Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lupus erythematosus (LE) represents an autoimmune disease with great clinical variability in which photosensitivity is a common feature for all forms and subsets. The nature and characteristics of clinical photosensitivity in LE have been elucidated through standardized phototesting procedures. The development of skin lesions after UV-injury is typically delayed starting from a few days up to three weeks after the irradiation, and may persist for months. Therefore, patients may not be aware of the detrimental effects of sunlight for their disease. The most photosensitive subset of LE is LE tumidus, followed by subacute cutaneous LE. Phototesting has also been crucial for studying the pathophysiology of LE-photosensitivity. Abnormalities of generation and clearance of UV-triggered apoptotic cells in LE are an important source of autoantigens. Recent data demonstrate the linkage of innate with adoptive immune pathways in UV-induced autoimmune response. Plasmocytoid dendritic cells (PDC) and their secreted IFN-alpha play a central role in the LE-pathogenesis. The recruitment of relevant leukocyte subsets is dependant on certain chemokines, which have been characterized in recent studies. An amplification cycle has been postulated, in which UV induces apoptosis and necrosis resulting in the production and release of chemokines. Subsequently, effector memory T cells as well as PDCs are recruited and activated perpetuating an amplification process that leads to UV-induced cutaneous LE lesion.
 ...
PMID:Clinic and pathophysiology of photosensitivity in lupus erythematosus. 1916 24

A number of uncommon, clinically diverse and poorly understood inflammatory skin diseases are linked by the presence of a set of histopathological elements that have traditionally been referred to as the "lichenoid tissue reaction/interface dermatitis" (LTR/IFD). The prototypic skin disease in this category is lichen planus. However, the LTR/IFD can also be seen in skin disorders associated with systemic illnesses (lupus erythematosus, dermatomyositis), and the skin changes of potentially fatal disorders such as graft-versus-host disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. It has been traditionally felt that cytotoxic T-lymphocytes represent the final effector cell type for the epidermal basal cell layer injury pattern that is common to LTR/IFD disorders. Recent work has suggested that a number of different LTR/IFD skin disorders share a common inflammatory signaling pathway involving the actions of plasmacytoid dendritic cell-derived IFN-alpha. This signaling pathway appears to amplify cytotoxic T cell injury to the epidermal basal cell compartment. This review will summarize the work implicating this pathway as well as the other cellular and molecular mechanisms that are thought to be responsible for the prototypic LTR/IFD disorder, lichen planus. It is hoped that a better understanding of the immunological commonalities shared by various LTR/IFD disorders will lead to more effective safer treatment options for these illnesses.
 ...
PMID:Lichenoid tissue reaction/interface dermatitis: clinical and histological perspectives. 1924 12

Using the Unc93b1 3d mutation that selectively abolishes nucleic acid-binding Toll-like receptor (TLR) (TLR3, -7, -9) signaling, we show these endosomal TLRs are required for optimal production of IgG autoAbs, IgM rheumatoid factor, and other clinical parameters of disease in 2 lupus strains, B6-Fas(lpr) and BXSB. Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement. The 3d mutation slightly reduced complete Freund's adjuvant (CFA)-mediated antigen presentation, but did not affect T-independent type 1 or alum-mediated T-dependent humoral responses or TLR-independent IFN production induced by cytoplasmic nucleic acids. These findings suggest that nucleic acid-sensing TLRs might act as an Achilles' heel in susceptible individuals by providing a critical pathway by which relative tolerance for nucleic acid-containing antigens is breached and systemic autoimmunity ensues. Importantly, this helps provide an explanation for the high frequency of anti-nucleic acid Abs in lupus-like systemic autoimmunity.
 ...
PMID:Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. 1957 51

