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4. Interferon-inducible gene 202b controls CD8+ T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice

Author

Dinesh, R, Hahn, BH, La Cava, A, and Singh, RP

Subjects
Genetics, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Antibodies, Antinuclear, B-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, DNA, Disease Models, Animal, Female, Forkhead Transcription Factors, Gene Expression Regulation, Gene Silencing, Immune Tolerance, Immunoglobulin Variable Region, Immunologic Factors, Intracellular Signaling Peptides and Proteins, Lupus Erythematosus, Systemic, Mice, Mice, Inbred NZB, Peptides, RNA, Messenger, RNA, Small Interfering, autoimmunity, systemic lupus erythematosus, T cells, gene expression, tolerance/suppression, Immunology
Abstract

Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T-cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8(+) Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8(+) T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1-4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8(+) T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8(+) Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)β and interleukin-2 (IL-2), but not of interferon (IFN)-γ, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8(+) T cells, IFNAR1, had no effect on the ability of CD8(+) T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide-induced regulatory CD8(+) Ti cells through effects on the expression of Foxp3 and the synthesis of TGFβ.

Published
2011

7. Evolutionary history of human Plasmodium vivax revealed by genome-wide analyses of related ape parasites

Author

Loy, DE, Plenderleith, LJ, Sundararaman, SA, Liu, W, Gruszczyk, J, Chen, Y-J, Trimboli, S, Learn, GH, MacLean, OA, Morgan, ALK, Li, Y, Avitto, AN, Giles, J, Calvignac-Spencer, S, Sachse, A, Leendertz, FH, Speede, S, Ayouba, A, Peeters, M, Rayner, JC, Tham, W-H, Sharp, PM, Hahn, BH, Loy, DE, Plenderleith, LJ, Sundararaman, SA, Liu, W, Gruszczyk, J, Chen, Y-J, Trimboli, S, Learn, GH, MacLean, OA, Morgan, ALK, Li, Y, Avitto, AN, Giles, J, Calvignac-Spencer, S, Sachse, A, Leendertz, FH, Speede, S, Ayouba, A, Peeters, M, Rayner, JC, Tham, W-H, Sharp, PM, and Hahn, BH

Abstract

Wild-living African apes are endemically infected with parasites that are closely related to human Plasmodium vivax, a leading cause of malaria outside Africa. This finding suggests that the origin of P. vivax was in Africa, even though the parasite is now rare in humans there. To elucidate the emergence of human P. vivax and its relationship to the ape parasites, we analyzed genome sequence data of P. vivax strains infecting six chimpanzees and one gorilla from Cameroon, Gabon, and Côte d'Ivoire. We found that ape and human parasites share nearly identical core genomes, differing by only 2% of coding sequences. However, compared with the ape parasites, human strains of P. vivax exhibit about 10-fold less diversity and have a relative excess of nonsynonymous nucleotide polymorphisms, with site-frequency spectra suggesting they are subject to greatly relaxed purifying selection. These data suggest that human P. vivax has undergone an extreme bottleneck, followed by rapid population expansion. Investigating potential host-specificity determinants, we found that ape P. vivax parasites encode intact orthologs of three reticulocyte-binding protein genes (rbp2d, rbp2e, and rbp3), which are pseudogenes in all human P. vivax strains. However, binding studies of recombinant RBP2e and RBP3 proteins to human, chimpanzee, and gorilla erythrocytes revealed no evidence of host-specific barriers to red blood cell invasion. These data suggest that, from an ancient stock of P. vivax parasites capable of infecting both humans and apes, a severely bottlenecked lineage emerged out of Africa and underwent rapid population growth as it spread globally.

Published
2018

8. Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses

Author

Goff, SP, Richard, J, Prevost, J, Baxter, AE, von Bredow, B, Ding, S, Medjahed, H, Delgado, GG, Brassard, N, Sturzel, CM, Kirchhoff, F, Hahn, BH, Parsons, MS, Kaufmann, DE, Evans, DT, Finzi, A, Goff, SP, Richard, J, Prevost, J, Baxter, AE, von Bredow, B, Ding, S, Medjahed, H, Delgado, GG, Brassard, N, Sturzel, CM, Kirchhoff, F, Hahn, BH, Parsons, MS, Kaufmann, DE, Evans, DT, and Finzi, A

Abstract

The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a "closed" conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect in vitro measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in in vitro cultures or ex vivo samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands.IMPORTANCE Emerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate ADCC

Published
2018

9. Selective Whole-Genome Amplification Is a Robust Method That Enables Scalable Whole-Genome Sequencing of Plasmodium vivax from Unprocessed Clinical Samples.

