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PubMed1996

Uniaxial tension inhibits tendon collagen degradation by collagenase in vitro.

Tendon structure is governed largely by factors regulating the anabolic and catabolic phases of tenocyte metabolism. Little is known about the mechanisms that regulate the synthesis, activation, and action of metalloproteinases, which are key enzymes in a multifactorial cascade controlling homeostasis of the extracellular matrix. In the present study, we investigated the effect of tension on collagenase-induced degradation of the tendon in vitro by assessing changes in structural and material properties measured during tensile failure tests. Devitalized right-left pairs of rabbit patella-patellar tendon-tibia units were maintained under culture conditions in the presence of 60 U/ml highly purified collagenase for 20 hours. One randomly selected unit from each animal was subjected to a tension that produced a constant 4% elongation or strain (n = 10); the contralateral unit served as a slack comparison (n = 10). In one series of experiments (immediate, n = 5), the tension was applied immediately prior to collagenase exposure. In a second series (delayed, n = 5), it was delayed for 4 hours to allow time for the collagenase to diffuse into the tendon. Additional devitalized and nonincubated units (n = 6) were used as normal controls. Collagenase exposure caused large decreases in stiffness and elongation to failure in slack units. This resulted in greater than 80% reductions in both maximum failure force and energy to failure. In contrast, the loaded unit in both experimental protocols had significantly greater stiffness than control units. In both the immediate and the delayed protocols, the loaded tendons had significantly higher stiffness and failed at significantly higher elongations and maximum forces than the slack tendons. Diffusion studies with and without tension showed the tension did not inhibit diffusion of collagenase into the tendon but did significantly decrease the water content from 64.6 to 57.8%. The data suggest that stresses and strains of the extracellular matrix may modify the kinetics of the bacterial collagenase-collagen interaction. Matrix stress and strain may be an important and overlooked factor that modulates the susceptibility of collagen to proteolytic degradation.

Animals↗
PubMed1998

Defective c-Mpl signaling in the syndrome of thrombocytopenia with absent radii.

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital defect with severe hypomegakaryocytic thrombocytopenia and bilateral radial aplasia. To elucidate a possible relationship between thrombocytopenia in TAR and defects in the thrombopoietin (TPO)/c-Mpl system, we examined TPO activity in sera from six patients and in vitro reactivity of the patients' platelets to recombinant human TPO. We found elevated TPO serum levels in all patients, excluding a TPO production defect as a pathomechanism for the thrombocytopenia. In contrast to healthy controls, however, platelets of TAR patients failed to respond to recombinant TPO as measured by testing TPO synergism to suboptimal concentration of platelet activators. Most interestingly, TPO-induced tyrosine phosphorylation of platelet proteins was completely absent (four out of five) or markedly decreased (one out of five). More detailed investigations of the signal cascades of c-Mpl demonstrated the absence of Jak2 phosphorylation after TPO stimulation in a TAR patient's platelets. A defect in the early events of c-Mpl signal transduction might be the reason for impaired megakaryocytopoiesis in TAR syndrome.

Blood Platelets↗
PubMed1992

Mental deterioration at epilepsy onset: a hypothesis.

In this study, we hypothesized a type of mental deterioration in epilepsy, characterized as a discontinued, cascading process, i.e. a sudden mental decline in a limited time interval, immediately after the onset of the seizures. The posttraumatic epilepsy model (PTE) may appear to be exceptionally useful in avoiding one of the major methodological obstacles for testing this hypothesis, i.e. the unavailability of test results obtained with the same battery of tests prior to and directly after the onset of the seizures. We propose a multicentre study in which a large group of patients are assessed, after recovering from the direct aftermath of head injury, but before the onset of PTE. This baseline provides an opportunity for longitudinal follow-up. Full recovery from head injury before the onset of PTE is to be expected in the mild and moderate groups of closed head injury patients. In this category, approximately 2000 head injured patients have to be assessed to obtain a reasonable group of approximately 100-200 PTE patients. This group will be followed during the critical period of 2-3 years after the onset of epilepsy.

