Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T H 2)-type allergic inflammation is not known.We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c + dendritic cells (DCs) and induced production of the T H 2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22).TSLP-activated DCs primed naïve T H cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-α, while downregulating IL-10 and interferon-γ. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis.TSLP expression was associated with Langerhans cell migration and activation in situ.These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLPAbout 20% of the population in Western countries suffers from allergic diseases, which include asthma, allergic rhinitis, atopic dermatitis and food allergy 1 . Allergic inflammation is the result of a complex immunological cascade that leads to dysregulated production of T helper type 2 (TH2)-derived cytokines such as interleukin 4 (IL-4), IL-5 and IL-13 2-4 , which trigger immunoglobulin E (IgE) production, eosinophilia and mucus production [5][6][7] . Dendritic cells (DCs), which are professional antigen-presenting cells 8 , play an important role in the pathogenesis of allergic diseases 9-11 . However, the initial signal that primes DCs to induce T cells to produce proallergic TH2 cytokines is unknown. Epithelial cells are located at the sites of allergen entry into the body and interact closely with DCs in situ. However, it is not known whether DCs play a role in triggering the allergic immune cascade. Although skin keratinocytes and mucosal epithelial cells produce proinflammatory cytokines such as IL-1, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-α (TNF-α) after activation 12 , none of these cytokines explain the mechanism that underlies the induction of allergic inflammation. Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, cloned from a murine thymic stromal cell line 13 . The TLSP receptor is a heterodimer that consists of the IL-7 receptor α chain (IL-7Rα) and a common γ-like receptor chain called TSLP receptor (TSLPR) [14][15][16][17] . Mouse TSLP supports murine early B and T cell developments 18,19 and does not appear to have any biological effects on murine DCs (unpublished data). In contrast, human TSLP activates CD11c + DCs, but does not appear to have any direct biological effects on B cells, T cells, NK cells, neutrophils or mast cells 17 . This is in accordance with the coexpression of IL-7Rα chain and TSLPR mRNA in CD11c + DCs, but not in other cell types. We show here that human TSLP potently activated ...
An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 triggers Th1 polarization of naive CD4(+) T cells and secretion of IFN-gamma. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4(+) T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.
The identification of the antigen recognition receptors for innate immunity, most notably the Toll-like receptors, has sparked great interest in therapeutic manipulation of the innate immune system. Toll-like receptor agonists are being developed for the treatment of cancer, allergies and viral infections, and as adjuvants for potent new vaccines to prevent or treat cancer and infectious diseases. As recognition grows of the role of inappropriate Toll-like receptor stimulation in inflammation and autoimmunity, significant efforts have begun to develop antagonists to Toll-like receptors as well.
SummaryIn Hodgkin's disease (HD), the Hodgkin and R.eed-Sternberg (HR.S) cells represent only a minute population in the diseased tissue. The investigation of lineage derivation and clonal origin of these cells has yielded conflicting results. We have analyzed HRS cells micromanipulated from infiltrated tissue sections of 10 primary HD patients for rearranged V genes, extending a previous study. Clonally related rearrangements were found in nine cases, indicating that HRS cells represent a dominant clone of B lineage-derived cells in at least a large fraction of cases of liD. Rearranged V. genes from HP.S cells carried a high load of somatic mutation, indicating that HRS cells are derived from germinal center (GC) cells or their progeny. Stop codons in some in-frame V gene rearrangements suggest that the HR.S ceil precursors reside inside GCs, have acquired crippling mutations that prevent antigenic selection, but escape apoptosis through some transforming event.
In the human, most IgM+IgD+ as well as CD5+ peripheral blood B cells express unmutated V genes and thus can be assigned to a pre-germinal centre (GC) stage of development. The memory B-cell compartment generated in the GC reaction and characterized by cells bearing somatically mutated V-region genes consists not only of class-switched cells, but also of IgM-only B cells and perhaps a subset of IgM+IgD+B cells expressing the CD27 antigen. Comparison of the rearranged V-region genes of human B-cell lymphomas with those of the normal B-cell subsets allows the identification of the progenitor cells of these tumours in terms of their stage of maturation. On this basis, most B-cell non-Hodgkin lymphomas, and in addition Hodgkin and Reed-Sternberg (HRS) cells in Hodgkin's disease (HD), are derived from B cells at a GC or post-GC stage of development. The mutation pattern indicates that the precursors of the tumour clones have been stringently selected for expression of a functional antigen receptor with one notable exception: HRS cells in classical (but not lymphocyte-predominant) HD appear to be derived from "crippled" GC B cells. Sequence analysis of rearranged V genes amplified from single tonsillar GC B cells revealed that the somatic hypermutation process introduces deletions and/or insertions into V-region genes more frequently than indicated by previous investigations. Presumably, this feature of the hypermutation mechanism is often responsible for the generation of heavy chain disease, and also several types of chromosomal translocations of oncogenes into immunoglobulin loci in human B-cell lymphomas.