Author

Miller, LH, Cowell, AN, Loy, DE, Sundararaman, SA, Valdivia, H, Fisch, K, Lescano, AG, Baldeviano, GC, Durand, S, Gerbasi, V, Sutherland, CJ, Nolder, D, Vinetz, JM, Hahn, BH, Winzeler, EA, Miller, LH, Cowell, AN, Loy, DE, Sundararaman, SA, Valdivia, H, Fisch, K, Lescano, AG, Baldeviano, GC, Durand, S, Gerbasi, V, Sutherland, CJ, Nolder, D, Vinetz, JM, Hahn, BH, and Winzeler, EA

Abstract

UNLABELLED: Whole-genome sequencing (WGS) of microbial pathogens from clinical samples is a highly sensitive tool used to gain a deeper understanding of the biology, epidemiology, and drug resistance mechanisms of many infections. However, WGS of organisms which exhibit low densities in their hosts is challenging due to high levels of host genomic DNA (gDNA), which leads to very low coverage of the microbial genome. WGS of Plasmodium vivax, the most widely distributed form of malaria, is especially difficult because of low parasite densities and the lack of an ex vivo culture system. Current techniques used to enrich P. vivax DNA from clinical samples require significant resources or are not consistently effective. Here, we demonstrate that selective whole-genome amplification (SWGA) can enrich P. vivax gDNA from unprocessed human blood samples and dried blood spots for high-quality WGS, allowing genetic characterization of isolates that would otherwise have been prohibitively expensive or impossible to sequence. We achieved an average genome coverage of 24×, with up to 95% of the P. vivax core genome covered by ≥5 reads. The single-nucleotide polymorphism (SNP) characteristics and drug resistance mutations seen were consistent with those of other P. vivax sequences from a similar region in Peru, demonstrating that SWGA produces high-quality sequences for downstream analysis. SWGA is a robust tool that will enable efficient, cost-effective WGS of P. vivax isolates from clinical samples that can be applied to other neglected microbial pathogens. IMPORTANCE: Malaria is a disease caused by Plasmodium parasites that caused 214 million symptomatic cases and 438,000 deaths in 2015. Plasmodium vivax is the most widely distributed species, causing the majority of malaria infections outside sub-Saharan Africa. Whole-genome sequencing (WGS) of Plasmodium parasites from clinical samples has revealed important insights into the epidemiology and mechanisms of drug resistance of

Published
2017

10. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus

Author

Borrow, P, Lewicki, H, Wei, X, Horwitz, MS, Peffer, N, Meyers, H, Nelson, JA, Gairin, JE, Hahn, BH, Oldstone, MB, and Shaw, GM

Abstract

The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30-72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.

Published
2016

11. Can Physical Signs or Magnetic Resonance Imaging Substitute for Diagnostic Arthroscopy in Knee Osteoarthritis Patients with Suspected Internal Derangements?: A Pilot Study

Author

William J. Arnold, L.L Seeger, Andrew L. Concoff, Schumaker Ms, D. J. Klashman, Paul H. Brion, Kenneth C. Kalunian, and Hahn Bh

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Radiography, Comparison standard, Arthroscopy, Magnetic resonance imaging, Osteoarthritis, medicine.disease, Surgery, Cruciate ligament, medicine.anatomical_structure, Rheumatology, medicine, Tears, Radiology, business, Diagnostic arthroscopy
Abstract

This pilot study was developed to compare the relative diagnostic accuracies of physical findings, magnetic resonance imaging (MRI) and arthroscopy for internal derangements in knee osteoarthritis (OA) patients. Nine patients with locking and/or giving way in 10 knees underwent MRI and arthroscopy; the relative diagnostic accuracies for meniscal tears were studied and compared with physical findings. Eleven meniscal and no cruciate ligament tears were noted by MRI and/ or arthroscopy. Using arthroscopy as the comparison standard, the sensitivity of MRI for meniscal tears was 33.3%, specificity was 96.6%, and diagnostic accuracy was 75.0%. No significant correlations between physical findings and MRI or arthroscopy findings were found. It seemed that participants with normal radiographs had false positive MRIs more frequently. These preliminary data suggest that physical findings may not be adequate for the diagnosis of meniscal tears in patients with associated knee OA. A larger study may be warranted to further test this hypothesis. Because the presence of a meniscal tear may change therapy toward specific physical therapy modalities and/or meniscal repair, knee OA patients with mechanical symptoms may require an MRI or arthroscopy to establish the presence of a meniscal tear. Further testing is required to confirm the suggestion from these cases that patients with normal or minimally abnormal radiographs may require a diagnostic arthroscopy rather than an MRI to demonstrate a meniscal tear.