Adolescent↗
PubMed1992

Mechanism of hyperthyroidism-induced modulation of the L-type Ca2+ current in guinea pig ventricular myocytes.

The positive inotropic effects of thyroid hormone in the heart, increased force and velocity of contraction have been mostly attributed to modulation of myosin ATPase isoenzymes (V1, V2 and V3), and sarcoplasmic reticulum Ca2+ pumping activity. In addition, we have suggested that the effects on ventricular contraction result from a thyroid hormone-induced increase in L-type Ca2+ current (ICa,L). Due to the central role of ICa,L in excitation-contraction coupling, we studied mechanisms whereby thyroid hormone augments this current. Since thyroid hormone modulates adenylate cyclase activity in various tissues, we tested the hypothesis that the hormone activates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A activation, Ca2+ channel phosphorylation and increased ICa,L. We therefore stimulated or inhibited different sites along the "adenylate cyclase cascade", and measured ICa,L and isometric twitch in ventricular myocytes and papillary muscles from euthyroid and hyperthyroid guinea pigs. Our major findings were as follows. In euthyroid myocytes, 0.1 microM isoproterenol (Iso) increased ICa,L (at VM = 0 mV) from -7.04 +/- 0.72 to -22.26 +/- 1.88 pA/pF, P < 0.05, while in hyperthyroid myocytes (ICa,L = -21.48 +/- 2.94 pA/pF), Iso was ineffective. In euthyroid myocytes, intracellular application of cAMP (50 microM) was as potent as Iso, but ineffective in hyperthyroid myocytes. In hyperthyroid myocytes, a protein kinase A inhibitor (2 microM) lowered ICa,L from -26.82 +/- 1.54 to -10.17 +/- 1.70 pApF (P < 0.05), but had no effect in euthyroid myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Immunochemical quantitation, size distribution, and cross-reactivity of lepidoptera (moth) aeroallergens in southeastern Minnesota.

With an immunochemical method, we analyzed outdoor air samples during a 3-year period for concentrations of the predominant local species of moth, Pseudaletia unipuncta (Haworth). Airborne particulates were collected on fiberglass filter sheets with an Accu-Vol sampler located 1.5 m above ground on the southeastern Minnesota prairie. Filter eluates analyzed by RIA inhibition contained concentrations of moth protein peaking in June and August to September of each year, with levels comparable to reported immunochemically measured levels of pollen and mold allergens. These peaks also corresponded with total numbers of moths captured in light traps. Moth-allergen activity was distributed in particle sizes ranging from 0.8 to greater than 4.1 micron when sized samples were obtained by use of an Andersen cascade impaction head. By RIA inhibition, there was cross-reactivity between P. unipuncta and insects of different genera, families, and orders, but not with pollens or molds. Forty-five percent of 257 patients with immediate positive skin tests to common aeroallergens had positive skin tests to one or more commercially available whole body insect extracts. Of 120 patients with allergic rhinitis believed to be primarily caused by ragweed sensitivity, 5% also had elevated specific IgE to moths. We conclude that airborne concentrations of Lepidoptera can be measured immunochemically and that moths may be a seasonal allergen in the United States.

Air Pollution↗
PubMed2005

Gene expression profiling of serum- and interleukin-1 beta-stimulated primary human adult articular chondrocytes--a molecular analysis based on chondrocytes isolated from one donor.

In order to understand the cellular disease mechanisms of osteoarthritic cartilage degeneration it is of primary importance to understand both the anabolic and the catabolic processes going on in parallel in the diseased tissue. In this study, we have applied cDNA-array technology (Clontech) to study gene expression patterns of primary human normal adult articular chondrocytes isolated from one donor cultured under anabolic (serum) and catabolic (IL-1beta) conditions. Significant differences between the different in vitro cultures tested were detected. Overall, serum and IL-1beta significantly altered gene expression levels of 102 and 79 genes, respectively. IL-1beta stimulated the matrix metalloproteinases-1, -3, and -13 as well as members of its intracellular signaling cascade, whereas serum increased the expression of many cartilage matrix genes. Comparative gene expression analysis with previously published in vivo data (normal and osteoarthritic cartilage) showed significant differences of all in vitro stimulations compared to the changes detected in osteoarthritic cartilage in vivo. This investigation allowed us to characterize gene expression profiles of two classical anabolic and catabolic stimuli of human adult articular chondrocytes in vitro. No in vitro model appeared to be adequate to study overall gene expression alterations in osteoarthritic cartilage. Serum stimulated in vitro cultures largely reflected the results that were only consistent with the anabolic activation seen in osteoarthritic chondrocytes. In contrast, IL-1beta did not appear to be a good model for mimicking catabolic gene alterations in degenerating chondrocytes.

