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Betty P Tsao

Publications and source records attributed to Betty P Tsao.

At least 19 recordsLinked to original sources
PubMed2026

A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with systemic lupus erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within IRF7. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA-binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in interferon-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of the corresponding risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits.

ancient DNA↗
PubMed2026

A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.

UNLABELLED: Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with Systemic Lupus Erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within the IRF7 gene. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in IFN-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of a homologous risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent genetic IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits. HIGHLIGHTS: Genetic analysis using modern and evolutionary datasets identifies a persistent and highly prevalent lupus-associated coding haplotype in IRF7 at 11p15 The IRF7 lupus risk haplotype increases IFN-α production by monocytes and airway epithelial cells The IRF7 lupus risk haplotype increases IRF7 DNA binding strength and alters DNA sequence specificity A homologous lupus risk variant in mouse Irf7 enhances control of vesicular stomatitis virus and exacerbates autoantibody production.

Journal Article↗
PubMed2006

Current topics in human SLE genetics.

Susceptibility to systemic lupus erythematosus (SLE) depends on genetic and environmental factors. Genome scan studies have identified eight chromosomal regions with significant linkage to SLE that are confirmed by individual cohorts, suggesting that susceptibility genes may be identified within each of these loci. Linkage studies and single nucleotide polymorphisms (SNPs) have led to the identification of positional candidate genes, and their functional allelic variants have demonstrated molecular pathogenesis of the disease. The discovery of positional candidate genes that are associated with various autoimmune diseases signifies a common pathway in the mechanism of these diseases. Copy polymorphisms in susceptibility genes provide evidence in how genetic plasticity affects complex phenotypes as seen in SLE.

Genetic Linkage↗
PubMed2006

Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort.

OBJECTIVE: To determine whether the tumor necrosis factor alpha (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA). METHODS: The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >or=2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score. RESULTS: Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n=49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n=140). Presence of the SE (n=137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n=52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequilibrium between DRB1*0301 and TNFA polymorphism (D'=0.84, r2=0.45, P<0.001). CONCLUSION: This study showed an association between the TNFA -308 polymorphism and progression of radiographic damage in patients with early seropositive RA. This association appeared to be independent of the SE, but might be dependent on other genetic variants in linkage disequilibrium with the -308 TNFA A allele and DRB1*0301. Further studies should be conducted to validate these results in both longitudinal observational cohorts and randomized clinical trials.

Arthritis, Rheumatoid↗
PubMed2006

Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus.

OBJECTIVE: To study 5 type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations. METHODS: Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real-time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) composite. RESULTS: Each gene was highly expressed in SLE patients compared with normal controls (P < or = 0.0003) or disease controls (P < or = 0.0008 except for MX1). IFN scores were positively associated with the SELENA-SLEDAI instrument score (P = 0.001), the SELENA-SLEDAI flare score (P = 0.03), and the physician's global assessment score (P = 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti-double-stranded DNA (anti-dsDNA) antibodies (P = 0.007) or hypocomplementemia (P = 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P = 0.02) and were positively associated with proteinuria (P = 0.009). CONCLUSION: The 5 IFN-inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti-dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.

Adult↗
PubMed2005

A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis that includes susceptibility gene(s) within the chromosome 1q41-1q42 region. Toll-like receptor 5 (TLR5), the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common stop codon polymorphism that abrogates signaling (allele C1174T) and is associated with an increased risk of infection. By using transmission disequilibrium testing in a cohort containing 199 affected patients and their 75 unaffected siblings and 326 parents, we found that allele 1174C, but not 1174T (with the stop codon), was preferentially transmitted to SLE-affected offspring (a 19:6 transmitted/not transmitted ratio, P = 0.009). In contrast, the alleles of the other three TLR5 SNPs did not exhibit preferential transmission. In addition, we found that allele 1174C was not preferentially transmitted to unaffected offspring (3:6 transmitted/not transmitted ratio, P value not significant). The allele frequency of 1174T in the probands was 3.2% compared with 5.8% in unaffected individuals, which was consistent with a protective association (odds ratio, 0.51; 95% confidence interval, 0.26-0.98; P = 0.041). Subjects with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines in comparison with individuals with the wild-type genotype. Together, these results indicate that the TLR5 stop codon polymorphism is associated with protection from the development of SLE. These data support a role for flagellated bacteria and the innate immune response in the development of SLE with implications for novel immunomodulatory treatment strategies.

