bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycobacterium avium complex immune reconstitution inflammatory syndrome: Long term outcomes
Authors: Riddell James , Kaul Daniel R , Karakousis Petros C , Gallant Joel E , Mitty Jennifer , Kazanjian Powel H
Published: October 2007

Background

To describe long term outcomes of Mycobacterium avium complex (MAC) immune reconstitution inflammatory syndrome (IRIS).

Methods

Cases of MAC IRIS were retrospectively identified at four HIV clinics (Michigan, Maryland, Rhode Island, and Indiana) from 1996–2004. Patients were included if they were initially diagnosed with AIDS and found to have evidence of focal MAC infection documented by tissue culture or PCR after initiating HAART, and at least 6 months of follow up.

Results

Among the 20 patients included, the mean age was 40 years, mean CD4 cell count was 24/mm3 at pretreatment baseline and 100/mm3 at time of MAC IRIS diagnosis. Sites of disease included lymph nodes (15 patients [8 peripheral, 8 abdominal and 1 peripheral and abdominal]), gastrointestinal tract (7) and liver (3). Sixteen patients (80%) responded to treatment and were disease free after a mean of 17.4 months of therapy for MAC IRIS; IRIS therapy was withdrawn in 6 without relapse. Four patients (non-responder group) had persistent or relapsing disease despite 27 months of ongoing MAC IRIS treatment. At the time of resolution or last follow-up, the mean CD4 cell count and viral load was 143/mm3 and 7,000 c/mL for responders, and 65/mm3 and 17,000 c/mL for non-responders, respectively. Most patients with peripheral adenopathy were responders (7/8; 88%); many with abdominal adenopathy (4/8; 50%) were nonresponders.

Conclusion

The majority of patients with MAC IRIS eventually responded to treatment. Our sample size was not adequate to perform statistical analysis, but there was a tendency towards adequate CD4 response to HAART and peripheral rather than intraabdominal adenopathy among responders.
Visualizing regulatory interactions in metabolic networks
Authors: Noack Stephan , Wahl Aljoscha , Qeli Ermir , Wiechert Wolfgang
Published: October 2007

Background

Direct visualization of data sets in the context of biochemical network drawings is one of the most appealing approaches in the field of data evaluation within systems biology. One important type of information that is very helpful in interpreting and understanding metabolic networks has been overlooked so far. Here we focus on the representation of this type of information given by the strength of regulatory interactions between metabolite pools and reaction steps.

Results

The visualization of such interactions in a given metabolic network is based on a novel concept defining the regulatory strength (RS) of effectors regulating certain reaction steps. It is applicable to any mechanistic reaction kinetic formula. The RS values are measures for the strength of an up- or down-regulation of a reaction step compared with the completely non-inhibited or non-activated state, respectively. One numerical RS value is associated to any effector edge contained in the network. The RS is approximately interpretable on a percentage scale where 100% means the maximal possible inhibition or activation, respectively, and 0% means the absence of a regulatory interaction. If many effectors influence a certain reaction step, the respective percentages indicate the proportion in which the different effectors contribute to the total regulation of the reaction step. The benefits of the proposed method are demonstrated with a complex example system of a dynamic E. coli network.

Conclusion

The presented visualization approach is suitable for an intuitive interpretation of simulation data of metabolic networks under dynamic as well as steady-state conditions. Huge amounts of simulation data can be analyzed in a quick and comprehensive way. An extended time-resolved graphical network presentation provides a series of information about regulatory interaction within the biological system under investigation.
Small non-coding RNAs, mammalian cells, and viruses: regulatory interactions?
Authors: Yeung Man Lung , Benkirane Monsef , Jeang Kuan-Teh
Published: October 2007

Recent findings suggest that mammalian cells can use small non-coding RNAs (ncRNA) to regulate physiological viral infections. Here, we comment on several lines of evidence that support this concept. We discuss how viruses may in turn protect, suppress, evade, modulate, or adapt to the host cell's ncRNA regulatory schema.
Requirements for the selective degradation of CD4 receptor molecules by the human immunodeficiency virus type 1 Vpu protein in the endoplasmic reticulum
Authors: Binette Julie , Dubé Mathieu , Mercier Johanne , Halawani Dalia , Latterich Martin , Cohen Éric A
Published: October 2007

Background

HIV-1 Vpu targets newly synthesized CD4 receptor for rapid degradation by a process reminiscent of endoplasmic reticulum (ER)-associated protein degradation (ERAD). Vpu is thought to act as an adaptor protein, connecting CD4 to the ubiquitin (Ub)-proteasome degradative system through an interaction with β-TrCP, a component of the SCFβ-TrCP E3 Ub ligase complex.

Results

Here, we provide direct evidence indicating that Vpu promotes trans-ubiquitination of CD4 through recruitment of SCFβ-TrCP in human cells. To examine whether Ub conjugation occurs on the cytosolic tail of CD4, we substituted all four Ub acceptor lysine residues for arginines. Replacement of cytosolic lysine residues reduced but did not prevent Vpu-mediated CD4 degradation and ubiquitination, suggesting that Vpu-mediated CD4 degradation is not entirely dependent on the ubiquitination of cytosolic lysines and as such might also involve ubiquitination of other sites. Cell fractionation studies revealed that Vpu enhanced the levels of ubiquitinated forms of CD4 detected in association with not only the ER membrane but also the cytosol. Interestingly, significant amounts of membrane-associated ubiquitinated CD4 appeared to be fully dislocated since they could be recovered following sodium carbonate salt treatment. Finally, expression of a transdominant negative mutant of the AAA ATPase Cdc48/p97 involved in the extraction of ERAD substrates from the ER membrane inhibited Vpu-mediated CD4 degradation.

