Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous reports have shown abnormal responses mediated via the TCR/CD3 pathway in T lymphocytes from systemic lupus erythematosus (SLE) patients. Recently, we and others have reported augmented TCR/CD3-mediated responses in lupus T cells. It is possible that the pattern of downstream biochemical signals triggered by TCR/CD3 ligation may be altered in T lymphocytes from patients with SLE, thus leading to abnormal distal cell responses. In this paper we have examined the phosphorylation of proteins on tyrosine residues in peripheral blood T lymphocytes from a group of SLE patients and controls. We found a lower frequency of constitutively tyrosine-phosphorylated 119- and 113-kDa substrates and an enhanced frequency of tyrosine-phosphorylated 66- and 25-kDa proteins in unstimulated cultures of SLE T lymphocytes, suggesting an altered pattern of tyrosine phosphorylation in T cells from patients in vivo. Additionally, the protein tyrosine phosphatase (PTP) activity of CD45 immunoprecipitates was lower in unstimulated lupus T cells and was enhanced after stimulation via the CD3 pathway in lupus but not control T lymphocytes. The present results seem to suggest abnormal regulation of in-vivo tyrosine phosphorylation in T cells from patients with SLE.
Lupus 1998
PMID:Abnormal pattern of tyrosine phosphorylation in unstimulated peripheral blood T lymphocytes from patients with systemic lupus erythematosus. 986 92

B cell receptor (BcR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated co-receptors. Mounting evidence indicates that abnormal BcR signaling, such as occurs in SHP-1 and Lyn-deficient mice, results in production of pathogenic autoantibodies and lupus-like glomerulonephritis, suggesting that altered signaling thresholds could underlie the development of systemic autoimmunity. To test this hypothesis, we investigated expression of BcR-associated signaling molecules in lymphocytes from patients with systemic lupus erythematosus (SLE) during inactive phases of the disease. We found that the transmembrane regulatory protein tyrosine phosphatase CD45 is expressed at abnormal levels. Strikingly, this reduction persisted during four months of follow-up. By contrast, despite its potent role as a regulator of thymus-independent immune responses and of B cell life span, the CD22 co-receptor is expressed at normal levels in B lymphocytes isolated ex vivo from SLE patients. We also noted unusual levels of the cytosolic protein tyrosine kinase Lyn and the protein tyrosine phosphatase SHP-1 in the lymphocytes of the patients. Since in normal B cells Lyn and SHP-1 act in concert within a common negative pathway in which CD45 counteracts SHP-I regulatory role, we propose that this feedback regulatory pathway is crippled to different degrees in human SLE B cells. Break of the balance between positive and negative signaling molecules likely modifies the BcR signaling thresholds. Such alterations, together with other factors, may contribute to the disruption of self-tolerance in this disease.
 ...
PMID:Expression of B cell receptor-associated signaling molecules in human lupus. 1168 80

Anti-lymphocyte autoantibodies are a well-recognized component of the autoimmune repertoire in human systemic lupus erythematosus (SLE) and have been postulated to have pathogenic consequences. Early studies indicated that IgM anti-lymphocyte autoantibodies mainly recognized T cells and identified CD45, a protein tyrosine phosphatase of central significance in the modulation of lymphocyte function, as the main antigenic target on T cells. However, more recent work indicates that lupus autoantibodies can also recognize B cells and that CD45 may also represent their antigenic target. In particular, IgM Abs encoded by V(H)4.34 appear to have special tropism for B cells, and strong, but indirect evidence suggests that they may recognize a B cell-specific CD45 isoform. Because V(H)4.34 Abs are greatly expanded in SLE, in the present study we investigated the antigenic reactivity of lupus sera V(H)4.34 IgG Abs and addressed their contribution to the anti-lymphocyte autoantibody repertoire in this disease. Our biochemical studies conclusively demonstrate that lupus IgG V(H)4.34 Abs target a developmentally regulated B220-specific glycoform of CD45, and more specifically, an N-linked N-acetyllactosamine determinant preferentially expressed on naive B cells that is sterically masked by sialic acid on B220-positive memory B cells. Strikingly, our data also indicate that this reactivity in SLE sera is restricted to V(H)4.34 Abs and can be eliminated by depleting these Abs. Overall, our data indicate that V(H)4.34 Abs represent a major component of the lupus IgG autoantibody repertoire and suggest that the carbohydrate moiety they recognize may act as a selecting Ag in SLE.
 ...
PMID:Lupus IgG VH4.34 antibodies bind to a 220-kDa glycoform of CD45/B220 on the surface of human B lymphocytes. 1503 44

The classical view of B cells in the biology of autoimmune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing antibodies (Ab) is far from being complete. Indeed, studies over the last decade suggest that B cells have extraordinarily diverse functions within the immune system other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating dentritic cells (DC) and T cell subsets function through cytokine production, and in activation of T cells. Receptor editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune diseases, including systemic lupus erythematosus (SLE), highlight their pivotal function. Transgenic (Tg) animal models have shown that sensitivity of B cells to B cell Ag receptor (BCR) cross-linking is correlated to autoimmunity. Indeed, negative signaling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domain-containing protein tyrosine phosphatase-1 (SHP-1) has also been documented. In fact, we have now reached a newer area whereby B cells returned as an important contributor to autoimmune disorders.
 ...
PMID:Dysfunctional B cells in systemic lupus erythematosus. 1554

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.
 ...
PMID:Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. 1562 Apr 63