Published
2000

12. Hybrid origin of SIV in chimpanzees

Author

Bailes, E., Gao, F., Bibollet-Ruche, F., Courgnaud, V., Peeters, M., Marx, Pa, Hahn, Bh, and Paul Sharp

Subjects
GENOME, SIDA, RECOMBINAISON GENETIQUE, VIRUS, PRIMATE, PHYLOGENIE, ANALYSE GENETIQUE
Published
2003

13. Timing the ancestor of the HIV-1 pandemic strains

Author

Muldoon, M., Theiler, J., Lapedes, A., Wolinsky, S., Gao, F., Gupta, R., Korber, B., Hahn, Bh H., and Bhattacharya, T.

Abstract

HIV-1 sequences were analyzed to estimate the timing of the ancestral sequence of the main group of HIV-1, the strains responsible for the AIDS pandemic. Using parallel supercomputers and assuming a constant rate of evolution, we applied maximum-likelihood phylogenetic methods to unprecedented amounts of data for this calculation. We validated our approach by correctly estimating the timing of two historically documented points. Using a comprehensive full-length envelope sequence alignment, we estimated the date of the last common ancestor of the main group of HIV-1 to be 1931 (1915-41). Analysis of a gag gene alignment, subregions of envelope including additional sequences, and a method that relaxed the assumption of a strict molecular clock also supported these results.

Published
2000

14. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes

Author

Gao, F., Bailes, E., Robertson, Dl, Chen, Yl, Rodenburg, Cm, Michael, Sf, Cummins, Lb, Arthur, Lo, Peeters, M., Shaw, Gm, Paul Sharp, and Hahn, Bh

Subjects
GENOME, SIDA, TECHNIQUE PCR, SIV.VIRUS IMMUNODEFICIENCE SIMIENNE, VIRUS, PRIMATE, PHYLOGENIE, ANALYSE GENETIQUE, SINGE
Published
1999

15. A novel CCR5 mutation common in sooty mangabeys reveals sivsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo

Author

Riddick, NE, Hermann, EA, Loftin, LM, Elliott, ST, Wey, WC, Cervasi, B, Taaffe, J, Engram, JC, Li, B, Else, JG, Li, Y, Hahn, BH, Derdeyn, CA, Sodora, DL, Apetrei, C, Paiardini, M, Silvestri, G, Collman, RG, Riddick, NE, Hermann, EA, Loftin, LM, Elliott, ST, Wey, WC, Cervasi, B, Taaffe, J, Engram, JC, Li, B, Else, JG, Li, Y, Hahn, BH, Derdeyn, CA, Sodora, DL, Apetrei, C, Paiardini, M, Silvestri, G, and Collman, RG

Abstract

In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (D2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5D24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5- independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely re

Published
2010

16. Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G

Author

Gao, F., Morrison, Sg, Robertson, Dl, Thornton, Cl, Craig, S., Karlsson, G., Sodroski, J., Morgado, M., Galvaocastro, B., Vonbriesen, H., Beddows, S., Weber, J., Paul Sharp, Shaw, Gm, Hahn, Bh, Osmanov, S., Heyward, Wl, Esparza, J., Vandeperre, P., Karita, E., Sempala, S., Tugume, B., Biryahwaho, B., Wasi, C., Rubsamenwaigmann, H., Holmes, H., Newberry, A., Ranjbar, S., Tomlinson, P., Bradac, J., Mullins, Ji, Delwart, El, Cheingsongpopov, R., Kaleebu, P., Myers, G., Korber, Btm, Chiphangwi, J., Taha, T., Desormeaux, J., Eiumtrakul, S., Natpratan, C., Khamboonruang, C., Miotti, P., Halsey, Na, Vlahov, D., Nelson, Ke, Phair, J., Cao, Y., Moore, Jp, Ho, Dd, Matocha, M., Fowler, A., Dilworth, S., Sharma, O., Brown, R., Dusing, S., Whitman, J., Hoekzema, D., and Vogel, F.

