation, CD83 upregulation and CXCR4 downregulation. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B-cell maturation within the GC in humans
Extracellular traps and PAD4 released by macrophages induce citrullination and auto-antibody production in autoimmune arthritis
No full textBarts Charity grant number MRC0177
Follicular dendritic cell differentiation is associated with distinct synovial pathotype signatures in rheumatoid arthritis
No full textFollicular dendritic cells (FDCs) fundamentally contribute to the formation of synovial ectopic lymphoid-like structures in rheumatoid arthritis (RA) which is associated with poor clinical prognosis. Despite this critical role, regulation of FDC development in the RA synovium and its correlation with synovial pathotype differentiation remained largely unknown. Here, we demonstrate that CNA.42(+) FDCs distinctively express the pericyte/fibroblast-associated markers PDGFR-β, NG2, and Thy-1 in the synovial perivascular space but not in established follicles. In addition, synovial RNA-Seq analysis revealed that expression of the perivascular FDC markers was strongly correlated with PDGF-BB and fibroid synovitis, whereas TNF-α/LT-β was significantly associated with lymphoid synovitis and expression of CR1, CR2, and FcγRIIB characteristic of mature FDCs in lymphoid follicles. Moreover, PDGF-BB induced CNA.42(+) FDC differentiation and CXCL13 secretion from NG2(+) synovial pericytes, and together with TNF-α/LT-β conversely regulated early and late FDC differentiation genes in unsorted RA synovial fibroblasts (RASF) and this was confirmed in flow sorted stromal cell subsets. Furthermore, RASF TNF-αR expression was upregulated by TNF-α/LT-β and PDGF-BB; and TNF-α/LT-β-activated RASF retained ICs and induced B cell activation in in vitro germinal center reactions typical of FDCs. Additionally, FDCs trapped peptidyl citrulline, and strongly correlated with IL-6 expression, and plasma cell, B cell, and T cell infiltration of the RA synovium. Moreover, synovial FDCs were significantly associated with RA disease activity and radiographic features of tissue damage. To the best of our knowledge, this is the first report describing the reciprocal interaction between PDGF-BB and TNF-α/LT-β in synovial FDC development and evolution of RA histological pathotypes. Selective targeting of this interplay could inhibit FDC differentiation and potentially ameliorate RA in clinically severe and drug-resistant patients
ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses
No full textAbstract
The proper regulation of ICOS and ICOS ligand (ICOSL) has been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant Ab production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that a disintegrin and metalloproteinase (ADAM)10 is the primary physiological sheddase of ICOSL in mice and humans. Using an in vivo system in which ADAM10 is deleted only on B cells, elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wild-type mice, interaction of ICOS/ICOSL results in ADAM10-induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper development and TH2 polarization, as seen in a house dust mite exposure model. In addition, enhanced TH1 and TH17 immune responses are seen in experimental autoimmune encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and rescues, at least in part, T follicular helper numbers and the abnormal Ab production previously reported in these mice. Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL, as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses.</jats:p
Механизм развития гуморального иммунного ответа на аллогенную трансплантацию орг
No full textThe problem of antibody-mediated rejection of donor organ remains extremely relevant. The main targets of the antibodies are mainly donor HLA-antigens (Human Leucocyte Antigens), expressed, in particular, by the cells of graft vascular endothelium. This review describes the mechanisms of the development of humoral alloimmunity which are based on B-cell recognition of epitopes of donor HLA-molecules and affinity maturation of B-cell receptors in the germinal centers of peripheral lymphatic system. Monitoring of epitope load and cross-reactivity indicators to evaluate HLA-compatibility of donor and recipient plays an important role in the prevention of allograft humoral rejection.Проблема гуморального, антителоопосредованного отторжения донорского органа остается крайне актуальной. Главной мишенью антител в основном являются донорские HLA-антигены (Human Leucocyte Antigens), экспрессируемые, в частности, клетками сосудистого эндотелия трансплантата. В данном обзоре рассматриваются механизмы развития гуморального аллоиммунитета, в основе которых лежит распознавание В-клетками реципиента эпитопов донорских HLA-молекул и созревание аффинности В‑клеточных рецепторов в герминативных центрах периферической лимфатической системы. Учет показателей эпитопной нагрузки и кросс-реактивности при анализе HLA-совместимости донора и реципиента играет важную роль в профилактике гуморального отторжения аллогенного трансплантата