Adult↗
PubMed2001

The Drosophila proteins Pelle and Tube induce JNK/AP-1 activity in mammalian cells.

The mammalian interleukin-1 (IL-1) signal transduction pathways display remarkable homology to the Toll signaling cascade in Drosophila. To address the question whether members of the Drosophila Toll pathway are functional in mammalian cells, inactive and constitutively active versions of the protein kinase Pelle and its regulator Tube were expressed in HeLa cells and tested for their impact on IL-1-dependent signaling events. The Drosophila proteins failed to induce the IL-1-responsive transcription factor, nuclear factor-kappaB, but selectively activated the IL-1-regulated kinase, c-Jun N-terminal kinase (JNK), thus resulting in elevated AP-1 activity. Activation of JNK/AP-1 activity was seen upon expression of a Pelle mutant lacking its C-terminal half or by a membrane-bound and multimerised Tube protein, showing the functionality of the Drosophila proteins in mammalian cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Ceramide induces apoptosis in neuroblastoma cell cultures resistant to CD95 (Fas/APO-1)-mediated apoptosis.

BACKGROUND/PURPOSE: Spontaneous tumor regression is a well-known characteristic in neuroblastomas. Because preliminary reports have shown that regression may be caused by apoptosis (a lethal cascade mediated by the CD95 (APO-1/Fas)-receptor), we analyzed the expression of CD95-receptors in 5 human neuroblastoma cell lines. Ceramides (known stimuli of apoptosis downstream from the CD95-receptor complex) also were used to test whether apoptosis would be induced in neuroblastoma cell cultures resistant to CD95-mediated programmed cell death. METHODS: The expression of the CD95-receptor was assessed by flow cytometry after incubation with either fluorisothiocyanate-conjugated (FITC) anti-CD95-antibody (UB2) or CD95-ligand for 16 hours. Apoptotic cell death was detected via microscopy, cell viability testing (MTT, 3-[4,5 dimehylthiazole-2-yl]-2,5 diphenyltetrazoliumbromide), and flow cytometric analysis after propidium iodide staining of the DNA. RESULTS: CD95-receptor expression was found on all neuroblastoma cell lines. Stimulation of the CD95-receptor of the malignant glioblastoma cell line LN229 (positive control) with either anti-CD95-antibody or CD95-ligand induced apoptosis. Apoptosis was not seen, however, in any of the neuroblastoma cell lines when the CD95-receptor was stimulated with anti-CD95-antibody or the CD95-ligand. Significant apoptosis was detected in all neuroblastoma cell lines after the addition of 25 micromol/L C2- and C6-ceramide. CONCLUSIONS: CD95-receptors are present on neuroblastoma cell lines, and these cells are resistant to apoptosis stimulated by anti-CD95-antibody or CD95-ligand. Apoptosis is induced, however, when these cells are treated with ceramide. A signal blockage downstream from the CD95-receptor complex and upstream of ceramide may account for this finding, and the "cellular FLICE inhibitory protein" (cFLIP) may be primarily responsible.

Apoptosis↗
PubMed2004

InsP3-mediated intracellular calcium signalling is altered by expression of synaptojanin-1.

Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] plays an important physiological role as a precursor for the InsP3-mediated intracellular calcium (Ca2+) signalling cascade. It also regulates membrane trafficking, actin function and transmembrane proteins. SJ-1 (synaptojanin-1), a phosphoinositide phosphatase, regulates the turnover of a PtdIns(4,5)P2 pool involved in clathrin and actin dynamics at the cell surface. We tested the interrelationship of this pool with PtdIns(4,5)P2 pools involved in Ca2+ signalling by expressing in Chinese-hamster ovary cells full-length SJ-1 or its 5-Pase (inositol 5-phosphatase) domain. SJ-1 significantly attenuated the generation of Ca2+ oscillations induced by ATP and the 5-Pase domain mimicked this effect. These changes correlated with increased PtdIns(4,5)P2 phosphatase activity of cellular extracts. Overexpression of the endoplasmic reticulum-anchored PtdIns(4)P phosphatase Sac1 did not affect Ca2+ oscillations, although it increased the Ca2+ efflux rate from intracellular stores. The ability of SJ-1 to alter intracellular Ca2+ signalling indicates a close functional interrelationship between plasma membrane PtdIns(4,5)P2 pools that control actin and endocytosis and those involved in the regulation of specific spatio-temporal Ca2+ signals.

Adenosine Triphosphate↗
PubMed2003

Hypothalamic digoxin, hemispheric chemical dominance, and inflammatory bowel disease.

The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. It was considered pertinent to assess the pathway in inflammatory bowel disease (ulcerative colitis and regional ileitis). Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. All the patients with inflammatory bowel disease were right-handed/left hemispheric dominant by the dichotic listening test. The following parameters were measured in patients with inflammatory bowel disease and in individuals with differing hemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free-radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition and RBC membrane Na+-K+ ATPase activity. Statistical analysis was done by ANOVA. In patients with inflammatory bowel disease there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Inflammatory bowel disease is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to immune activation, defective glycoprotein bowel antigen presentation, and autoimmunity and a schizophreniform psychosis important in its pathogenesis. The biochemical patterns obtained in inflammatory bowel disease is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with peptic ulcer disease were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Inflammatory bowel disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

Adult↗
PubMed2006

Modular DAG-RNN architectures for assembling coarse protein structures.

We develop and test machine learning methods for the prediction of coarse 3D protein structures, where a protein is represented by a set of rigid rods associated with its secondary structure elements (alpha-helices and beta-strands). First, we employ cascades of recursive neural networks derived from graphical models to predict the relative placements of segments. These are represented as discretized distance and angle maps, and the discretization levels are statistically inferred from a large and curated dataset. Coarse 3D folds of proteins are then assembled starting from topological information predicted in the first stage. Reconstruction is carried out by minimizing a cost function taking the form of a purely geometrical potential. We show that the proposed architecture outperforms simpler alternatives and can accurately predict binary and multiclass coarse maps. The reconstruction procedure proves to be fast and often leads to topologically correct coarse structures that could be exploited as a starting point for various protein modeling strategies. The fully integrated rod-shaped protein builder (predictor of contact maps + reconstruction algorithm) can be accessed at http://distill.ucd.ie/.

Algorithms↗
PubMed1999

In vitro comparison of salbutamol hydrofluoroalkane (Airomir) metered dose inhaler aerosols inhaled during pediatric tidal breathing from five valved holding chambers.

Amounts of salbutamol delivered from chlorofluorocarbon (CFC)-free metered dose inhalers (MDIs) (Airomir; 3M, St. Paul, MN) in particle sizes appropriate for inhalational treatment with five common holding chambers (NES [or Nebuchamber] spacer [Astra Draco AB, Lund, Sweden], AeroChamber [Trudell Medical, London, Ontario, Canada], OptiChamber [Health-scan Products, Cedar Grove, NJ], Vent170 spacer [Nordac Design, Waterloo, Ontario, Canada], and E-Z Spacer [WE Pharmaceuticals, Ramona, CA]) when used under simulated pediatric tidal breathing conditions were determined. Five devices of each type were tested with Airomir hydrofluoroalkane (HFA) inhalers (100 micrograms of salbutamol). Each device was connected to face replicas representative of 7-month-old (infant) and 2-year-old (toddler) children, and aerosol was also inhaled into an Andersen cascade impactor (Graseby Andersen, Smyrna, GA) using a valve system and simulated tidal breathing patterns representative of children of these ages. Amounts of drug inhaled in fine particles with the HFA formulation are significantly less (up to 46% less) with the E-Z Spacer (P < 0.01) compared with amounts inhaled in previous studies with the CFC formulation but are nearly the same with other holding chamber types (e.g., differing by < 6% for the AeroChamber). With the HFA formulation, the metal NES spacer delivered significantly more salbutamol in fine particles (P < 0.01) than any of the other holding chambers. Amounts of salbutamol inhaled in fine particles during pediatric tidal breathing from valved holding chambers with Airomir varies considerably between holding chamber types.