Subjects
viruses
Abstract

Present knowledge of human immunodeficiency virus type 1 (HIV-1) envelope immunobiology has been derived almost exclusively from analyses of subtype B viruses, yet such viruses represent only a minority of strains currently spreading worldwide. To generate a more representative panel of genetically diverse envelope genes, we PCR amplified, cloned, and sequenced complete gp160 coding regions of 35 primary (peripheral blood mononuclear cell-propagated) HTV-1 isolates collected at major epicenters of the current AIDS pandemic. Analysis of their deduced amino acid sequences revealed several important differences from prototypic subtype B strains, including changes in the number and distribution of cysteine residues, substantial length differences in hypervariable regions, and premature truncations in the gp41 domain. Moreover, transiently expressed glycoprotein precursor molecules varied considerably in both size and carbohydrate content. Phylogenetic analyses of full-length env sequences indicated that the panel included members of all major sequence subtypes of HTV-1 group M (clades A to G), as well as an intersubtype recombinant (FIB) from an infected individual in Brazil. In addition, all subtype E and three subtype G viruses initially classified on the basis of partial env sequences were found to cluster in subtype A in the 3' half of their gp41 coding region, suggesting that they are also recombinant. The biological activity of PCR-derived env genes was examined in a single-round virus infectivity assay, This analysis identified 20 clones, including 1 from each subtype (or recombinant), which expressed fully functional envelope glycoproteins. One of these, derived from a patient with rapid CD4 cell decline, contained an amino acid substitution in a highly conserved endocytosis signal (Y721C), as well as a premature truncation of its gp41 domain, which lacked 17 amino acids. Several other env constructs mediated virus entry with very poor efficiency, although they did not contain sequence changes predicted to alter protein function. These results indicate that the env genes of primary HTV-1 isolates collected worldwide can vary considerably in their genetic, phylogenetic, and biological properties. The panel of env constructs described here should prove valuable for future structure-function studies of naturally occurring envelope glycoproteins as well as AIDS vaccine development efforts targeted against a broader spectrum of viruses.

Published
1996

19. Infection of a yellow baboon with simian immunodeficiency virus from African green monkeys:evidence for cross-species transmission in the wild

Author

Jin, Mj, Rogers, J., Phillipsconroy, Je, Allan, Js, Desrosiers, Rc, Shaw, Gm, Paul Sharp, and Hahn, Bh

Subjects
SIV, animal diseases, viruses, ANTIBODIES, HIV-2, SEROEPIDEMIOLOGIC SURVEY, SUBSTITUTION, TANTALUS MONKEYS, CHIMPANZEE, SEQUENCE, PRIMATE LENTIVIRUS, PREVALENCE
Abstract

Many African primates are known to be naturally infected with simian immunodeficiency viruses (SIVs), but only a fraction of these viruses has been molecularly characterized. One primate species for which only serological evidence of SIV infection has been reported is the yellow baboon (Papio hamadryas cynocephalus). Two wild-living baboons with strong SIVAGM seroreactivity were previously identified in a Tanzanian national park where baboons and African green monkeys shared the same habitat (T. Kodama, D. P. Silva, M. D. Daniel, J. E. Phillips-Conroy, C. J. Jolly, J. Rogers, and R. C. Desrosiers, AIDS Res. Hum. Retroviruses 5:337-343, 1989). To determine the genetic identity of the viruses infecting these animals, we used PCR to examine SIV sequences directly in uncultured leukocyte DNA. Targeting two different, nonoverlapping genomic regions, we amplified and sequenced a 673 bp gag gene fragment and a 908-bp env gene fragment from one of the two baboons. Phylo-genetic analyses revealed that this baboon was infected with an SIVAGM strain of the vervet subtype. These results provide the first direct evidence for simian-to-simian cross-species transmission of SIV in the wild.

Published
1994

26. Evolution and probable transmission of intersubtype recombinant human immunodeficiency virus type 1 in a Zambian couple

Author

Salminen, MO, Carr, JK, Robertson, DL, Hegerich, P, Gotte, D, Koch, C, Sanders-Buell, E, Gao, F, Sharp, PM, Hahn, BH, Burke, DS, McCutchan, FE, Salminen, MO, Carr, JK, Robertson, DL, Hegerich, P, Gotte, D, Koch, C, Sanders-Buell, E, Gao, F, Sharp, PM, Hahn, BH, Burke, DS, and McCutchan, FE

Abstract

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1) results from the introduction of mutations by an error-prone reverse transcriptase and from recombination of the two RNA genomes packaged in the virion during the synthesis of proviral DNA. The occurrence of multiple, genetically distant HIV-1 subtypes and their geographic intermixing set up conditions for dramatic, rather than gradual, changes in genotype whenever genomes from different subtypes are copackaged in virions. Here we describe, for the first time, the sequential generation of multiple different, but related, intersubtype HIV-1 recombinants within an infected individual. Full-length gag and env genes were recovered directly from peripheral blood mononuclear cells or from primary virus cultures, using serial blood samples from a Zambian woman and a sample from her spouse. DNA sequencing and phylogenetic analysis established that two different A/C recombinant forms of HIV-1 predominated at two time points in the woman. A related but distinct recombinant HIV-I was recovered from her spouse. Intersubtype recombination apparently played a central role in the evolution of HIV-1 in this couple and may contribute substantially to the rapid emergence of HIV-1 variants whenever mixed-subtype HIV-1 infections occur.

