R-matrix Floquet theory for laser-assisted electron-atom scattering

A new version of the R-matrix Floquet theory for laser-assisted electron-atom scattering is presented. The theory is non-perturbative and applicable to a non-relativistic many-electron atom or ion in a homogeneous linearly polarized field. It is based on the use of channel functions built from field-dressed target states, which greatly simplifies the general formalism.Comment: 18 pages, LaTeX2e, submitted to J.Phys.

Electron exchange model potential: Application to positronium-helium scattering

The formulation of a suitable nonlocal model potential for electron exchange is presented, checked with electron-hydrogen and electron-helium scattering, and applied to the study of elastic and inelastic scattering and ionization of ortho positronium (Ps) by helium. The elastic scattering and the $n = 2$ excitations of Ps are investigated using a three-Ps-state close-coupling approximation. The higher ($n\ge 3$) excitations and ionization of Ps atom are treated in the framework of Born approximation with present exchange. Calculations are reported of phase shifts, and elastic, Ps-excitation, and total cross sections. The present target elastic total cross section agrees well with experimental results at thermal to medium energies.Comment: 16 latex pages, 7 postscript figure

Predicting Hemagglutinin MHC-II Ligand Analogues in Anti-TNFα Biologics: Implications for Immunogenicity of Pharmaceutical Proteins

<div><p>The purpose of this study was to evaluate the extent of overlapping immunogenic peptides between three pharmaceutical biologics and influenza viruses. Clinical studies have shown that subsets of patients with rheumatoid arthritis (RA) develop anti-drug antibodies towards anti-TNFα biologics. We postulate that common infectious pathogens, including influenza viruses, may sensitize RA patients toward recombinant proteins. We hypothesize that embedded within infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are ligands of class II major histocompatibility complex (MHC-II) that mimic T cell epitopes derived from influenza hemagglutinin (HA). The rationale is that repeated administration of the biologics would reactivate HA-primed CD4 T cells, stimulating B cells to produce cross-reactive antibodies. Custom scripts were constructed using MATLAB to compare MHC-II ligands of HA and the biologics; all ligands were predicted using tools in Immune Epitope Database and Resources (IEDB). We analyzed three HLA-DR1 alleles (0101, 0401 and 1001) that are prominent in RA patients, and two alleles (0103 and 1502) that are not associated with RA. The results indicate that 0401 would present more analogues of HA ligands in the three anti-TNFα biologics compared to the other alleles. The approach led to identification of potential ligands in IFX and ADA that shares sequence homology with a known HA-specific CD4 T cell epitope. We also discovered a peptide in the complementarity-determining region 3 (CDR-3) of ADA that encompasses both a potential CD4 T cell epitope and a known B cell epitope in HA. The results may help generate new hypotheses for interrogating patient variability of immunogenicity of the anti-TNFα drugs. The approach would aid development of new recombinant biologics by identifying analogues of CD4 T cell epitopes of common pathogens at the preclinical stage.</p></div

HA analogues in infliximab (IFX) heavy (HC) and light (LC) chains.

<p>The heavy chain was analyzed for (a) RA-associated HLA alleles (0101, 0401 and 1001) and (b) non-RA associated alleles (0103 and 1502). The light chain was also analyzed for (c) RA-associated HLA alleles (0101, 0401 and 1001) and (d) non-RA associated alleles (0103 and 1502). Matching biologic and viral ligand pairs are placed based on degrees of similarity and predicted relative binding strengths to the HLA allele. Each point represents a matching pair, identified based on their unique coordinates: the percentile ranking of a biologic sequence to the MHC allele (<i>P</i>_<i>d</i>; x-axis), percentile ranking of the HA peptide homologous to the biologic sequence, to the same allele (<i>P</i>_<i>v</i>; y-axis). Open blue circles represent biologic sequences that share 8 (out of 15) identical and similar amino acids (as defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.t001" target="_blank">Table 1</a>) with a HA ligand, whereas closed circles in red indicate pairs with at least 9 identical or similar amino acids. Arrows labeled “NLE” or “PAV” point to analogues in biologics that mimic the influenza CD4 T cell epitope HA_530–541 (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.t003" target="_blank">Table 3</a>). Only the Fab regions were considered. Analyses for pre-2009 HA sequences (PA10 and NY1050) can be found in S4. Datasets containing the sequences can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s005" target="_blank">S5 Fig</a></p

HA analogues in adalimumab (ADA) heavy (HC) and light (LC) chains.

<p>The heavy chain was analyzed for (a) RA-associated HLA alleles (0101, 0401 and 1001) and (b) non-RA associated alleles (0103 and 1502). The light chain was analyzed for (c) RA-associated HLA alleles (0101, 0401 and 1001) and (d) non-RA associated alleles (0103 and 1502). X axis and Y axis are defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.g003" target="_blank">Fig 3</a> legend. Only the Fab regions were considered. Arrows labeled “YCA” or “PAV” point to analogues in biologics that mimic the influenza CD4 T cell epitope HA_530–541 (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.t003" target="_blank">Table 3</a>). Analyses for pre-2009 HA sequences (PA10 and NY1050) can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s004" target="_blank">S4 Fig</a> Datasets containing the sequences can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s005" target="_blank">S5 Fig</a>.</p

Predicting Hemagglutinin MHC-II Ligand Analogues in Anti-TNFα Biologics: Implications for Immunogenicity of Pharmaceutical Proteins - Fig 6

<p>(a) Molecular representation of an ADA analogue that resembles a known B cell epitope in HA Zhao et al. (2011) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.ref049" target="_blank">49</a>]. The ADA CDR3 peptide was mapped to the B cell epitope by searching for known epitopes in IEDB. Images were generated using Molecular Operating Environment (MOE). Crystal structures of HA (PDB entry: 4M4Y, residues 174–182) and ADA (PDB entry: 3WD5, heavy chain residues 102–111) were used in the modeling. (b) The distances between the Cβ of the first and last amino acids are 14.55 and 15.64 Angstroms in ADA HC and HA, respectively. Locations of the side chains were labeled with single amino acid letter codes.</p

HA analogues in etanercept (ETN).

<p>The polypeptide was analyzed for (a) RA-associated HLA alleles (0101, 0401 and 1001) and (b) non-RA associated alleles (0103 and 1502). The entire polypeptide, inclusive of TNFR and IgG1 CH2 and CH3, were considered. X axis and Y axis are defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.g003" target="_blank">Fig 3</a> legend. Analyses for pre-2009 HA sequences (PA10 and NY1050) can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s004" target="_blank">S4 Fig</a> Datasets containing the sequences can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s005" target="_blank">S5 Fig</a></p

Comparison of HA ligand analogues in anti-TNFα biologics^a.

<p>^aCorresponds in part to datasets <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s004" target="_blank">S4</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#pone.0135451.s005" target="_blank">S5</a> Figs.</p><p>^bTotal number of analogues mapped (8 of 15 identical or similar amino acids) to HA ligands; biologic and viral ligands are ranked within the 10^th percentile were tallied</p><p>^cNumber of sequences containing at least 9 (out of 15) identical or similar amino acids mapped to a HA ligand.</p><p>Comparison of HA ligand analogues in anti-TNFα biologics<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135451#t002fn001" target="_blank">^a</a>.</p

Schematic depiction of strategy used in identifying analogues of MHC class II ligands in HA sequences and anti-TNFα biologics.

<p>Analogues were identified from five anti-TNFα biologics polypeptides (heavy and light chains), five HLA-DR1 alleles, and five H1N1 influenza-HA sequences.</p