Dehydroepiandrosterone-sulfate, the sulfated form of dehydroepiandrosterone, is the most abundant steroid in young adults, but gradually declines with aging. In humans, the clinical application of dehydroepiandrosterone targeting some collagen diseases, such as systemic lupus erythematosus, as an adjunctive treatment has been applied in clinical trial. Here, we report that dehydroepiandrosterone may negatively regulate the mitogen-activated protein kinase pathway in humans via a novel dual specificity protein phosphatase, DDSP (dehydroepiandrosterone-enhanced dual specificity protein phosphatase). DDSP is highly homologous to LCPTP/HePTP, a tissue-specific protein tyrosine phosphatase (PTP) which negatively regulates both ERK and p38-mitogen-activated protein kinase, and is transcribed from the PTPN7 locus by alternative splicing. Although previous reports have shown that the mRNA expression of the LCPTP/HePTP gene was inducible by extracellular signals such as T-cell antigen receptor stimulation, reverse transcribed (RT)-PCR experiments using specific sets of primers suggested that the expression of LCPTP/HePTP was constitutive while the actual inducible sequence was that of DDSP. Furthermore DDSP was widely distributed among different types of human tissues and specifically interacted with p38-mitogen-activated protein kinase. This inducible negative regulation of the p38-mitogen-activated protein kinase-dependent pathway may help to clarify the broad range of dehydroepiandrosterone actions, thereby aiding the development of new preventive or adjunctive applications for human diseases.
 ...
PMID:Dehydroepiandrosterone negatively regulates the p38 mitogen-activated protein kinase pathway by a novel mitogen-activated protein kinase phosphatase. 1577 5

Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE. Because these reports on association were not always evaluated in multiple ethnic groups and because ethnic difference in allele frequency of the variants has been also reported, we investigated allele frequencies of nine SNPs in four autoimmune-disease-associated loci in Caucasian, African-descent, and Japanese populations. Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively). Of note, three SNPs in the three loci that had allele frequency more than 8% in the Caucasian population were either not polymorphic at all or extremely rare in the Japanese population. Our data suggest that ethnic variations of polymorphisms should be evaluated in detail, and differences should be incorporated into investigations of susceptibility variants for common diseases.
 ...
PMID:Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. 1588 54

In order to better understand the genetic factors that initiate systemic lupus erythematosus (SLE), we are using both linkage and association approaches to identify susceptibility genes for the disease. Association studies have recently identified three HLA Class II haplotypes as well as a functional missense polymorphism in protein tyrosine phosphatase (PTP) PTPN22 as important risk alleles for SLE. Here, we will review these data, and explain how these findings contribute to an understanding of the genetic architecture of human SLE.
 ...
PMID:Progress towards understanding the genetic pathogenesis of systemic lupus erythematosus. 1599 5

The gene PTPN22 is located on chromosome 1p13 and encodes a protein tyrosine phosphatase called the lymphoid-specific phosphatase (Lyp). Lyp is expressed in lymphocytes, where it physically associates through its proline-rich motif (called P1) with the SH3 domain of the protein tyrosine kinase Csk, an important suppressor of the Src family of kinases Lck and Fyn, which mediate TCR signaling. Therefore, it is said that interaction between Lyp and Csk enables these effectors to inhibit T-cell activation synergistically. It was reported that a missense single nucleotide polymorphism , R620W (rs2476601), 1858C->T encodes an amino-acid change in the P1 proline-rich motif of the gene PTPN22 and is associated with SLE in North American white individuals. PTPN22 gene polymorphisms were genotyped in 571 Swedish SLE patients and 1042 healthy controls using TaqMan SNP Genotyping Assay. Differences were observed between cases and control subjects at both the allele (chi(2)=11.2895;P=0.0007,1df) and genotype (chi(2)=10.2243;P=0.0013, 1df) levels. We also found evidence of a genetic association between PTPN22 and renal disorder (chi(2)=9.5660;P=0.0019). We then analyzed if in patients with renal disorder associations with PDCD1 and PTPN22 were independent. Our data suggest that this appears to be the case although we observed some degree of interaction.
 ...
PMID:The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1. 1605 72

A functional single nucleotide polymorphism (SNP) C1858T in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encoding an intracellular phosphatase with negative regulatory effects on T-cell activation is associated with some autoimmune diseases in Caucasians. Taking into account firstly, that SNP frequencies may vary across populations and, secondly, that replication studies are important to confirm previous associations, we examined the influence of PTPN22 polymorphism in 621 Colombian patients with four autoimmune diseases. Accordingly, 298 patients with rheumatoid arthritis (RA), 143 with systemic lupus erythematosus (SLE), 70 with primary Sjogren's syndrome (pSS) and 110 with Type 1 diabetes (T1D) were studied. The control group consisted of 308 matched healthy individuals. Genotyping of PTPN22 was performed by the real-time polymerase chain reaction technology, using the Taq Man 5'-allele discrimination assay. The 1858 T allele was found to be a risk factor for pSS (odds ratio (OR)=2.42), SLE (OR=2.56), and T1D (OR=1.83). A lower but nonsignificant trend was observed for RA (OR=1.26). These results confirm the influence of PTPN22 in autoimmunity and indicate that autoimmune phenotypes could represent pleiotropic outcomes of nonspecific disease genes that underlie similar immunogenetic mechanisms.
 ...
PMID:PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. 1616 73


1 2 3 4 5 Next >>