Published
1997

32. Some antiphospholipid antibodies recognize conformational epitopes shared by beta(2)-glycoprotein I and the homologous catalytic domains of several serine proteases.

Author

Lin WS, Chen PC, Yang CD, Cho E, Hahn BH, Grossman J, Hwang KK, and Chen PP

Abstract

OBJECTIVE: To test the hypothesis that some antiphospholipid antibodies (aPL) in patients with the antiphospholipid syndrome (APS) recognize a conformational epitope shared by beta(2)-glycoprotein I (beta(2)GPI; the major autoantigen for the antiphospholipid antibodies) and the homologous catalytic domains of several serine proteases (such as thrombin, activated protein C [APC], and plasmin) involved in hemostasis. METHODS: We generated 4 new IgG monoclonal aPL (2 screened against beta(2)GPI, 1 against thrombin, and 1 against protein C) from 2 APS patients. The monoclonal antibodies (mAb) were analyzed for binding to beta(2)GPI, thrombin, APC, and plasmin, as well as for anticardiolipin antibody (aCL) activity. To demonstrate a shared epitope between beta(2)GPI and a serine protease, 1 mAb was studied by cross-inhibition analysis. RESULTS: Both of the IgG anti-beta(2)GPI mAb bound to thrombin, APC, and plasmin. On the other hand, the 1 anti-thrombin mAb and the 1 anti-protein C mAb also bound to beta(2)GPI. Moreover, the binding of 1 cross-reactive mAb to beta(2)GPI was inhibited by alpha-thrombin (which contains only the catalytic domain of thrombin). All 4 mAb displayed aCL activity. CONCLUSION: Taken together with the findings that some aCL bind to several serine proteases that participate in hemostasis and share homologous catalytic domains, these data demonstrate that some aCL in APS patients recognize one or more conformational epitopes shared by beta(2)GPI and the catalytic domains of disease-relevant serine proteases. [ABSTRACT FROM AUTHOR]

Published
2007
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33. The complexity of care for patients with rheumatoid arthritis: metrics for better understanding chronic disease care.

Author

Kahn KL, MacLean CH, Liu H, Rubenstein LZ, Wong AL, Harker JO, Chen W, Fitzpatrick DM, Bulpitt KJ, Traina SB, Mittman BS, Hahn BH, and Paulus HE

Abstract

BACKGROUND: Patients with rheumatoid arthritis (RA) provide an important opportunity for understanding care of patients with a serious chronic condition. OBJECTIVES: We sought to characterize the complexity of care for patients with RA, including metrics describing the patient, the disease, and use of the health care system across time and place. METHODS: We undertook a prospective cohort study of 568 community-dwelling patients with RA by using observational data from clinically detailed telephone interviews at baseline and 2 years later in addition to medical record abstraction. Health status, comorbidity, use of disease-modifying antirheumatic drugs, visits, providers, provider types, encounter settings, and the discontinuity between patients and providers were studied. RESULTS: Within a 12-month window, 568 patients had 8686 outpatient encounters with the health care system with a mean of 3.41 unique providers per patient associated with a mean of 5 primary care and 6 rheumatologist visits. Half did not see a primary care physician, and 20% did not see a rheumatologist during 6-month periods despite their use of potentially toxic drugs, a mean of 4 comorbidities and progressive RA. Over the course of 24 months, 29% of patients changed their primary care provider, and 15% changed their rheumatologist. Patients were moderately impaired with mean SF-12 physical component score 37 (SD, 9). CONCLUSION: Patients with RA have frequent encounters with multiple providers and also frequent discontinuity of care. Recognizing the complexity of the care of patients with a chronic disease across multiple dimensions provides an opportunity to better understand challenges and opportunities in delivering high quality care. [ABSTRACT FROM AUTHOR]

Published
2007
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34. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus.

Author

Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, and Tsao BP

Abstract

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

Published
2006
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35. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis.