Conclusion

Taken together, these results are consistent with a model whereby HIV-1 Vpu targets CD4 for degradation by an ERAD-like process involving most likely poly-ubiquitination of the CD4 cytosolic tail by SCFβ-TrCP prior to dislocation of receptor molecules across the ER membrane by a process that depends on the AAA ATPase Cdc48/p97.
The wild boar (Sus scrofa) Lymphocyte function-associated antigen-1 (CD11a/CD18) receptor: cDNA sequencing, structure analysis and comparison with homologues
Authors: Bergh Philippe GAC Vanden , Zecchinon Laurent LM , Fett Thomas , Desmecht Daniel JM
Published: October 2007

Background

The most predominantbeta2-integrin lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18,alphaLbeta2), expressed on all leukocytes, is essential for many adhesive functions of the immune system. Interestingly, RTX toxin-producing bacteria specifically target this leukocytebeta2-integrin which exacerbates lesions and disease development.

Results

This study reports the sequencing of the wild boarbeta2-integrin CD11a and CD18 cDNAs. Predicted CD11a and CD18 subunits share all the main structural characteristics of their mammalian homologues, with a larger interspecies conservation for the CD18 than the CD11a. Besides these strong overall similarities, wild boar and domestic pig LFA-1 differ by 2 (CD18) and 1 or 3 (CD11a) substitutions, of which one is located in the crucial I-domain (CD11a, E168D).

Conclusion

As most wild boars are seropositive to the RTX toxin-producing bacteriumActinobacillus pleuropneumoniaeand because they have sustained continuous natural selection, future studies addressing the functional impact of these polymorphisms could bring interesting new information on the physiopathology ofActinobacillus pleuropneumoniae-associated pneumonia in domestic pigs.
Neutrophil granulocytes uniquely express, among human blood cells, high levels of Methionine-sulfoxide-reductase enzymes
Authors: Achilli Cesare , Ciana Annarita , Rossi Antonio , Balduini Cesare , Minetti Giampaolo
Published: October 2007

L-Methionine (Met), in its free form or when inserted in proteins, is sensitive to oxidation of its thioether group by reactive oxygen species from exogenous or endogenous sources. Two stable diastereomers of Met sulfoxide [Met-(O)] may be formed [Met-S-(O) and Met-R-(O)], but these can be reduced by two classes of Methionine-sulfoxide-reductase (Msr) enzymes: MsrA, which reduces the S, and MsrB, which reduces the R sulfoxide. In this study, we have examined the levels of expression of Msr in human blood cells by enzymatic activity assay, Western blotting, and RT-PCR of purified populations of polymorphonuclear neutrophils and eosinophils, mononuclear cells, platelets, and erythrocytes. Our data indicate that of the blood cells analyzed, neutrophils expressed the highest activity, which was mainly of MsrB type. During degranulation of activated neutrophils, Msr activity was not released but remained confined within the cell, indicating a non-granular localization. Immunoprecipitation and RT-PCR studies indicated the almost complete lack of mitochondrial forms of Msrs in granulocytes. It is thus likely that Msrs are important as antioxidant/repair systems for neutrophils, cells with enormous capacity for the generation of reactive oxidants and hence, susceptible to oxidative damage.
Distinct receptor repertoire formation in mouse NK cell subsets regulated by MHC class I expression
Authors: Hayakawa Yoshihiro , Watt Sally V , Takeda Kazuyoshi , Smyth Mark J
Published: October 2007

The acquisition of inhibitory MHC-specific receptors occurs during NK cell differentiation and has been considered important in regulating NK cell responsiveness. NK cell differentiation has been studied on the basis of cell surface phenotype, function, and proliferative capacity. Together with phenotypically immature Mac-1lo NK cells, the mature Mac-1hi NK cell pool can be dissected further into two functionally distinct CD27hi and CD27lo subsets. Two major inhibitory receptors, CD94/NKG2A and Ly-49, are expressed on mouse NK cells. The acquisition of the CD94/NKG2A receptor seems to be an early event, whereas Ly-49 receptor expression is considered a relatively late event during NK cell ontogeny. In this study, we demonstrated a distinct NK cell inhibitory receptor repertoire formation within mature NK cell populations as defined by Mac-1 and CD27. By analyzing mice deficient in MHC class I expression or NKG2D ligand transgenic mice, we have shown that the inhibitory receptor repertoire can be modulated according to the differentiation/maturation status of NK cells, and the receptor acquisition is imprinted at an early stage of NK cell development by MHC class I interactions.
State‐of‐the‐Art Treatment of Coccidioidomycosis Skeletal Infections
Authors: BLAIR JANIS E.
Published: October 2007