Recent evidences suggest a significant role of Plasmacytoid dendritic cells (PDC) role in the pathogenesis of lupus erythematosus (LE) via production of type I IFN. Taking advantage on the availability of multiple reagents (CD123, BDCA2, and CD2ap) specifically recognizing PDC on fixed tissues, we investigated the occurrence of PDC in a cohort of 74 LE patients. The large majority of LE biopsies (67/74; 90.5%) showed cutaneous infiltration of PDC. PDC were more frequently observed (96.4 vs 72.2) and numerous in cutaneous LE compared to systemic LE (SLE) and correlated with the density of the inflammatory infiltrate (r=0.40; p<0.001). PDC reduction in SLE might be related to a broader tissue distribution of this cellular population, as indicated by their occurrence in kidneys in 11 out of 24 (45.8%) cases studied. The distribution of cutaneous PDC showed two distinct patterns. More commonly, PDC were observed within perivascular inflammatory nodules in the dermis, associated with CD208+ mature DC and T-bet+ cells [D-PDC]. A second component was observed along the dermal-epithelial junction [J-PDC], in association with cytotoxic T-cells in areas of severe epithelial damage. Notably, chemerin reactivity was observed in 64% of LE biopsies on endothelial cells and in the granular layer keratinocytes. Cutaneous PDC in LE strongly produced type I IFN, as indicated by the diffuse MxA expression, and the cytotoxic molecule granzyme B. This study confirms cutaneous PDC infiltration as hallmark of LE. The topographical segregation in D-PDC and J-PDC suggests a novel view of the role of these cells in skin autoimmunity.
 ...
PMID:Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage. 1962

Lupus-prone female New Zealand Mixed (NZM)2328 mice develop high titers of anti-nuclear and anti-dsDNA autoantibodies. Despite high expression of type I IFNs, these mice do not develop autoantibodies to the small nuclear ribonucleoprotein (snRNP) complex. Thus, additional genetic factors must regulate the generation of anti-snRNP autoantibodies. In contrast, despite much lower expression of type 1 IFNs, the diabetes-prone NOD mice spontaneously make anti-snRNP autoantibodies, albeit at a low incidence. To determine whether combination of high type I IFN response of NZM mice with appropriate susceptibility genes of NOD mice would result in anti-snRNP Ab response, cohorts of (NZM2328 x NOD)F(1) mice were generated and characterized for development of autoimmunity. In comparison with parental strains, the PBMCs from F(1) mice showed intermediate expression of type I IFN-responsive genes and augmented expression of IL-6 transcripts. TLR7 expression was similar in all strains. The F(1) mice had very high incidence and titer of anti-snRNP autoantibodies, anti-nuclear Abs, and anti-dsDNA autoantibodies. The levels of anti-snRNP autoantibody correlated with the expression levels of type I IFN-responsive genes. None of the F(1) mice developed diabetes, and only female mice developed severe renal disease. Our data demonstrate that only in presence of appropriate susceptibility genes, anti-snRNP autoantibodies are induced and type I IFNs amplify this response. A synergy between IL-6 and type I IFNs might be critical for amplifying overall autoantibody responses in systemic lupus erythematosus. In NZM/NOD F(1) mouse, genetic complementation between NZM and NOD genes leads to expression of phenotypes similar to those seen in certain lupus patients.
 ...
PMID:Genetic complementation results in augmented autoantibody responses to lupus-associated antigens. 1966 95

T cells from lupus patients have hypomethylated DNA and overexpress genes normally suppressed by DNA methylation that contribute to disease pathogenesis. We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells. We therefore asked if lupus T cells also overexpress KIR, and if the proteins are functional. T cells from lupus patients were found to overexpress KIR genes, and expression was proportional to disease activity. Abs to the stimulatory molecule KIR2DL4 triggered IFN-gamma release by lupus T cells, and production was proportional to disease activity. Similarly, cross-linking the inhibitory molecule KIR3DL1 prevented the autoreactive macrophage killing that characterizes lupus T cells. These results indicate that aberrant T cell KIR expression may contribute to IFN overproduction and macrophage killing in human lupus, and they suggest that Abs to inhibitory KIR may be a treatment for this disease.
 ...
PMID:Stimulatory and inhibitory killer Ig-like receptor molecules are expressed and functional on lupus T cells. 1967 66