Author

McMahon M, Grossman J, FitzGerald J, Dahlin-Lee E, Wallace DJ, Thong BY, Badsha H, Kalunian K, Charles C, Navab M, Fogelman AM, and Hahn BH

Abstract

OBJECTIVE: Women with systemic lupus erythematosus (SLE) have a 7-50-fold increased risk of coronary artery disease (CAD). In the general population, oxidized low-density lipoprotein (ox-LDL) increases the risk for CAD. Normal high-density lipoproteins (HDLs) protect LDL from oxidation; proinflammatory HDLs do not. This study was undertaken to determine whether patients with SLE, who have chronic inflammation that causes oxidative damage, have more proinflammatory HDL and higher levels of ox-LDL, thus predisposing them to atherosclerosis. METHODS: One hundred fifty-four women with SLE, 48 women with rheumatoid arthritis (RA), and 72 healthy controls were studied. The ability of the patients' HDL to prevent oxidation of normal LDL was measured. Values >1.0 (the value assigned for LDL oxidation in the absence of HDL) after the addition of HDL indicated proinflammatory HDL. Plasma ox-LDL levels were measured as the amount of oxidation produced by the patient's LDL after the removal of HDL. RESULTS: SLE patients had more proinflammatory HDL (mean +/- SD score 1.02 +/- 0.57, versus 0.68 +/- 0.28 in controls [P < 0.0001] and 0.81 +/- 0.22 in RA patients [P = 0.001 versus SLE patients]). A higher proportion of SLE patients had proinflammatory HDL: 44.7% of SLE patients versus 4.1% of controls and 20.1% of RA patients had scores >1.0 (P < 0.006 between all groups). Levels of ox-LDL correlated with levels of proinflammatory HDL (r = 0.37, P < 0.001). SLE patients with CAD had significantly higher proinflammatory HDL scores than patients without CAD (P < 0.001). CONCLUSION: HDLs are proinflammatory in a significant proportion of SLE patients and are associated with elevated levels of ox-LDL. Abnormal HDLs impair the ability to prevent LDL oxidation and may predispose to atherosclerosis. [ABSTRACT FROM AUTHOR]

Published
2006
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37. Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome.

Author

Lu C, Horizon AA, Hwang K, FitzGerald J, Lin W, Hahn BH, Wallace DJ, Metzger AL, Weisman MH, and Chen PP

Abstract

OBJECTIVE: To test the hypotheses that some plasmin-reactive anticardiolipin antibodies (aCL) may bind to tissue plasminogen activator (tPA) and that some of the tPA-reactive aCL may inhibit tPA activity. METHODS: We studied the reactivity of 8 patient-derived monoclonal aCL with tPA and examined the presence of IgG anti-tPA antibodies in patients with the antiphospholipid syndrome (APS). The effects of the reactive monoclonal aCL on the activity of tPA were also examined. RESULTS: Six patient-derived plasmin-reactive monoclonal aCL bound to tPA. Analysis of plasma samples revealed that 10 of 80 APS patients (12.5%) and 1 of 81 systemic lupus erythematosus patients (1.2%) had antibodies against fibrin-associated tPA, based on a cutoff value equal to the mean + 2SD of the level in 28 normal subjects. Of the 6 tPA-reactive monoclonal aCL, 2 of them (CL1 and CL15) inhibited tPA activity. CONCLUSION: Some of the plasmin-reactive aCL in APS patients may bind to tPA. Of the tPA-reactive aCL, some (such as CL1 and CL15) may inhibit tPA activity and, thus, may be prothrombotic in the host. [ABSTRACT FROM AUTHOR]

Published
2005

38. 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.

Author

Wu H, Cantor RM, Graham DSC, Lingren CM, Farwell L, Jager PL, Bottini N, Grossman JM, Wallace DJ, Hahn BH, Julkunen H, Hebert LA, Rovin BH, Birmingham DJ, Rioux JD, Yu CY, Kere J, Vyse TJ, and Tsao BP

Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2005

39. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial.

Author

Buyon JP, Petri MA, Kim MY, Kalunian KC, Grossman J, Hahn BH, Merrill JT, Sammaritano L, Lockshin M, Alarcón GS, Manzi S, Belmont HM, Askanase AD, Sigler L, Dooley MA, Von Feldt J, McCune WJ, Friedman A, Wachs J, and Cronin M

Abstract

Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.Setting: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states.Patients: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE.Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group.Measurements: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite.Results: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.Limitations: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis.Conclusions: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo. [ABSTRACT FROM AUTHOR]

Published
2005
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40. The role of VH determinants in systemic lupus erythematosus.

Author

Kalsi, JK and Hahn, BH

Subjects
*SYSTEMIC lupus erythematosus, *PEPTIDES, *DNA antibodies, *IMMUNOREGULATION
Abstract