Abstract:  Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Typically a respiratory illness, coccidioidomycosis can rarely present as extrapulmonary infection. Skeletal coccidioidomycosis occurs in 20% to 50% of disseminated infections. Skeletal coccidioidomycosis is a chronic and progressive infection that eventually results in bone destruction and loss of function and often involves adjacent structures, such as joints, muscles, and tendons and other soft tissues. Sinus tract formation may occur. This infection may be multifocal. Although radiographs, white blood cell count scans, and other imaging methods identify and define relevant abnormalities, histopathologic examination with culture of the involved bone is the only means to confirm the diagnosis. Serologic testing is adjunctive, and complement fixation titers can be evaluated serially to assess response to treatment. A number of studies addressing the efficacy of various antifungal agents have been performed, and the results of these studies as they pertain to skeletal coccidioidomycosis are summarized herein. Among the various studies, response rates ranged from 23% to 100%, but relapse was common. A combination of medical therapy—often, itraconazole or fluconazole—and surgical débridement is often needed to control skeletal coccidioidomycosis. Early diagnosis and treatment are critical to avoid long‐term problems with chronically infected bones and joints. Anatomical issues, diagnostic studies, and data related to treatment of this form of extrapulmonary coccidioidomycosis are reviewed in this article.
Ecological Niche Modeling of Coccidioides spp. in Western North American Deserts
Authors: BAPTISTA‐ROSAS RAÚL C. , HINOJOSA ALEJANDRO , RIQUELME MERITXELL
Published: October 2007

Abstract:  Coccidioidomycosis is an endemic infectious disease in western North American deserts caused by the dimorphic ascomycete Coccidioides spp. Even though there has been an increase in the number of reported cases in the last years, few positive isolations have been obtained from soil samples in endemic areas for the disease. This low correlation between epidemiological and environmental data prompted us to better characterize the fundamental ecological niche of this important fungal pathogen. By using a combination of environmental variables and geospatially referenced points, where positive isolations had been obtained in southern California and Arizona (USA) and Sonora (Mexico), we have applied Genetic Algorithm for Rule Set Production (GARP) and Geographical Information Systems (GIS) to characterize the most likely ecological conditions favorable for the presence of the fungus. This model, based on environmental variables, allowed us to identify hotspots for the presence of the fungus in areas of southern California, Arizona, Texas, Baja California, and northern Mexico, whereas an alternative model based on bioclimatic variables gave us much broader probable distribution areas. We have overlapped the hotspots obtained with the environmental model with the available epidemiological information and have found a high match. Our model suggests that the most probable fundamental ecological niche for Coccidioides spp. is found in the arid lands of the North American deserts and provides the methodological basis to further characterize the realized ecological niche of Coccidioides spp., which would ultimately contribute to design smart field‐sampling strategies.
Diagnosis of Coccidioidomycosis by Culture
Authors: SUTTON DEANNA A.
Published: October 2007

Abstract: The recovery ofCoccidioidesspp. by culture and confirmation utilizing the AccuProbe nucleic acid hybridization method by GenProbe remain the definitive diagnostic method. Biosafety considerations from specimen collection through culture confirmation in the mycology laboratory are critical, as acquisition of coccidioidomycosis by laboratory workers is well documented. The designation ofCoccidioidesspp. as select agents of potential bioterrorism has mandated strict regulation of their transport and inventory. The genus appears generally susceptible,in vitro,although no defined breakpoints exist. Susceptibility testing may assist in documenting treatment failures.
Deep Solitary Brain Mass in a Four‐Month‐Old Male with Disseminated Coccidioidomycosis
Authors: NOLT JENNIFER D. , GEERTSMA FRANCESCA R.
Published: October 2007

Abstract:  Parenchymal brain involvement from disseminated coccidioidomycosis occurs rarely and there are few documented pediatric cases. We report a four‐month‐old male infant with a cerebellar lesion seen in the brain on computed tomography (CT). Coccidioides immitis (C. immitis) grew on bronchoscopic fluid samples and serum titers to C. immitis were 1:1024. Antifungal treatment was initiated and after 3 months, CT scans demonstrated brain mass resolution and serum titers were decreased.
Coccidioidomycosis and Pregnancy
Authors: SPINELLO IRENE M. , JOHNSON ROYCE H. , BAQI SHEHLA
Published: October 2007

Abstract:  Coccidioidomycosis (CM) is a fungal infection endemic to the southwestern United States, northwestern Mexico, and parts of Central and South America. CM has been recognized as a complicating factor in pregnancy since at least the 1940s, and seems to be a relatively uncommon infection during pregnancy. The disease presentation during pregnancy includes a wide clinical spectrum that ranges from mild influenza‐like illness and pneumonia, especially in the first two trimesters of pregnancy. The third trimester of pregnancy is a time of high risk for dissemination. Immunologic and hormonal changes during pregnancy and the postpartum period may account for any increased frequency and severity of disease observed during pregnancy. Early diagnosis and appropriate aggressive therapeutic intervention with careful monitoring usually result in good outcome.
Coccidioidomycosis in Patients Who Have Undergone Transplantation
Authors: BLAIR JANIS E.
Published: October 2007