Aerosols↗
PubMed2002

Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel.

New solubilizers, including Sorporol 230, Sorporol 120Ex, Aceporol 345-T, Aceporol 460 and Riciporol 335, as potential new delivery vehicles for paclitaxel were investigated, since recent studies have shown that the paclitaxel delivery vehicle Cremophor EL significantly alters the pharmacokinetics of paclitaxel. Cremophor EL and Tween 80 were used as a reference. As in the case of Cremophor EL, alteration of blood distribution of paclitaxel occurred in the presence of all tested vehicles. Also, no differences in the affinity of paclitaxel for the tested solubilizers was found during equilibrium dialysis experiments. The different vehicles could be distinguished by a different rate of esterase-mediated breakdown, which was correlated with the fatty acid content of the solubilizers. The activation of the complement cascade was less pronounced for all solubilizers, except Riciporol 335, compared to Cremophor EL. The strategies presented here provide the possibility to rapidly screen future candidate delivery vehicles with optimal characteristics for use as a solubilizer in clinical formulations of paclitaxel or other poorly water-soluble drugs.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Expression, crystallization and crystallographic analysis of DegS, a stress sensor of the bacterial periplasm.

Regulated proteolysis is a key event in transmembrane signalling between intercellular compartments. In Escherichia coli, a protein DegS has been identified as being a periplasmic stress sensor for unfolded or misfolded outer membrane proteins (OMPs). Activation of DegS initiates a proteolytic cascade which results in the transcription of periplasmic genes under sigmaE control, most importantly chaperones and proteases. DegS has been cloned and expressed as full-length protein and in an N-terminally truncated form. Both proteins were tested for crystallization and two forms of well diffracting crystals of the truncated form were obtained. Crystals of form I diffract to 3.5 A and belong to space group P2(1)3, while crystals of form II diffract to 2.2 A and belong to space group I23. Crystals of form II were soaked with a consensus peptide representing the C-termini of outer membrane proteins and data to 2.4 A resolution were collected. Molecular-replacement trials using a homologous protease domain indicate the presence of two molecules in the asymmetric unit of crystal form I. The correctness of the molecular-replacement solution was verified by identifying radiation-damage-induced structural changes.

Crystallization↗
PubMed2001

Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.

Stem cells, which regenerate tissue by producing differentiating cells, also produce cells that renew the stem cell population. Signals from regulatory microenvironments (niches) are thought to cause stem cells to retain self-renewing potential. However, the molecular characterization of niches remains an important goal. In Drosophila testes, germ line and somatic stem cells attach to a cluster of support cells called the hub. The hub specifically expresses Unpaired, a ligand activating the JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling cascade. Without JAK-STAT signaling, germ line stem cells differentiate but do not self-renew. Conversely, ectopic JAK-STAT signaling greatly expands both stem cell populations. We conclude that the support cells of the hub signal to adjacent stem cells by activation of the JAK-STAT pathway, thereby defining a niche for stem cell self-renewal.

Animals↗
PubMed2004

Anti-inflammatory properties of BHUx, a polyherbal formulation to prevent atherosclerosis.