The V-regions of anti-DNA antibodies contain determinants which can drive the autoimmune in SLE. Most of the evidence comes from murine studies where VH-derived epitopes accelerate the disease process in lupus prone-mice and can elicit mild inflammatory changes reminiscent of lupus in healthy animals. T helper cells reactive with VH peptides arise spontaneously during the disease and are thought to assist production of both anti-peptide antibodies and the generation of autoantibodies that deposit in the glomeruli. In mice stimulatory epitopes may be unique to autoantibodies. As tolerogens VH peptides may delay or diminish the autoimmune response by altering the production of cytokines. An artificial VH peptide, (pCONCENSUS) has been derived and this inhibits responses to VH and other autoantigens but leaves the murine immune system intact and able to generate reponses to external antigens. Limited number of studies of V-region determinants of human anti-DNA MAbs indicate prior sensitization of lupus T cells to VH determinants and that V-region reactive T cells are not deleted in periphery of healthy individuals. [ABSTRACT FROM AUTHOR]

Published
2002
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43. Antibody-nucleic acid complexes. Identification of the antigenic determinant of a murine monoclonal antibody specific for single-stranded nucleic acids

Author

Liszewski Mk, Ebling Fm, Hahn Bh, Tellam Jt, and Theodore W. Munns

Subjects
Guanine, medicine.drug_class, DNA, Single-Stranded, Guanosine, Biology, Monoclonal antibody, Biochemistry, Sepharose, Epitopes, Mice, chemistry.chemical_compound, medicine, Animals, Nucleotide, chemistry.chemical_classification, Binding Sites, Oligonucleotide, Osmolar Concentration, Antibodies, Monoclonal, Hydrogen-Ion Concentration, Molecular biology, chemistry, Immunoglobulin G, biology.protein, Nucleic acid, Nucleic Acid Conformation, RNA, Antibody
Abstract

Cloned hybrid cells, selected for their ability to secret an IgG 2a immunoglobulin specific for single-stranded (ss) nucleic acids, were obtained by fusion of spleen cells from an unimmunized autoimmune MRL/1 pr male mouse with nonsecreting myeloma cells (MOPC-21, line Sp2/0-Ag 14). Designated MRss-1, this monoclonal antibody was (i) propagated by intraperitoneal injection of hybrid cells to pristane-treated. Balb/c mice, (ii) purified from the bulk of other proteins in ascites extracts by chromatography with DEAE-Sephacel adsorbent, and (iii) radiochemically labeled via reductive methylation using NaB3H4 and formaldehyde. The binding of 3H-labeled antibody to immobilized ssDNA- agarose, calf thymus) or soluble (fd DNA) ssDNA was rapid and dependent upon ssDNA and ionic strength, but not hydrogen ion concentration. Optimal binding occurred in both low and intermediate salt concentration (0.1-0.25 M NaCl), yet was completely abolished above 0.30 M NaCl. The presence of guanine (Gua)-containing mono-, oligo-, and polynucleotides also abolished and/or decreased 3H-labeled antibody binding to ssDNA-agarose. In these competition assays, the amount of Gua-containing mono-and oligonucleotides required to inhibit antibody binding by 50% (0.2-1.0 mg/mL) exceeded those of poly(G), rRNA, and fd DNA (i.e., 0.03-0.1 microgram/mL) by 4 orders of magnitude. In contrast, (deoxy)ribose 5'-phosphate as well as other nucleic acid derivatives devoid of Gua failed to inhibit antibody binding. The above findings were substantiated by the observation that 3H-labeled antibody bound to guanosine (G)- and guanidylate (pG)-conjugated Sepharose, yet not to other nucleoside (A, C, and U)- or nucleotide (pA, pC, and pU)-conjugated adsorbents. Last, the introduction of the methyl group at the N-2, O-6, and N-7 positions in the Gua ring system completely abolished antibody binding. Collectively, these results demonstrate that the MRss-1 antibody recognized single-stranded nucleic acid substrates by virtue of their content of guanidylate residues and, more specificity, by the presence of the Gua base moiety.

Published
1982

44. Antibody-nucleic acid complexes. Antigenic domains within nucleosides as defined by solid-phase immunoassay

Author

M K Liszewski, T W Munns, and Hahn Bh

Subjects
Guanosine, Enzyme-Linked Immunosorbent Assay, Antigen-Antibody Complex, Biochemistry, Antibodies, Epitopes, chemistry.chemical_compound, Antigen, Nucleic Acids, medicine, Bovine serum albumin, Immunoassay, medicine.diagnostic_test, biology, Antibodies, Monoclonal, Nucleosides, Molecular biology, Uridine, chemistry, biology.protein, Haptens, Nucleoside, Hapten, Keyhole limpet hemocyanin
Abstract