Abstract:  In the early years of transplantation in Arizona, coccidioidomycosis occurred in 7% to 9% of recipients, with a mortality rate as high as 72% in some cases. In current transplant programs, however, evolution of immunosuppression and institution of targeted prophylaxis have resulted in coccidioidal infection rates ranging from 1% to 2%. The clinical characteristics of this infection among transplant recipients range from asymptomatic to fulminant and fatal. Dissemination is common, and mortality is high (28%). Because serologic response is often absent or slow, diagnosis can be challenging and often requires invasive diagnostic procedures. Pharmacologic treatment follows the guidelines of the Infectious Diseases Society of America, but control of infection may also dictate a decrease in immunosuppressant treatment. After infection is controlled, secondary azole prophylaxis is recommended to prevent relapse. Patients with a history of coccidioidomycosis may undergo successful transplantation when disease is inactive and azole prophylaxis is instituted. The incidence of donor‐derived coccidioidomycosis is not known. The risk of coccidioidal infection among transplant recipients visiting in or relocating to an endemic area is low, and routine prophylaxis for this group is not recommended.
Molecular Cloning and Expression of a cDNA Encoding a Coccidioides posadasii 1,2‐α‐Mannosidase Identified in the Coccidioidal T27K Vaccine by Immunoproteomic Methods
Authors: LUNETTA JENNINE M. , SIMMONS KEIRA A. , JOHNSON SUZANNE M. , PAPPAGIANIS DEMOSTHENES
Published: October 2007

Abstract:  The coccidioidal T27K vaccine is protective in mice against respiratory challenge with Coccidioides posadasii (C. posadasii) arthroconidia. The vaccine is a subcellular multicomponent preparation that has not been fully characterized. To identify potential protective antigens in the heterogeneous mixture, the vaccine has been separated by two‐dimensional gel electrophoresis and then analyzed for seroreactive proteins using immunoblot analysis with pooled sera from patients with coccidioidomycosis. Two seroreactive spots of identical apparent molecular weight were identified and sequenced using tandem mass spectrometry. Three peptides were generated, two of which matched a tentative consensus sequence in the TIGR C. posadasii 2.0 gene index database that is similar to fungal 1,2‐α‐mannosidases. The 5′ and 3′ ends of the mannosidase cDNA were mapped using rapid amplification of cDNA ends (RACE) polymerase chain reaction (PCR), and a full‐length cDNA was then obtained using reverse‐transcription (RT) PCR. The cDNA was cloned and sequenced and expressed as a recombinant protein. The predicted protein consists of 519 amino acids, has a theoretical molecular weight and pI of 56,918 Da and 4.84, respectively, and is very similar (>60%) to other fungal 1,2‐α‐mannosidases. Class I 1,2‐α‐mannosidase enzyme activity was also detected in the T27K vaccine using the substrate, Man‐α‐1,2‐Man‐α‐OCH3 in a spectrophotometric assay.
Virulence Mechanisms of Coccidioides
Authors: HUNG CHIUNG‐YU , XUE JIANMIN , COLE GARRY T.
Published: October 2007

Abstract: 
Coccidioides is a fungal respiratory pathogen of humans that can cause disease in both immunosuppressed and immunocompetent individuals. We describe here three mechanisms by which the pathogen survives in the hostile host environment: production of a dominant spherule outer wall glycoprotein (SOWgp) that modulates host immune response and results in compromised cell‐mediated immunity to coccidioidal infection, depletion of SOWgp presentation on the surface of endospores, which prevents host recognition of the pathogen when the fungal cells are most vulnerable to phagocytic defenses, and induction of elevated production of host arginase I and coccidioidal urease, which contribute to tissue damage at sites of infection. Arginase I competes with inducible nitric oxide synthase (iNOS) in macrophages for the common substrate, L‐arginine, and thereby reduces nitric oxide (NO) production and increases the synthesis of host orinithine and urea. Host‐derived L‐ornithine may promote pathogen growth and proliferation by providing a pool of the monoamine, which could be taken up and used for synthesis of polyamines via metabolic pathways of the parasitic cells. We have shown that high concentrations of Coccidioides‐ and host‐derived urea at infection sites in the presence of urease produced and released by the pathogen, results in secretion of ammonia and contributes to alkalinization of the microenvironment. We propose that ammonia and enzymatically active urease released from spherules during the parasitic cycle of Coccidioides exacerbate the severity of coccidioidal infection by contributing to a compromised immune response to infection and damage of host tissue at foci of infection.
Fluctuations in Climate and Incidence of Coccidioidomycosis in Kern County, California
Authors: TALAMANTES JORGE , BEHSETA SAM , ZENDER CHARLES S.
Published: October 2007

Abstract:  Coccidioidomycosis (Valley Fever) is a fungal infection found in the southwestern United States, northern Mexico, and some places in Central and South America. The fungi that cause it (Coccidioides immitis and Coccidioides posadasii) are normally soil dwelling, but, if disturbed, become airborne and infect the host when their spores are inhaled. It is thus natural to surmise that weather conditions, which foster the growth and dispersal of Coccidioides, must have an effect on the number of cases in the endemic areas. This article reviews our attempts to date at quantifying this relationship in Kern County, California (where C. immitis is endemic). We have examined the effect on incidence resulting from precipitation, surface temperature, and wind speed. We have performed our studies by means of a simple linear correlation analysis, and by a generalized autoregressive moving average model. Our first analysis suggests that linear correlations between climatic parameters and incidence are weak; our second analysis indicates that incidence can be predicted largely by considering only the previous history of incidence in the county—the inclusion of climate‐ or weather‐related time sequences improves the model only to a relatively minor extent. Our work therefore suggests that incidence fluctuations (about a seasonally varying background value) are related to biological and/or anthropogenic reasons, and not so much to weather or climate anomalies.
Coccidioides Niches and Habitat Parameters in the Southwestern United States
Authors: FISHER FREDERICK S. , BULTMAN MARK W. , JOHNSON SUZANNE M. , PAPPAGIANIS DEMOSTHENES , ZABORSKY ERIK
Published: October 2007

