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Anthony Quinn

Publications and source records attributed to Anthony Quinn.

16 recordsLinked to original sources
PubMed2006

Dominant CTL-inducing epitopes on GAD65 are adjacent to or overlap with dominant Th-inducing epitopes.

Immune responses to GAD65 are associated with progression to T1D in NOD mice and humans. Our previous data suggested that dominant CTL-inducing and Th-inducing determinants might preferentially occur in proximal GAD65 sequences. Using a panel of 192 GAD65 peptides we discovered that four of the eight CTL-inducing peptides, including those most biologically relevant, were proximal to previously described I-A(g7)-restricted determinants that characterize natural islet autoimmunity in NOD mice. The CTL determinants 546-554 and 88-98 were presented by GAD65-expressing cells and were displayed on pancreatic LNC, along with 268-278, following beta cell damage. p546-554-specific CTL were detectable in young naive mice and transferred significant islet inflammation into NOD.scid mice. These findings demonstrate that unique regions of GAD65 may be favored during antigen processing, such that diverse dominant epitopes are produced from overlapping sequences, which can engage distinct T cell subsets. Additionally, cross-presentation may enhance GAD65-specific CTL responses in T1D.

Amino Acid Sequence↗
PubMed2006

Altered susceptibility to EAE in congenic NOD mice: Altered processing of the encephalitogenic MOG35-55 peptide by NOR/LtJ mice.

NOD mice (H-2 g7) naturally develop autoimmune diabetes, while the congenic NOR/LtJ mice (H-2 g7) are resistant. To determine if defective immune regulation renders NOD susceptible to autoimmune disease, we compared MOG35-55-induced EAE in NOD mice to that of NOR/LtJ. In two of three immunization protocols, the NOR/LtJ mice developed significantly reduced indices and severity of clinical disease, in spite of an exaggerated autoimmune response to MOG35-55. Characterization of the responding T cell repertoires revealed that V beta 8+ Th cells directed toward the MOG42-55 core epitope were dominant in both strains. Interestingly, CD8+ CTL were absent or significantly reduced in MOG35-55 lymphoblasts from NOR/LtJ mice, which poorly processed the MOG39-47 CTL epitope from MOG35-55. Thus, while particular MHC class II alleles may be associated with increased risk, molecules involved in the processing of key epitopes may be influential in the progression of autoimmune disease.

Animals↗
PubMed2006

Assembly of ultrathin polymer multilayer films by click chemistry.

Layer-by-layer (LbL) assembly is a versatile and robust technique for fabricating tailored thin films of diverse composition. Herein we report a new method of covalent coupling, click chemistry, to facilitate the LbL assembly of thin films. Linear film growth was observed using both UV-vis and FTIR spectroscopy, and film thicknesses were determined by ellipsometry and atomic force microscopy. The assembled films are shown to be stable in a wide pH range. This technique offers the potential to enable the synthesis of new types of stable and responsive LbL films from a variety of polymers.

Journal Article↗
PubMed2006

T cells to a dominant epitope of GAD65 express a public CDR3 motif.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes, and serve as a model for type 1 diabetes (T1D) and natural autoimmunity. T cell responses to the pancreatic islet antigen glutamic acid decarboxylase 65 (GAD65) can be detected in the spleens of young prediabetic NOD mice, which display a unique MHC class II molecule. Here, we report that a distinct TcR beta chain and CDR3 motif are utilized by all NOD mice in response to a dominant determinant on GAD65, establishing a public repertoire in the spontaneous autoimmunity to an important islet cell antigen. GAD65 530-543 (p530)-reactive T cells preferentially utilize the Vbeta4, Dbeta2.1 and Jbeta2.7 gene segments, with a CDR3 that is characterized by a triad of amino acids, DWG, preceded by a polar residue. In addition, we used CDR3 length spectratyping, CDR3-specific reverse transcriptase-PCR and direct TcR sequencing to show that the TcR beta chain structural patterns associated with p530-specific T cells consistently appeared in the islets of young NOD mice with insulitis, but not in the inflamed islets of streptozotocin-treated C57BL/6 mice, or in inflamed NOD salivary glands. To our knowledge, this is the first report to demonstrate that a public T cell repertoire is used in spontaneous autoimmunity to a dominant self-determinant. These findings suggest that defined clonotypes and repertoires may be preferentially selected in haplotypes predisposed to spontaneous autoimmunity.

Amino Acid Motifs↗
PubMed2005

Insulin-dependent diabetes loci Idd5 and Idd9 increase sensitivity to experimental autoimmune encephalomyelitis.