Chromosomes, Human, Pair 1↗
PubMed2005

Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.

OBJECTIVE: Recent case-control studies show associations of the minor T allele (of the C1858T single-nucleotide polymorphism corresponding to the R620W amino acid substitution) of PTPN22 with multiple autoimmune diseases, including systemic lupus erythematosus (SLE). We performed family-based association studies of this polymorphism in 4 independent cohorts containing SLE patients and their parents and/or other family members. METHODS: A total of 2,689 individuals from 902 independent Caucasian families with SLE were genotyped using polymerase chain reaction pyrosequencing (cohorts 1 and 2) and the Sequenom MassArray system (cohorts 3 and 4). The transmission disequilibrium test (TDT) and the pedigree disequilibrium test (PDT) were conducted to assess the evidence of association. RESULTS: The 1858 C > T allele frequencies of the parents showed no deviation from Hardy-Weinberg equilibrium within each cohort. No evidence of preferential transmission of the T allele from heterozygous parents to their affected offspring was observed in each of the 4 cohorts or in the combined sample. Consistent with the TDT result, the PDT analysis revealed no significant association between the T allele and SLE. In 54 of the 661 SLE patients (cohorts 1 and 3) with documented autoimmune thyroid disease, the T allele frequency was higher than in individuals with SLE alone (16.7% versus 8.5%; P = 0.008, odds ratio 2.16 [95% confidence interval 1.25-3.72]). CONCLUSION: The R620W polymorphism of the PTPN22 gene is not a major risk allele for SLE susceptibility in our sample of Caucasian individuals from northern America, the UK, or Finland, but it appears to be a risk factor for the concurrent autoimmune diseases of autoimmune thyroid disease and SLE.

Arginine↗
PubMed2005

Maternal HLA class II compatibility in men with systemic lupus erythematosus.

OBJECTIVE: Maternal-fetal cell transfer during pregnancy can lead to long-lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother-son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women. METHODS: HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers. RESULTS: Sons with SLE were HLA-identical with their mothers (bidirectionally compatible) for the basic HLA-DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio [OR] 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE-associated HLA genes (encoding HLA-DR2 or HLA-DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus. CONCLUSION: We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation.

Adolescent↗
PubMed2004

CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B.

We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.

Adult↗
PubMed2004

Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23.

OBJECTIVE: To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE. METHODS: Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model-free statistical linkage procedures. RESULTS: Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12-13, and 17q21-23) and 4 novel (3p24, 10q23-24, 13q32, and 18q22-23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23-24, and 18q22-23, was derived primarily from the Caucasian families, while linkage to 17q21-23 was seen primarily in the non-Caucasian families. CONCLUSION: Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.

Chromosome Mapping↗
PubMed2004

Interaction between RANKL and HLA-DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort.