HIN200 is a human IFN-inducible gene and homologous to murine IFI202 gene, which was identified as a candidate gene for SLE susceptibility in lupus mouse model. We determined these gene expressions in leukocytes from 20 SLE patients and 10 healthy controls and in renal biopsies from 29 SLE patients and 15 kidney donors using sensitive real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The expressions of MNDA, IFIX, IFI16 and AIM2 genes significantly increased in leukocytes but not in kidney biopsies from SLE patients as compared to the control individuals, with P = 0.0003, P = 0.0056, P = 0.0002 and P < 0.0001, respectively. We also assessed the expression profiles of IFIX and IFI16 isoforms using semi-quantitative RT-PCR. We found up-regulation of B isoform (short product) of IFI16 in SLE patients. In addition, the expression levels were analyzed in correlation with disease activity and clinical characteristics. Interestingly, higher expression of MNDA was observed in patients who were positive for anti-dsDNA antibodies than in patients who were negative (P = 0.0276). In conclusion, it is suggested that the HIN200 genes have a role in SLE pathogenesis. Our study also observed a possible important role of a specific short isoform of IFI16 as well as a link between MNDA and anti-dsDNA antibody production.
Lupus 2009 Oct
PMID:Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR. 1976 80

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
 ...
PMID:Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. 1981 95

Increased Type I IFNs or IFN-I have been associated with human systemic lupus erythematosus. Interestingly augmenting or negating IFN-I activity in murine lupus not only modulates systemic autoimmunity, but also impacts lupus nephritis, suggesting that IFN-I may be acting at the level of the end-organ. We find resident renal cells to be a dominant source of IFN-I in an experimental model of autoantibody-induced nephritis. In this model, augmenting IFN-I amplified antibody-triggered nephritis, whereas ablating IFN-I activity ameliorated disease. One mechanism through which increased IFN-I drives immune-mediated nephritis might be operative through increased recruitment of inflammatory monocytes and neutrophils, though this hypothesis needs further validation. Collectively, these studies indicate that an important contribution of IFN-I toward the disease pathology seen in systemic autoimmunity may be exercised at the level of the end-organ.
 ...
PMID:Type I interferons produced by resident renal cells may promote end-organ disease in autoantibody-mediated glomerulonephritis. 1986 99

Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are polyA-, non-coding RNAs that are expressed abundantly in all forms of cells latently infected with EBV. EBERs (EBER1 and EBER2) contribute to the clonal proliferation of EBV-negative Burkitt's lymphoma (BL) cells in soft agar, tumorigenicity in SCID mice, up-regulation of the bcl-2 oncoprotein, resistance to apoptosis, and maintenance of malignant phenotypes in BL cells. EBERs induce the expression of interleukin (IL)-10 in BL cells, insulin-like growth factor 1 (IGF-I) in gastric and nasopharyngeal carcinoma cells, IL-9 in T cells, and IL-6 in lymphoblastoid cell lines. Additionally, each of these cytokines acts as an autocrine growth factor. In BL cells, EBERs bind the double-stranded RNA-activated protein kinase PKR, inhibit its phosphorylation, and thereby prevent IFN-alpha-mediated apoptosis. In epithelial cells, EBERs confer resistance to Fas-mediated apoptosis by blocking PKR activity. EBERs form complexes with PKR, ribosomal protein L22, lupus erythematosis-associated antigen (La), and retinoic acid-inducible gene I (RIG-I). In BL cells, EBERs activate RIG-I signaling and induce the expression of type-I IFNs and interferon stimulated genes (ISGs) through the activation of RIG-I substrates, nuclear factor-kappa B (NF-kappaB), and IFN regulatory factor 3 (IRF-3), and anti-inflamatory cytokine IL-10 through IRF-3 but not NF-kappaB signaling. EBERs also play critical roles in the growth transformation of B lymphocytes. Although EBER1 and EBER2 exhibit similarities in their primary (54%) and secondary structures, recent findings have shown that recombinant EBVs carrying only the EBER2 gene play a greater role in the growth transformation of B lymphocytes than EBVs carrying only the EBER1 gene. Thus, EBERs play multiple roles in various cell types, and we present a model that highlights the functions of EBERs in EBV-mediated oncogenesis in BL cells.
 ...
PMID:Modulation of innate immunity system by Epstein-Barr virus-encoded non-coding RNA and oncogenesis. 1988 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>