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B-lymphocyte subpopulations are equally susceptible to Epstein,Barr virus infection, irrespective of immunoglobulin isotype expression

IMMUNOLOGY, Issue 4 2003
Barbro Ehlin-Henriksson
Summary While Epstein,Barr virus (EBV) is known to establish latency in the memory B-cell compartment, there is controversy as to whether the memory or the naïve B cell is the initial target for infection. Here we have explored the infectability of the B-cell subsets contained in peripheral blood and tonsils, as distinguished by their surface expression of the immunoglobulin isotypes that help to define naïve and memory pools. First we show that both CD21 and major histocompatibility complex (MHC) class II molecules , respectively, the major receptor and co-receptor for EBV on B cells , are expressed at similar levels on blood and tonsillar B cells, irrespective of surface immunoglobulin class, indicating that each of the subsets demonstrate an equal potential, at least for infection. Then, following in vitro infection of total tonsillar B cells, we found that the relative frequencies of immunoglobulin (Ig)M-, IgG- and IgA-positive cells containing EBV-encoded Epstein,Barr virus nuclear antigen 5 (EBNA5) protein at 48 hr were similar to those of the starting population. However, IgD expression was uniformly decreased, probably as a consequence of cellular activation. These data indicate that recirculating B cells have both the potential for, and susceptibility to, initial infection by EBV, irrespective of the immunoglobulin isotype expressed. [source]

Ethanol-Induced Cephalic Apoptosis Requires Phospholipase C-Dependent Intracellular Calcium Signaling

ALCOHOLISM, Issue 3 2003
Katherine A. Debelak-Kragtorp
Background: Although the ability of ethanol to elicit neural crest cell apoptosis is well documented, the initial target of ethanol in these cells, and the biochemical pathway leading to their apoptosis, have yet to be determined. Recent work in preimplantation mouse embryos demonstrates that ethanol induces a phospholipase-C (PLC)-dependent calcium transient that mediates ethanol's effects. We tested whether a similar effect on calcium and PLC is involved in ethanol-induced neural crest apoptosis. Methods: Chicken embryos were collected and loaded with Fluo-3-AM to assess the effects of ethanol on intracellular calcium levels. Pharmacological agents were used to determine the sources and mechanism of intracellular calcium increases. In separate experiments, embryos were treated in ovo with pharmacological modulators of calcium signaling prior to ethanol exposure, and resulting levels of cell death were assessed by using the vital dye acridine orange. Results: Ethanol exposure caused a localized increase in intracellular calcium levels in embryonic neural folds within 15 sec of ethanol exposure. Ethanol-induced apoptosis was specifically blocked by chelation of intracellular calcium before ethanol exposure. Pretreatment with the PLC inhibitor U73122 blocked ethanol-induced apoptosis as well as the intracellular calcium transient. Depletion of extracellular calcium resulted in a partial block of ethanol-induced apoptosis. Conclusions: Ethanol exposure alters calcium signaling within the neurulation-stage chicken embryo in a PLC-dependent manner. Increases in intracellular calcium and PLC activity are necessary for ethanol's induction of apoptosis within cephalic populations. These effects likely represent an early and crucial event in the pathway leading to ethanol-induced cell death. [source]

Post-translational modifications of the major linear epitope 169,190aa of Ro60 kDa autoantigen alter the autoantibody binding

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2006
A. G. Terzoglou
Summary Ro60 kDa is a member of the Ro/LaRNP ribonucleoprotein complex and its major linear B cell epitope, corresponding to the region 169,190aa, has been found to be the initial target of the autoimmune response in patients with systemic lupus erythematosus. This sequence contains one serine and two arginine amino acid residues, which can potentially be modified post-translationally by phosphorylation or citrullination, respectively. The aim of this study was to develop an immunoassay for anti-Ro60 kDa epitope antibody detection and to investigate the changes in the antigenicity of the Ro60 kDa epitope when it is post-translationally modified, by either citrullination or phosphorylation. Peptide analogues corresponding to the unmodified form of the epitope, its phosphorylated form, and a form with both arginine residues citrullinated were synthesized. The peptide coating conditions were investigated and it was found that the use of highly hydrophilic surfaces increase the efficiency of the coating, as well as the sensitivity of the method for anti-peptide antibody detection. All peptides were tested by the optimized enzyme-linked immunosorbent assay (ELISA) against 119 sera from patients with primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis with anti-Ro/SSA reactivity, 20 sera from patients with systemic diseases without anti-Ro/SSA immune reactivity, as well as against 65 sera from normal individuals. A large proportion of the tested sera reacted against all three peptide analogues, although with a preference for the unmodified form of the epitope. In conclusion, post-translational modifications of the major Ro60 kDa B cell epitope can alter the autoantibody binding. [source]

Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus

ARTHRITIS & RHEUMATISM, Issue 3 2009
Brian D. Poole
Objective The U1 small nuclear RNPs are common targets of autoantibodies in lupus and other autoimmune diseases. However, the etiology and progression of autoimmune responses directed against these antigens are not well understood. The aim of this study was to use a unique collection of serial samples obtained from patients before and after the development of nuclear RNP (nRNP) antibodies to investigate early humoral events in the development of anti-nRNP autoimmunity. Methods Lupus patients with sera available from both before and after the development of nRNP antibody precipitin were identified from the Oklahoma Clinical Immunology Serum Repository. Antibodies in the serial samples were analyzed by enzyme-linked immunosorbent assay, Western blotting, solid-phase epitope mapping, and competition assays. Results The first-detected nRNP antibodies targeted 6 common initial epitopes in nRNP A, 2 in nRNP C, and 9 in nRNP 70K. The initial epitopes of nRNP A and nRNP C were significantly enriched for proline and shared up to 95% sequence homology. The initial nRNP 70K humoral epitopes differed from those of nRNP A and nRNP C. The initial antibodies to nRNP A and nRNP C were cross-reactive with the SmB,-derived peptide PPPGMRPP. Antibody binding against all 3 nRNP subunits diversified significantly over time. Conclusion Autoantibodies to nRNP A and nRNP C initially targeted restricted, proline-rich motifs. Antibody binding subsequently spread to other epitopes. The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading. [source]