OBJECTIVE: To determine whether the RANKL and HLA-DRB1 "shared epitope" (SE) genotypes contribute to the development of rheumatoid arthritis (RA). METHODS: We studied 237 patients with early RA (within 15 months of symptom onset) who were seropositive for rheumatoid factor. HLA-DRB1 genotyping was performed using the polymerase chain reaction (PCR)-based oligonucleotide probe assay. RANKL polymorphisms were analyzed using PCR pyrosequencing for SNP1 and fluorescence-based PCR for the presence or absence of the TAAA insertion. RESULTS: The presence of SE-containing DRB1*04 alleles was associated with an earlier age at RA onset (mean +/- SD 47 +/- 12.7 years versus 53 +/- 12.5 years in SE- patients; P = 0.0004). The 2 novel RANKL polymorphisms were in strong linkage disequilibrium (P < 0.0001) and were associated with earlier ages at disease onset (e.g., for the CC versus CT/TT genotypes, 44 +/- 13.5 years versus 51 +/- 12.7 years; P = 0.0080). The mean age at disease onset in SE+ patients with the RANKL-CC genotype (35 +/- 7.2 years) was a mean of 18 years younger than in SE- patients with RANKL-CT/TT (53 +/- 12.5 years; P < 0.0001) and was 17 years younger than in SE- patients with RANKL-CC (52 +/- 13.2 years; P = 0.0005). The proportion of patients with both the SE and RANKL risk alleles was highest (23%) in those who developed RA during their third decade of life (ages 20-30 years), with a declining trend among those who developed RA during their fourth (16%), fifth (5%), and sixth or later (0%) decades. Interestingly, 92% of the patients diagnosed as having RA between ages 20 and 30 years carried at least 1 of the RA-associated DRB1*04 alleles, suggesting a strong influence of the SE in the early onset of RA. The majority of patients who developed RA symptoms in their third to fifth decades (74 of 119 [62%]) carried at least 1 copy of the DRB1*04 alleles; in contrast, fewer than half of the patients who developed RA in their sixth decade or later (50 of 118 [42%]) had DRB1*04 alleles. RANKL genotypes were not associated with erosive disease at baseline or with the yearly progression rate of radiographic joint damage. CONCLUSION: This study provides the first evidence that novel RANKL polymorphisms were associated with an earlier age at RA onset in SE+, but not SE-, patients and that an interaction between SE-containing HLA-DRB1 and RANKL polymorphisms increased the disease penetrance, resulting in a mean age at RA onset that was 18-20 years younger. Our results also suggested genetic differences between patients with early-onset and those with late-onset RA.

Adult↗
PubMed2004

Current advances in the human lupus genetics.

Genetic predisposition has been firmly established as a key element in susceptibility to systemic lupus erythematosus (SLE). During the past three decades, association studies have assessed many genes for potential roles in predisposing to SLE. These studies have identified a few risk factors including hereditary deficiency of complement components, major histocompatibility complex class II alleles, and allelic variants for the Fc portion of IgG (FCGR) genes. In recent years, a few groups have completed linkage analyses in data sets from families containing multiple members affected with SLE. Results from these initial genome scans are encouraging; approximately eight chromosomal regions have been identified exhibiting evidence for significant linkage to SLE and have been confirmed using independent cohorts (1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12q24, and 16q12), suggesting the high likelihood of the presence of one or multiple SLE susceptibility genes at each locus. Another approach of linkage analyses conditioned on pedigrees where one affected member manifesting a particular clinical condition has also identified many chromosomal regions linked to SLE. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. Within 2q35-37, an intronic single nucleotide polymorphism (SNP) of the positional candidate gene program cell death 1 gene has been associated with SLE susceptibility. The SLE-associated SNP affects a transcription factor, RUNX1, binding site. Recently, SNPs of novel positional candidate genes that influence RUNX1 binding motifs have also been associated with other autoimmune diseases, suggesting the possibility of a common theme shared among susceptibility genes for autoimmune diseases. In the coming years, susceptibility genes responsible for the observed linkage will be identified, and will lead to further delineating genetic pathways involved in susceptibility to SLE.

Animals↗
PubMed2004

Update on human systemic lupus erythematosus genetics.