Abstract:  To determine habitat attributes and processes suitable for the growth of Coccidioides, soils were collected from sites in Arizona, California, and Utah where Coccidioides is known to have been present. Humans or animals or both have been infected by Coccidioides at all of the sites. Soil variables considered in the upper 20 cm of the soil profile included pH, electrical conductivity, salinity, selected anions, texture, mineralogy, vegetation types and density, and the overall geomorphologic and ecological settings. Thermometers were buried to determine the temperature range in the upper part of the soil where Coccidioides is often found. With the exception of temperature regimes and soil textures, it is striking that none of the other variables or group of variables that might be definitive are indicative of the presence of Coccidioides. Vegetation ranges from sparse to relatively thick cover in lower Sonoran deserts, Chaparral‐upper Sonoran brush and grasslands, and Mediterranean savannas and forested foothills. No particular grass, shrub, or forb is definitive. Material classified as very fine sand and silt is abundant in all of the Coccidioides‐bearing soils and may be their most common shared feature. Clays are not abundant (less than 10%). All of the examined soil locations are noteworthy as generally 50% of the individuals who were exposed to the dust or were excavating dirt at the sites were infected. Coccidioides has persisted in the soil at a site in Dinosaur National Monument, Utah for 37 years and at a Tucson, Arizona site for 41 years.
Coccidioidal Meningitis
Authors: WILLIAMS PAUL L.
Published: October 2007

Abstract:  Coccidioidal meningitis affects between 200 to 300 persons annually within the endemic area of the United States, with much larger numbers expected in epidemic years. Because this represents a chronic disease for survivors, several thousand patients may be under treatment at any given time. Epidemiology, background, and diagnosis are reviewed. Azole therapy has replaced intrathecal amphotericin B for induction and maintenance therapy for this disease, given its ease of administration and equivalent efficacy in controlling infection even at the cost of losing the opportunity for cure. Both itraconazole and fluconazole have demonstrated efficacy, but have not been compared in randomized human studies. One of the uses of intrathecal amphotericin B is as “add on” therapy in failing azole regimens without evidence of antagonism. Details of therapeutic approach are reviewed. Approach to diagnosis and management of the two principal potentially life threatening complications, hydrocephalus and vasculitis, is also discussed.
Safety, Antigenicity, and Efficacy of a Recombinant Coccidioidomycosis Vaccine in Cynomolgus Macaques (Macaca fascicularis)
Authors: JOHNSON SUZANNE M. , LERCHE NICHOLAS W. , PAPPAGIANIS DEMOSTHENES , YEE JOANN L. , GALGIANI JOHN N. , HECTOR RICHARD F.
Published: October 2007

Abstract:  The safety, immunogenicity and efficacy of recombinant Ag2/PRA106 + CSA chimeric fusion protein (CFP) vaccine in ISS/Montanide adjuvant–administered intramuscular (IM) was assessed in adult female cynomolgus macaques challenged with Coccidioides posadasii. Animals received three immunizations with either 5 μg CFP, 50‐μg CFP, or adjuvant alone and were challenged 4 weeks following the final immunization. Although significant antibody response was produced in response to vaccination, there were no discernable adverse effects, suggesting that the vaccine was well tolerated. Upon intratracheal challenge, all animals showed evidence of disease. Two animals that received 5‐μg doses of CFP were euthanatized prior to the study's end because of severe symptoms. Animals vaccinated with 50‐μg doses of CFP showed evidence of enhanced sensitization compared to adjuvant controls and animals vaccinated with 5‐μg doses of CFP. This was based on higher serum anti‐CFP titers, enhanced secretion of interferon‐gamma (IFN‐γ) from stimulated bronchoalveolar lavage mononuclear cells (BALMC), reduced pulmonary radiologic findings following intratracheal challenge, reduced terminal complement fixation titers, and reduced necropsy findings. Overall the vaccine was well tolerated, induced sensitization, and resulted in a protective response when given at the higher 50‐μg dose. Additional experiments may be needed to optimize the vaccination and to confer greater protection against lethal challenge.
The Role of IL‐10 in Genetic Susceptibility to Coccidioidomycosis on Mice
Authors: FIERER JOSHUA
Published: October 2007

Abstract:  Epidemiological and clinical studies have confirmed that coccidioidomycosis is more severe in African American and Filipino patients than in Caucasians, suggesting a genetic basis for susceptibility in humans. We discovered that inbred strains of mice also vary greatly in their susceptibility to Coccidioides immitis infections, and although resistance is the dominant phenotype, it is a multigenic trait in mice. We found a strong direct correlation between susceptibility in mice and the amount of IL‐10 made in response to infection. We then showed that IL‐10‐deficient mice are much more resistant to infection than the parent C57BL/6 strain. Finally, we showed that genetically resistant mice that are transgenic for IL‐10 and so overproduce that cytokine are more susceptible to C. immitis. This is in part due to suppression of NOS2 expression by IL‐10.
Type I Interferons Inhibition of Inflammatory T Helper Cell Responses in Systemic Lupus Erythematosus
Authors: MANGINI ALYSON J. , LAFYATIS ROBERT , MAGUIRE VAN SEVENTER JEAN
Published: October 2007