Dendritic cells (DCs) are professional antigen-presenting cells that have an extraordinary capacity to stimulate naïve T cells and initiate primary immune responses. Here we review progress in understanding the additional functions of DCs in regulating the types of T cell-mediated immune responses and innate immunity to microbes. In addition, evidence for the existence of myeloid and lymphoid DC lineages and their different functions are summarized. We propose that the diverse functions of DCs in immune regulation are dictated by the instructions they received during innate immune responses to different pathogens and from their evolutionary lineage heritage.
Recent studies suggest plasmacytoid predendritic cells (pDCs) and myeloid dendritic cells (mDCs) have the functional plasticity to produce similar amounts of type 1 interferons (IFNs) and interleukin-12 (IL-12), challenging the concept and existence of DC subsets with distinct function. In this study, we demonstrate that previous studies showed human pDCs produce large amounts of IL-12 because of contaminating mDCs. Using highly purified human DC subsets, we found that although pDCs make 300 times more IFN-␣ than mDCs and mDCs make 13 times more IL-12 p70 than pDCs in response to all the toll-like receptor ligands and CD40 ligands, pDCs rapidly make large amounts of IFN-␣ within the first 12 hours of activation and become refractory to further stimulation. pDCs preferentially expressed the transcriptional factors critical for type 1 IFN, but not for IL-12 transcription, and they dedicated 60% of new transcriptional activity to make 19 type 1 IFN subtypes. This study provides formal proof that the plasticity of DC subsets is limited and that different DC subsets evolve to perform distinct functions in linking innate and adaptive immunity. ( IntroductionAlthough all nucleated mammalian cell types have the ability to produce type 1 interferons (IFNs) in response to infection by an appropriated virus, enabling neighboring cells to resist viral infection, human plasmacytoid predendritic cells (pDCs), or type 1 IFN-producing cells (IPCs), have the ability to produce hundreds to thousands times more type 1 IFNs than other cell types after encounters with DNA and RNA viruses. [1][2][3][4][5][6] This phenomenon, together with the selective expression of toll-like receptor 7 (TLR7) and TLR9 7-9 -which, respectively, recognize viral RNA and DNA 10,11 -by human pDCs/IPCs, suggests that pDCs/IPCs are specialized in the viral recognition and production of type 1 IFNs. By contrast, human myeloid dendritic cells (mDCs) selectively express TLR2, TLR3, TLR4, TLR5, TLR6, and TLR8 and have the ability to produce high levels of interleukin-12 (IL-12), but only low levels of type 1 IFNs, on bacterial and viral infection. 7,8 These findings have led to an evolution model suggesting that there are 2 unique antigen-presenting cell (APC) systems in humans, with pDCs specialized in making type 1 IFNs and mDCs specialized in making IL-12. This hypothesis is challenged, however, by studies showing that, in response to lipopolysaccharide (LPS) or CpGoligodeoxynucleotide (ODN) plus CD40 ligand (CD40L), pDCs produce as much IL-12 as do mDCs 2,9 and that, in response to electroporated poly(I:C), mDCs produce as much IFN-␣ as pDCs. 12 An alternative instruction model, therefore, has been proposed, suggesting that pDCs and mDCs have the functional plasticity to produce similar amounts of IFN-␣ and IL-12, depending on the stimulus.The question is whether the evolution model and the instruction model of DC development and maturation are mutually exclusive. Current literature on DC subsets is confusing. The confusion appears to be caused by species...
Objective. To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE).Methods. Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine-and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. Conclusion. Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFN␣-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production Dr.
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