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Biomedical subjects

Bevra H Hahn

Publications and source records attributed to Bevra H Hahn.

30 records · Page 2Linked to original sources
PubMed2004

Differences between CD8+ T cells in lupus-prone (NZB x NZW) F1 mice and healthy (BALB/c x NZW) F1 mice may influence autoimmunity in the lupus model.

Immunization with portions of a murine antibody to DNA induced Ig peptide-reactive peripheral CD8+ inhibitory T (Ti) cells in non-autoimmune (BALB/c x NZW) F1 (CWF1) mice. Those Ti suppressed in vitro production of IgG anti-DNA by lymphocytes from MHC-matched, lupus-prone (NZB x NZW) F1 (BWF1) mice, primarily via secretion of transforming growth factor-beta (TGF-beta). However, splenic CD8+ cells from immunized BWF1 mice failed to suppress anti-DNA. Therefore, BWF1 mice were studied for defects in peripheral CD8+ T cells. The potential to suppress autoimmunity mediated by activated CD4+ helper T and B cells in BWF1 mice was assessed. As BWF1 mice aged, peripheral CD8+ T cells expanded little; fewer than 10% displayed surface markers of activation and memory. In contrast, quantities of splenic CD4+ T and B cells increased; high proportions displayed activation/memory markers. In old compared to young BWF1 mice, splenic cell secretion of two cytokines required for generation of CD8+ T effectors, IL-2 and TGF-beta, was decreased. Immunizing BWF1 mice activated peptide-reactive CD8+ T cells, but their number was decreased compared to young BWF1 or old normal mice. While peptide-reactive splenic CD8+ T cells from immunized BWF1 mice did not survive in short-term cultures, similar CD8+ T cell lines from immunized CWF1 mice expanded and on transfer into BWF1 mice delayed autoimmunity and prolonged survival. Therefore, CD8+ T cells in old BWF1 mice are impaired in expansion, acquisition of memory, secretion of cytokine, and suppression of autoimmunity. Understanding these defects might identify targets for therapy in systemic lupus erythematosus.

Animals↗
PubMed2004

Development and evaluation of a patient self-report case-finding method for rheumatoid arthritis.

OBJECTIVE: To describe the development and evaluation of a patient self-report case-finding method for rheumatoid arthritis (RA) not dependent on direct contact with the treating physicians. METHODS: The American College of Rheumatology criteria for RA diagnosis were adapted for patient self-report using a questionnaire, and alternative scoring algorithms were evaluated to balance case-finding sensitivity and specificity. Positive rheumatoid factor tests were used to identify 1053 individuals in 2 large healthcare organizations; 440 agreed to receive study materials. Case-finding results were validated by medical record review (MRR) for a random sample of 90 patients. Three scoring algorithms were compared with MRR for likelihood of RA diagnosis. Cases not classifiable by algorithm were flagged and reviewed by 2 expert physicians for likelihood of RA diagnosis. RESULTS: Pilot testing demonstrated that patients comprehended the questionnaire and were willing to answer the questions. Completed questionnaires were returned by 265 (60%) of the 440 patients contacted. Following expert physician review of 16 flagged cases in the 90-patient MRR subsample, the most accurate scoring algorithm demonstrated 80% sensitivity, 67% specificity, 74% accuracy, and 77% positive predictive value for detecting early RA. CONCLUSION: The case-finding method represents a promising tool for identifying RA patients, with potential application in research and quality-assurance activities. RELEVANCE: This case-finding method should be useful in research and quality-assurance efforts requiring identification of RA patients treated by all types of providers in healthcare organizations in which centralized laboratory data are available.

Arthritis, Rheumatoid↗
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

A thrombin-cross-reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C.

OBJECTIVE: To test the hypotheses that some thrombin-reactive anticardiolipin antibodies (aCL) may bind to protein C (PC) and/or activated PC (APC), and that some of the PC- and APC-reactive aCL may inhibit PC activation and/or the function of APC. METHODS: We studied the reactivity of patient-derived monoclonal aCL with PC and APC. We examined the effects of the reactive antibodies on PC activation and on the activity of APC in plasma coagulation. RESULTS: Five of 5 patient-derived, thrombin-reactive monoclonal aCL bound to PC and APC. In addition, 1 patient-derived monoclonal antiprothrombin antibody (APT) that displayed aCL activity and reacted with thrombin also bound to PC and APC. Of these 6 PC- and APC-reactive aCL/APT, all failed to inhibit PC activation, but 1 (CL15) shortened the plasma coagulation time in the presence of exogenous APC and thus inhibited the anticoagulant function of APC. CONCLUSION: Most of the thrombin-reactive aCL in patients with antiphospholipid syndrome may bind to PC and APC. Of the APC-reactive aCL, some (like CL15) may inhibit the anticoagulant function of APC and are thus likely to be prothrombotic in the host.