Abstract:  T helper (Th) cells play a central role in systemic lupus erythematosus (SLE). Activated autoreactive Th cells provide the help required for autoreactive B cells to differentiate and produce pathogenic autoAbs. Both autoAb‐containing immune complexes and direct effects of inflammatory Th cells promote tissue injury and organ damage. In SLE, triggering of plasmacytoid dendritic cell (pDC) Toll‐like receptors by autoimmune complexes containing nucleic acid autoantigens stimulates pDC secretion of high levels of type I interferons (IFN‐α/β). Study of SLE patients and murine disease models implicate these type I IFNs as key disease effectors. However, the role of pDC‐derived type I IFNs in regulating the inflammatory function of Th cells in SLE is unknown. Although, type I IFNs are classically considered to promote Th1‐mediated inflammation, they can also act as potent inhibitors of both Th1 and Th17 inflammatory cell responses. Work of ourselves and others leads us to hypothesize that if initiated during stages of SLE when Th cell‐mediated tissue inflammation is absent or minimal, such as early in the disease or during periods of remission, type I IFN neutralization will disrupt the cycle of systemic autoimmune induction and disease. However, if initiated during advanced stages of disease when there is substantial ongoing Th1 (and possibly Th17) cell‐mediated inflammation, targeting type I IFNs will exacerbate the Th cell‐mediated inflammatory disease and thus potentiate end‐organ damage and destruction. This has important implications for the application of the numerous anti‐type I IFN therapies currently under development for SLE treatment.
Sun‐Induced Life‐Threatening Lupus Nephritis
Authors: SCHMIDT ENNO , TONY HANS‐PETER , BRÖCKER EVA‐BETTINA , KNEITZ CHRISTIAN
Published: October 2007

Abstract:  Photosensitivity is a widely known characteristic of both cutaneous and systemic lupus erythematosus (LE). However, sun‐induced organ involvement is rarely reported in LE. We describe a 34‐year‐old woman who had been in complete remission of systemic LE for more than 8 years without treatment. After sunbathing, she developed acute sunburn followed by cutaneous LE in sun‐exposed areas. Six weeks later, a lupus nephritis was diagnosed and high serum levels of anti‐double‐stranded (ds) DNA and anti‐Ro/SSA antibodies were detected. Treatment with systemic cyclophosphamide and prednisolone led to septicemia requiring assisted ventilation for more than 2 weeks and repeated hemodialysis. Clinical remission was achieved 3 months later by the use of prednisolone and mycophenolate mofetile. Meanwhile, mild proteinuria persisted, anti‐dsDNA antibodies normalized. We hypothesize that the sunburn‐induced keratinocyte necrosis/apoptosis exposed intracellular antigens as trigger for the generation of autoantibodies that finally mediated immune‐complex nephritis. The patient highlights the impact of UV light not only on skin but also on internal organ involvement in LE.
Blood Concentrations of Hydroxychloroquine and Its Desethyl Derivative Correlate Negatively with the Percentage of CD45RO+ Cells among CD4+ Lymphocytes in Hydroxychloroquine‐Treated Lupus Patients
Authors: SAILLER LAURENT , PUISSANT BÉNÉDICTE , MÉLIANI PASCAL , CASTEX JEAN OLIVIER , SAIVIN SYLVIE , ADOUE D , FOURNIE B , ARLET PHILIPPE , MONTASTRUC JEAN‐LOUIS , LAPEYRE‐MESTRE MARYSE , POURRAT JACQUES , BLANCHER ANTOINE
Published: October 2007

Abstract:  The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ‐treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ‐treated lupus patients (mean HCQ dose: 4.93 ± 1.58 mg/kg/day; mean duration of the disease: 122 ± 64 months). [HCQ] and [DHCQ] were determined by high‐performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti‐CD3, ‐CD4, ‐CD8, ‐CD25, ‐DR, ‐CD45RA,‐CD45RO, ‐CD19, ‐CD38, and ‐CD86 antibodies. sIL2‐R serum concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55–1935) and 353.43 (median: 286 ng/mL; range: 118–1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P= 0.0002 and P= 0.03) and with compliance to the treatment (P= 0.004 and P= 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO+ cell frequency among CD3+CD4+ cells (P= 0.03 and P= 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2‐R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO+ expression was negatively influenced by [HCQ] (P= 0.005), and positively influenced by smoking habits (P= 0.005) and age (P= 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO+ expression. Lupus patients had less CD3+CD4+CD45RO+ cells than controls (P= 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4+CD45RO+ lymphocytes in a concentration‐dependent pattern.
Advances in Lupus and Sjögren's Syndrome
Authors: RAMOS‐CASALS MANUEL , KHAMASHTA MUNTHER A.
Published: October 2007

Abstract:  Dr. Josep Font (Barcelona, 1953–2006) devoted his professional career to the care of patients with systemic autoimmune diseases (SAD). In 1995, he created the Department of Autoimmune Diseases at the Hospital Clinic in Barcelona, a pioneering unit in Europe specifically dedicated to the clinical management of these patients. The research output of Dr. Font has been prodigious, with a total of over 500 scientific articles published in 25 years, and was especially focused on the clinical and immunological characterization of systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS). This review briefly analyzes some of the main contributions of Josep Font to our current knowledge about these diseases. In SLE, the research was centered on the epidemiological and clinical characterization, the study of cardiovascular and vasculitic involvements, and the investigation of the etiopathogenic role of the innate immunity. In primary SS, basic research conducted by Dr. Font contributed to a better understanding of the autoimmune etiopathogenesis of the disease, while the clinical research expanded our knowledge about the systemic and immunological expression of the disease and its frequent association with lymphoma, other SAD, and chronic viral infections.
Regulatory T Cells and Systemic Lupus Erythematosus
Authors: PARIETTI VÉRONIQUE , CHIFFLOT HÉLÈNE , MULLER SYLVIANE , MONNEAUX FANNY
Published: October 2007