The usefulness of solid-phase immunoassays for the characterization of anti-nucleoside antibodies was investigated. Antibodies specific for guanosine (G), 7-methyl-guanosine (m7G), and cytidine (C) were obtained from the serum of rabbits immunized with nucleoside-KLH (keyhole limpet hemocyanin) conjugates. Solid-phase assays consisted of measuring the ability of these antibodies to be retained by microtiter wells containing immobilized nucleoside-BSA (bovine serum albumin) conjugates. Nucleosides employed as haptens included adenosine (A), N6-methyl-A (m6A), guanosine (G), N2,N2-dimethyl-G (m22G), 1-methyl-G (m1G), O6-methyl-G (m6G), 7-methyl-G (m7G), cytidine (C), 5-methyl-C (m5C), uridine (U), and ribothymidine (T). Spectral analysis of these conjugates revealed that 15-20 nucleosides were coupled to each BSA molecule. Quantitative information regarding the various reactions associated with these assays was obtained by employing antigen and antibody (IgG) preparations radiochemically labeled via reductive methylation using NaB3H4 and formaldehyde (specific activities 0.6-2.1 X 10(6) cpm/micrograms). Data obtained with 3H-labeled antigens indicated that the adsorption of all nucleoside-BSA conjugates was uniform and irreversible with respect to the assay conditions used. Assays designed to measure antibody binding in the presence of excess antigen revealed that (i) nonspecific binding to immobilized BSA was negligible, (ii) as little as 0.5 ng of bound antibody could be detected, (iii) antibody retention was directly proportional to antibody concentration, and (iv) each anti-nucleoside antibody cross-reacted to a considerable extent with nonhomologous haptens.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1984

45. Antibody-nucleic acid complexes. Conformational and base specificities associated with spontaneously occurring poly- and monoclonal anti-DNA antibodies from autoimmune mice

Author

Hahn Bh, Theodore W. Munns, and Liszewski Mk

Subjects
Aging, Guanine, medicine.drug_class, Enzyme-Linked Immunosorbent Assay, Mice, Inbred Strains, Antigen-Antibody Complex, Monoclonal antibody, Binding, Competitive, Biochemistry, Epitope, Sepharose, Mice, chemistry.chemical_compound, Species Specificity, Antigen, medicine, Animals, Autoantibodies, biology, Antibodies, Monoclonal, DNA, Molecular biology, chemistry, Polyclonal antibodies, biology.protein, Nucleic acid, Female, Antibody
Abstract

An enzyme-linked immunosorbent assay (ELISA) was developed to characterize spontaneously occurring, mono-and polyclonal anti-DNA antibodies. The assay consists of adsorbing single- (ss) and double-stranded (ds) DNA and various nucleoside-bovine serum albumin conjugates (e.g., A-, G-BSA, etc.) to microtiter wells and assesses the ability of various antibodies to bind to these immobilized antigens. The conformational and base specificity of two monoclonal antibodies (designated MRss-1 BWds-3) was examined in this manner. The exclusive binding of MRss-1 to ssDNA and guanosine-BSA (G-BSA) confirms our previous findings [Munns, T.W., Liszewski, M.K., Tellam, J.T., Ebling, F. M., & Hahn, B.H. (1982) Biochemistry 21,2929-2936] that this antibody recognizes single-stranded nucleic acids by virtue of their guanine content. The extensive binding of BWds-3 to dsDNA, its limited binding to ssDNA, and complete absence of binding to nucleoside-BSA antigens implied a double-stranded conformational specificity. Further, competitive studies with naturally occurring and synthetic alternating copolymers indicated that BWds-3 preferentially recognized the native dsDNA antigens. ELISA analysis of the spontaneously occurring, polyclonal anti-DNA antibodies from MRL/lpr and NZB/NZW-F1 mice revealed that the majority of anti-ssDNA antibodies bound to nucleoside-BSA conjugates. Anti-G antibodies were most prominent in both strains of mice, yet lesser and more variable quantities of anti-A, -C, -U, and -T antibodies were also detected. Preadsorption of serum with G-BSA/Sepharose resulted in the complete removal of anti-G antibodies and a 60% reduction in anti-ssDNA antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1984

46. The Acquired Immunodeficiency Syndrome: An Update

Author

Henry Masur, Phillip D. Markham, H C Lane, Anthony S. Fauci, Edward P. Gelmann, and Hahn Bh

Subjects
Pediatrics, medicine.medical_specialty, Health services, Acquired immunodeficiency syndrome (AIDS), business.industry, Public health, Research methodology, Internal Medicine, medicine, General Medicine, medicine.disease, business, Virology
Abstract

The acquired immunodeficiency syndrome continues to be a major public health problem in the United States, and recently its spread worldwide has accelerated. The syndrome is caused by a hu...

Published
1985

47. Lupus Erythematosus

Author

Avioli Lv and Hahn Bh

Subjects
medicine.medical_specialty, Lupus erythematosus, business.industry, Internal Medicine, Medicine, business, medicine.disease, Dermatology
Published
1975

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