PURPOSE OF REVIEW: Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome scans using family collections that differ greatly in ethnic compositions and geographic locations have identified several strong, confirmed SLE susceptibility loci. Evidence implicating individual gene polymorphisms (or haplotypes) within some of the linked intervals has been reported. This review highlights recent findings that may lead to the identification of putative genes and new insights in the pathogenesis of SLE. RECENT FINDINGS: Eight of the best-supported SLE susceptibility loci are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, and 16q12. These are chromosomal regions exhibiting genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected member manifesting a particular clinical condition have also yielded many chromosomal regions linked to SLE. The linked interval on chromosome 6p has been narrowed to 0.5 approximately 1.0 Mb (million basepairs) of 3 MHC class II containing risk haplotypes in white subjects. Cumulative results have shown that hereditary deficiencies of complement component C4A (a MHC class III gene) confer risk for SLE in almost all ethnic groups studied. The FcgammaR genes (located at 1q23) have been convincingly demonstrated to play an important role in susceptibility to SLE (and/or lupus nephritis). The evidence for the intronic single nucleotide polymorphism of program cell death gene 1 (PDCD1 at 2q37) to confer susceptibility is promising but not yet compelling. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. SUMMARY: Further replications of linkage and association are the immediate task. The respective contribution of each susceptibility gene, relationships between genotypes and phenotypes, and potential interactions between susceptibility gene products need to be elucidated. This line of investigation is now well poised to provide novel insights into how genetic variants can affect functional pathways leading to the development of SLE.

Genetic Predisposition to Disease↗
PubMed2003

Identification and characterization of SmD183-119-reactive T cells that provide T cell help for pathogenic anti-double-stranded DNA antibodies.

OBJECTIVE: The C-terminal peptide of amino acids 83-119 of the SmD1 protein is a target of the autoimmune response in human and murine lupus. This study was undertaken to test the hypothesis that SmD1(83-119)-reactive T cells play a crucial role in the generation of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies. METHODS: Splenic or lymph node T cells derived from unmanipulated as well as SmD1(83-119)-immunized NZB/NZW mice were analyzed in vitro by enzyme-linked immunospot (ELISpot) assay to determine T cell help for anti-dsDNA generation induced by the SmD1(83-119) peptide. Cytokines expressed by these T cells were measured by ELISpot assay, enzyme-linked immunosorbent assay, and flow cytometry. SmD1(83-119)- and ovalbumin-specific T cell lines were generated and characterized. RESULTS: The SmD1(83-119) peptide, but not the control peptides, significantly increased the in vitro generation of anti-dsDNA antibodies in cultures from unmanipulated NZB/NZW mice. Interferon-gamma (IFNgamma), interleukin-2 (IL-2), IL-4, transforming growth factor beta, and IL-10 production increased in response to the peptide in young mice; only IFNgamma and IL-2 were increased in older, diseased mice. Activation of SmD1(83-119)-reactive T cells by immunization of NZB/NZW mice resulted in elevated anti-dsDNA synthesis and, later, increased antibodies to SmD1(83-119). Most cells in SmD1(83-119)-specific CD4+ T cell lines helping both antibodies had increased intracellular expression of IFNgamma, and most expressed both IFNgamma and IL-4. CONCLUSION: The SmD1(83-119) peptide plays an important role in generating T cell help for autoantibodies, including anti-dsDNA, and activates different subsets of T cells as defined by distinct cytokine expression. This peptide is an interesting target structure for the modulation of autoreactive T cells, and its characterization may contribute to our understanding of the role of autoantigen-reactive T cells in the pathogenesis of SLE.

Animals↗
PubMed2003

Identification and characterization of a peptide mimetic that may detect a species of disease-associated anticardiolipin antibodies in patients with the antiphospholipid syndrome.