BHUx is a polyherbal formulation consisting of water-soluble fractions of five medicinal plants (Commiphora mukul, Terminalia arjuna, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica). The present study was undertaken to evaluate its antioxidant and antiinflammatory effects. BHUx, standardized by HPLC fingerprinting and filtered through 0.2 microm filter paper, was employed for different studies under in vivo and in vitro conditions. Under in vivo conditions, BHUx significantly reduced inflammation in the carrageenan-induced rat paw oedema model of inflammation, suggesting its anti-inflammatory properties. In order to test the mechanism of action of BHUx, further in vitro studies were undertaken on cumene-hydroperoxide-induced lipid peroxidation (CHP) in liver homogenate, LPS-induced NO production in peritoneal macrophages and on key enzymes of arachidonic acid cascade, involved in the mediation of inflammation. Under the conditions, BHUx showed concentration-dependent inhibition of CHP-induced lipid peroxidation in liver homogenate, suggesting its antioxidant properties. Similarly the potent anti-inflammatory effects of BHUx are evident by (a) preferential inhibition of COX-2 (IC50 for COX-2 = 80 microg/ml and IC50 for COX-1 = 169 microg/ml), (b) low ratios in the IC50 values of COX-2/COX-1 (0.47), (c) decreased production of NO in LPS-induced peritoneal macrophages and (d) inhibition of 5-LOX (IC50 = 795 microg/ml). BHUx also showed a preference for inhibiting 15-lipoxygenase (IC50 = 44 microg/ml), a key enzyme implicated in LDL oxidation. These studies suggest that BHUx is acting mainly at three levels, i.e., as a potent natural antioxidant, by reduction of key inflammatory mediators of arachidonic acid cascade and by preventing 15-LOX-mediated LDL oxidations, to prevent atherosclerosis.

Analgesics↗
PubMed2001

Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas.

A large east Texas family with autosomal dominant inheritance of a novel bleeding disorder has been identified. The disorder is characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors are all within normal limits. To determine the molecular basis of this disease, a candidate gene linkage analysis in this kindred was done. Initially it was hypothesized that the cause of the disease in this family could be an antithrombin III (AT3) mutation that resulted in a constitutively active AT3 in the absence of heparin binding. Linkage studies using DNA from the family and an intragenic polymorphic marker within the AT3 gene showed that the disease mapped to this locus. The coding region and intron/exon junctions of AT3 were sequenced using the proband's DNA, but this analysis failed to identify a mutation. Additional family members were recruited for the study, and 16 polymorphic markers around the AT3 gene were analyzed. Using 2 recombinants, the critical interval for the defective gene was narrowed to approximately 1.5 Mb, centromeric to AT3. The factor V (FV) gene was mapped into the disease interval and sequenced; there were no mutations found. Elucidation of the genetic defect causing the bleeding disorder in this family may reveal a novel protein involved in the coagulation cascade.

Adult↗
PubMed2002

Lowering anti-dsDNA antibodies--what's new?

Antibodies to dsDNA are specific to SLE and are pathogenic, both due to their ability to deposit in tissues through a variety of mechanisms, and to their ability, when present in immune complexes, to activate inflammatory cells. The relationship of serum anti-dsDNA antibody levels to disease activity is a complex one and the factors that determine whether or not such antibodies will be pathogenic in an individual SLE patient are incompletely understood. Although anti-dsDNA antibodies can be made by naïve B cells and B cells belonging to the B1 and marginal zone subsets, pathogenic anti-dsDNA antibodies have the hallmarks of germinal center development and exposure to T cell help, including accumulation of somatic mutations and class switching to the IgG isotype. Epitope spreading may result in aquisition of cross-reactivities with multiple target organ antigens and aquisition of a memory phenotype will allow these B cells to acquire antigen presentation functions that amplify the autoreactive response. In the early stages of disease, or after remission induction protocols, autoreactive B cells may be susceptible to treatments that target T cell costimulation or that deplete or tolerize naïve and mature B cells. Therapeutic approaches targeting innate immune responses or regulatory T cells are starting to be tested in pre-clinical models. In later disease stages, memory and plasma cell accumulation may render patients more resistant to this type of therapeutic approach. Deposition of anti-dsDNA antibodies in target tissues can stimulate an inflammatory cascade that leads to tissue damage. A number of murine models have now been developed that show that interruption of this cascade can prevent or reverse such damage. This type of approach may be beneficial for individuals with established disease. As we learn more about the specific defects that cause SLE, it may become possible to individualize therapy based on patient specific biologic markers.

Animals↗