Amino Acid Sequence↗
PubMed2003

Leptin-based immune intervention: current status and future directions.

Current understanding of the role of leptin has expanded from its narrow association with obesity to a variety of effects on different biological processes including immune function. More specifically, leptin links nutritional status and energy balance to regulation of pro-inflammatory T-helper 1 immune responses. This has prompted several studies of targeted intervention with leptin antagonists in rodents to suppress onset and/or progression of chronic inflammation and autoimmunity. This review presents current preclinical evidence and potential applications for leptin-based immune approaches aimed at improving therapy for chronic and autoimmune conditions.

Animals↗
PubMed2002

Induction of autoantibody production is limited in nonautoimmune mice.

Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the V(H) region of anti-DNA Abs (hereafter called anti-V(H) T cells). Immunization with anti-DNA mAb, its gamma-chain or peptides derived from its V(H) region induced anti-V(H) Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFbeta; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFbeta Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.

Amino Acid Sequence↗
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↗
PubMed2002

Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus.

OBJECTIVE: Six recent genome scans of different systemic lupus erythematosus (SLE) multiplex family cohorts showed multiple putative susceptibility loci. In the present study, we examined 4 previously identified loci to replicate findings of significant linkage to 1q23 and 16q12, and to support findings of suggestive linkage to 14q21-23 and 20p12 in a cohort of 115 multiethnic nuclear families containing 145 SLE-affected sibpairs. METHODS: Model-free, multipoint linkage analyses (SIBPAL2, SAGE version 4.0) and exclusion mapping (GeneHunter) were performed. RESULTS: Linkages to 1q23 (peak at D1S2675, mean allele sharing [MAS] 0.56; P = 0.003) and to 16q12 (peaks between D16S753 and D16S757, MAS 0.57; P = 0.003) were confirmed, but linkage evidence at 20p12 was weak and inconsistent (MAS 0.52-0.56; from P = 0.005 to P not significant). Evidence for linkage to 1q23 and 16q12 was stronger in 68 non-Caucasian affected sibpairs than in 77 Caucasian affected sibpairs. Exclusion mapping ruled out linkage at 14q21-23 (lambda(s) [sib recurrence risk or genotypic risk ratio] = 1.8). Because the pericentromeric region of chromosome 16 has been identified by genome scans in several autoimmune diseases, we postulated that it might harbor an autoimmune modifier gene. To explore this possibility, we tested for an interaction between 16q12 and 1q23, and between 16q12 and 20p12. Haplotype sharing at 1q23 increased concomitantly with increased haplotype sharing at 16q12 (P = 0.008 by nonparametric Jonckheere-Terpstra exact statistical test). No evidence supporting an interaction between 16q12 and 20p12 was observed. Analysis of sibpairs sharing 2 alleles at 16q12 also showed increased allele sharing at 1q23 (MAS from 0.56 to 0.65). CONCLUSION: These data support the presence of SLE susceptibility genes at 1q23 and 16q12, particularly in non-Caucasians. The skewed distribution of haplotypes suggests that genetic interaction of these two loci may affect SLE susceptibility.

Adolescent↗
PubMed2002

Fcgamma receptor IIIA polymorphism in Korean patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the presence of various autoantibodies and the deposition of immune complex, which is cleared by Fcgamma receptors. Genotype analysis was done to investigate whether the FcgammaRIIIA-176F/V polymorphism is a risk factor for SLE in Koreans. We genotyped 145 Korean SLE patients and 75 control subjects for FcgammaRIIIA-176F/ V. After amplifying a 1.7-kb fragment containing the Fcgamma/RIIIA-176F/V polymorphic site using two FcgammaRIIIA gene-specific primers, we performed a nested polymerase chain reaction (PCR) for allele-specific genotyping at position 559 in FcgammaRIIIA. FcgammaRIIIA genotype or allele distribution was not significantly different between lupus patients and controls, and also between lupus nephritis patients and healthy controls. Neither creatinine clearance, 24 h urine proteinuria, number of American College of Rheumatology (ACR) criteria, nor the Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index was different according to the genotype. In conclusion, FcgammaRIIIA-176F/V polymorphism is not associated with SLE in Koreans.

Asian People↗