Abstract:  Regulatory T cells, especially CD4+CD25+ T cells, “natural killer” T cells and γδ T cells, are central in the maintenance of peripheral tolerance and the protection from the development of autoimmune diseases. Numerical or functional modifications of these cell populations were demonstrated to lead to the breakdown of tolerance and the emergence of autoimmunity. Involvement of regulatory T cells in the pathogenesis of systemic autoimmune diseases, such as systemic lupus erythematosus, might be of first importance. In murine models and patients with lupus, these regulatory T cells seem to be reduced in number. Functional deficiencies have also been described in a few studies. A better knowledge of regulatory T cell functional properties in systemic autoimmune diseases is essential to manipulate these cells and hopefully to restore immune tolerance.
A Potential Trigger of Nephritogenic Anti‐DNA Antibodies in Lupus Nephritis
Authors: HIRABAYASHI Y. , OKA Y. , TADA M. , TAKAHASHI R. , ISHII T.
Published: October 2007

Abstract:  Anti‐DNA antibodies play an essential role in the pathogenesis of lupus nephritis. Mammalian DNA alone, however, is poorly immunogenic. We speculated that the antigenic trigger for the production of human nephritogenic anti‐DNA antibodies is a non‐DNA substance. The cDNA library from peripheral blood lymphocytes (PBLs) of a patient with active lupus nephritis was screened using the single‐chain Fv of a human monoclonal nephritogenic O‐81 anti‐DNA antibody in a two‐hybrid system. A clone containing the gene of an endoplasmic reticulum (ER) stress‐inducible protein, Herp, was obtained. The O‐81 antibody bound to recombinant Herp protein synthesized by Escherichia coli. Immunization with Herp elicited both anti‐double‐stranded DNA (anti‐dsDNA) and anti‐single‐stranded (anti‐ssDNA) antibodies in BALB/c mice and formed deposits of IgG in renal glomeruli. Anti‐DNA antibodies purified from SLE sera bound to Herp. Moreover, anti‐Herp antibodies showed specific binding to DNA. Herp was spontaneously expressed in PBLs of patients with active SLE, but not in PBLs of healthy subjects. These results imply that an inducible intracellular self‐protein represents a candidate trigger for human nephritogenic anti‐DNA autoantibodies. Any cell stress causing ER stress, such as viral infection, ultraviolet radiation, and chemicals, might be responsible for anti‐DNA antibody production via Herp.
A Central Role of Nucleosomes in Lupus Nephritis
Authors: FENTON KRISTIN A. , PETTER REKVIG OLE
Published: October 2007

Abstract:  Lupus nephritis is characterized by the presence of subendothelial and subepithelial immune complexes and thickening of the glomerular basement membranes (GBM). Electron‐dense structures (EDS) in mesangium and GBM have been demonstrated to constitute target structures for nephritogenic autoantibodies in vivo. Whether these antibodies bind nucleosomal antigens within the EDS or cross‐react with components of the GBM has not been resolved. Data recently published point at intra‐GBM‐associated nucleosomes as target for the nephritogenic autoantibodies. Colocalization IEM has demonstrated that autoantibodies and experimental antibodies against DNA, histones, or transcription factors like TATA box‐binding protein colocalize in the EDS. By using terminal transferase in situ nick‐end labeling in combination with immune electron microscopy to detect DNA specifically in human and murine SLE kidneys, we were able to detect DNA within the EDS of nephritic glomeruli that corresponded with the detected autoantibodies.
Systemic Lupus Erythematosus
Authors: FENG PAO‐HSII
Published: October 2007

Abstract:  This review documents the remarkable progress systemic lupus erythematosus (SLE) has made in the past 40 years especially in Asia. It provides a kaleidoscope in terms of prevalence, ethnic and regional variations, disease manifestation, treatment strategies, and outcome. From a seminal paper on the use of intravenous cyclophosphamide in 1964 from Singapore to the use of mycophenolate mofetil in 2000 from Hong Kong and Guangzhou, the prognosis of lupus has changed dramatically in the last few decades. With more targeted therapies and better translational research, this progress is set to continue in the coming years. From an acute fulminating illness, lupus has now evolved to one with a chronic, relapsing course. The main causes of morbidity and mortality are now either treatment‐related or patient‐related rather than the disease itself. The present time is one of unprecedented growth of new therapeutic approaches and reevaluation of past treatment modalities. With improving socioeconomic conditions in the region, we anticipate further rapid progress in disease outcome. Although living with the wolf is still an ordeal for our patients, optimism has now replaced nihilism in the lupus world. There is light at the end of the tunnel.
Intima‐Media Thickness
Authors: COLOMBO BARBARA MARIA , MURDACA GIUSEPPE , CAITI MATTEO , RODRIGUEZ GUIDO , GRASSIA LIDIA , ROSSI EDORADO , INDIVERI FRANCESCO , PUPPO FRANCESCO
Published: October 2007