OBJECTIVE: To test the feasibility of applying a mimetic (specific for a patient-derived prothrombotic anticardiolipin antibody [aCL]) to study the homologous, disease-associated aCL in patients with antiphospholipid syndrome (APS). METHODS: We used the CL15 monoclonal aCL to screen 17 phage-display peptide libraries. Peptides (corresponding to recurrent peptide sequences) and their derivatives were synthesized and analyzed for binding to CL15 and for their abilities to inhibit CL15 from binding to cardiolipin. A peptide was chosen and used to study CL15-like IgG aCL in plasma samples from patients with APS, patients with systemic lupus erythematosus (SLE) but without APS, and normal healthy donors. RESULTS: Library screening with CL15 yielded 4 recurrent peptide sequences. Analyses of peptides showed that peptide CL154C reacted with antibody CL15 and inhibited binding of CL15 to cardiolipin, indicating that peptide CL154C may be a peptide mimetic for the CL15 aCL. Initial studies with plasma samples revealed that CL154C-reactive IgG was present (positivity defined as the mean + 3 SD optical density of the 25 normal controls) in 15 of 21 APS patients and 1 of 12 SLE patients. CONCLUSION: These findings suggest that it is feasible to develop a specific enzyme-linked immunosorbent assay for each immunologically and functionally distinct disease-associated aCL. Additional testing of CL154C with a larger number of APS patients and SLE patients, as well as identification of peptide mimetics for each distinct aCL, will reveal the diagnostic potential of CL154C and other mimetics in identifying patients with aCL who are at risk of developing life-threatening thrombosis.

Adolescent↗
PubMed2003

The genetics of human systemic lupus erythematosus.

Genetic dissection of human systemic lupus erythematosus (SLE) has been under intense studies during the past decade. Although the complexity inherent to polygenic, multifactorial diseases is challenging, several new insights have been obtained in the past several years using linkage and association studies of families containing SLE patients as well as case-control studies of populations. In addition, recent advances in our understanding of the human genome and emerging technology have been providing new tools in analyses of complex traits, such as SLE. An overview of our current understanding of the genetic basis of SLE and a brief review of findings of linkage and association studies are described here.

Animals↗
PubMed2002

Familiality and co-occurrence of clinical features of systemic lupus erythematosus.

OBJECTIVE: To evaluate familiality of 15 clinical and laboratory features in systemic lupus erythematosus (SLE)-affected sibpairs, and to estimate correlations with the age at SLE diagnosis in affected sibpairs and parent-offspring pairs. METHODS: Concordance rates and sibling risk ratios were used as indicators of familiality for 15 manifestations of SLE. Pearson's correlations and paired t-tests were used to compare the age at SLE diagnosis in affected sibpairs and in parent-offspring pairs. RESULTS: Increased sibling risk ratios (1.9-3.9) for thrombocytopenia, discoid rash, neurologic disorder (defined as seizure or psychosis), and hemolytic anemia were observed in 159 SLE-affected sibpairs. Among these clinical features, paired expression of hemolytic anemia plus thrombocytopenia and hemolytic anemia plus neurologic disorder appeared to be more frequent in 709 SLE patients than would be expected by chance (P < 0.00001 and P < 0.007, respectively). The ratio of the presence of both hemolytic anemia and neurologic disorder was approximately 13 times higher in the younger affected sib than in the older affected sib (P < 0.02). Familiality of patient age at SLE diagnosis, as observed by relative correlations, was greater in 125 affected sibpairs (r = 0.67, P < 0.0001) than in 37 affected parent-offspring pairs (r = 0.47, P = 0.003). The median +/- SD age at SLE diagnosis was significantly lower in offspring (21.5 +/- 10.1 years) than in their parents (41.6 +/- 15.8 years) (P < 0.0001) but was not different in sibpairs. The combined non-Caucasian sibpairs had a younger mean age at SLE diagnosis compared with Caucasian sibpairs (P = 0.014). CONCLUSION: Evidence for familiality of thrombocytopenia, discoid rash, neurologic disorder, hemolytic anemia, and co-occurring neurologic disorder plus hemolytic anemia in SLE was observed in 159 affected sibpairs. Familiality of the age at SLE diagnosis in relative pairs suggests that shared genes and/or shared environmental exposures impact disease susceptibility. Shared immediate environmental triggers appear less compelling, because the average time between dates of diagnosis was 11 years in parent-offspring pairs and 7.5 years in affected sibpairs. The significantly earlier age at disease diagnosis in offspring compared with their parents suggests that some forms of anticipation might play a role in susceptibility to SLE. Stratifying families by subphenotypes that are familial may reduce heterogeneity and facilitate identification of genetic risk factors for SLE.

Age of Onset↗