Abstract:  Accelerated atherosclerosis is an emerging problem in patients with systemic lupus erythematosus (SLE). We planned an observational study to determine whether in patients with SLE carotid intima‐media thickness (IMT) represents an early sign of accelerated atherosclerosis and to confirm that SLE adds to the traditional cardiovascular Framingham risk factors. Thirty females with SLE (age 18–65 years) underwent anamnestic, clinical, and laboratory evaluation and B‐mode ultrasonography of carotid arteries, which provides a direct and noninvasive assessment of subclinical atherosclerosis. IMT measurements were performed on the right and left common carotid arteries 1.0 cm proximal to the carotid bulb and the mean IMT value was calculated with a dedicated software. The Framingham Point Score was also calculated for each subject. SLE patients showed a mean IMT value of 0.73 ± 0.12 (SD) mm. This value is significantly (P < 0.05) higher than that reported for an age‐matched healthy female control population (0.66 ± 0.11 SD mm). A preliminary evaluation of the Framingham Point Score, estimating the 10‐year risk for women to develop cardiovascular events, indicated an increased risk of early cardiovascular events in SLE patients. In our study we have shown that patients with SLE have an increased mean IMT value compared with a healthy females control. Moreover, the evaluation of the Framingham Point Score suggests that SLE is an additional risk factor for cardiovascular disease.
DNA Methylation and Systemic Lupus Erythematosus
Authors: BALADA EVA , ORDI‐ROS JOSEP , VILARDELL‐TARRÉS MIQUEL
Published: October 2007

Abstract: Several studies have indicated the importance of DNA hypomethylation in the etiology of systemic lupus erythematosus (SLE). Different enzymes linked to the DNA methylation process have been described. The identification of all these enzymes means that cells have the capacity to modify their methylation patterns. Therefore, to obtain a deeper understanding of the role this epigenetic mechanism may have on SLE, the enzymes involved in the DNA methylation mechanism must be thoughtfully analyzed. In fact, studies of enzymes (other than DNMT1) in this autoimmune disease are still lacking. We have recently investigated the simultaneous gene expression of DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 in SLE patients. Here we review some of the studies that focus on the relationship between DNA methylation and SLE as well as we report our recent findings in this field. We suggest some alternative hypothesis that could help to understand the causes of the global DNA hypomethylation observed in the CD4+T cells of these patients.
Drug‐Induced Lupus
Authors: BORCHERS ANDREA T. , KEEN CARL L. , GERSHWIN M. ERIC
Published: October 2007

Abstract:  Drug‐induced lupus (DIL) is a rare adverse reaction to a large variety of drugs with features resembling those of idiopathic systemic lupus erythematosus (SLE). It usually develops only after months and, quite commonly, years of treatment with the offending agent, although latencies of days or weeks have been described in some instances. There are some indications that the risk of DIL can increase with higher daily and cumulative doses and with longer duration of therapy. There are no definitive and commonly accepted diagnostic criteria for DIL, but the following guidelines have been proposed: (a) sufficient and continuing exposure to a specific drug, (b) at least one symptom compatible with SLE, (c) no history suggestive of SLE before starting the drug, and (d) resolution of symptoms within weeks (sometimes months) after discontinuation of the putative offending agent. In addition, it is frequently suggested that the presence of ANA is required for the diagnosis of DIL. However, negative ANA test results should not automatically preclude such a diagnosis, particularly if a patient has other autoantibodies associated with SLE/DIL.
Altered Expression of Fcγ and Complement Receptors on B Cells in Systemic Lupus Erythematosus
Authors: GERGELY PÉTER , ISAÁK ANDREA , SZEKERES ZSUZSANNA , PRECHL JÓZSEF , ERDEI ANNA , NAGY ZSOLT B. , GERGELY JÁNOS , POÓR GYULA
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyper‐reactivity, autoantibody production, immune complex (IC) deposition, and multiple organ damage. The contribution of IC and B cell–mediated changes in the pathogenesis of SLE is well established, however, the exact role of IC‐binding receptors expressed on B cells, Fcγ receptors, and complement receptors CR1 and CR2 in these pathological processes is unclear. Development of lupus‐like symptoms in mice defective for the inhibitory FcγRIIb and genetic association of certain FcγR genes with SLE demonstrate a significant role for these receptors but reports indicating alterations of Fcγ or complement receptor‐mediated B cell functions in human SLE are relatively few. The present review highlights a selected set of data including our own discussing the significance of animal models, genetics, and functional alterations of these IC‐binding receptors in the etiopathogenesis of SLE.
Highly Specific Novel Method for Isolation and Purification of Lupus Anti‐DNA Antibody via Oligo‐(dT) Magnetic Beads
Authors: PAVLOVIC MIRJANA , CHEN RAN , KATS ANNA M. , CAVALLO MICHELLE F. , SACCOCIO SETH , KEATING PATRICIA , HARTMANN JAMES X.
Published: October 2007

Abstract:  A novel method for isolation and purification of anti‐ssDNA antibodies from human sera is developed. The process involves: antibody purification based on their affinity for single‐stranded sequence of thymidines and removal of remaining components via protein G coated magnetic beads, with high affinity for only IgG subclass. The high degree of purity and molecular weights of healthy versus lupus anti‐ssDNA antibodies were confirmed by SDS‐PAGE and silver staining. Western blot confirmed IgG isotype. This novel technique allows for diagnostic purposes, structural and functional analysis of anti‐DNA antibodies, and studies of their role in autoimmune diseases.