The spontaneous development of autoimmune diabetes in NOD mice suggests that they are unable to establish and maintain immunologic self-tolerance. Congenic NOD mice expressing B10-derived alleles are protected from pancreatic beta cell destruction and autoimmune diabetes. To determine if the B10 alleles in loci Idd5 and Idd9 could influence susceptibility to autoimmunity in other organs, we compared MOG35-55-induced EAE in NOD mice to that of diabetes-resistant NOD.B10.Idd5 and NOD.B10.Idd9 mice. Surprisingly, the severity and chronicity of EAE were enhanced in the diabetes-resistant congenic mice. Our findings indicate that some alleles may influence susceptibility to immune-mediated damage in an organ or tissue-specific fashion, and highlight the necessity of disease-specific investigations.

Animals↗
PubMed2005

Contact angle saturation in electrowetting.

Electrowetting is the phenomenon of contact angle decrease under the influence of an external voltage applied across the solid/liquid interface. Electrowetting offers an interesting possibility to enhance the wettability of hydrophobic materials without altering the chemical composition of the system and thus could be incorporated in various microfluidic devices. Electrowetting is fundamentally an electrocapillary effect occurring on an insulated solid electrode (hence the change of the solid/liquid interfacial tension with voltage follows Lippmann's equation). A limiting contact angle value larger than zero is achieved even at very large external voltages. Saturation precludes full wetting of the substrate and restricts the magnitude of the capillary force variation. Contact angle saturation has been given various interpretations (e.g., charge trapping, air ionization) but appears to reflect a natural thermodynamic limit rather than being simply a defective property. The limiting value of the contact angle is given by the Young equation when the value of the solid/liquid interfacial tension reaches zero. The model is in excellent agreement with our own results and often gives an adequate description of published data. It also suggests that the saturation limit is determined by the material properties of the system and electrowetting at voltages exceeding this threshold is essentially a nonequilibrium process.

Electrochemistry↗
PubMed2004

Molecular profile of the T cell receptors of regulatory and effector CD4+ T cells recognizing overlapping determinants on glutamic acid decarboxylase (524-543).

Glutamic acid decarboxylase (GAD65) is one of the autoantigens that initiates pathogenic T cell responses against insulin-secreting pancreatic beta cells in Type 1 diabetes (T1D). Previously it was shown that spontaneously arising pathogenic T cell responses in the NOD mouse model are confined to GAD530-543 (p530). However, regulatory T cell subpopulations, which can prevent diabetes, can also be generated, for example, by immunization with GAD524-538 (p524) or GAD524-543. Interestingly, two functionally distinct subpopulations of T cells which recognize overlapping determinants of GAD524-543, p524 and p530, utilize distinct TCR Vbeta families, Vbeta4 for pathogenic, and Vbeta12 for regulatory T cells. We characterized T cell receptors (TCRs) from each subpopulation of T cells and visualized p524-specific TCR/p524/I-A(g7) and p530-specific TCR/p530/I-A(g7) complexes via molecular modeling to help us understand, at a molecular level, the in vivo expansion of p524- or p530-specific T cells in the NOD model of T1D. The absolute restriction in Vbeta usage but not Valpha usage and conserved CDR3beta lengths for both T cell subpopulations demonstrates that the beta chains are main contributors in shaping both p524/I-A(g7) and p530/I-A(g7) restricted TCRs. However, only Vbeta4+ T cells but not Vbeta12+ T cells contain a common motif (DWG) in CDR3beta and may involve all of CDR1beta, CDR2beta, and CDR3beta in the recognition of the C-terminus of p530. These observations imply that the spontaneously arising p530-restricted TCRs may be selected under stringent structural frameworks to bind p530/I-A(g7) with high affinity. Thus, the pathogenic p530-specific T cells may arise from a small pool of autoreactive T cells upon breaking tolerance.

Amino Acid Motifs↗
PubMed2004

Epidermal and hair follicle progenitor cells express melanoma-associated chondroitin sulfate proteoglycan core protein.

Basal keratinocytes in the epidermis and hair follicle are biologically heterogeneous but must include a stable subpopulation of epidermal stem cells. In animal models these can be identified by their retention of radioactive label due to their slow cycle (label-retaining cells) but human studies largely depend on in vitro characterization of colony forming efficiency and clonogenicity. Differential integrin expression has been used to detect cells of increased proliferative potential but further stem cell markers are urgently required for in vivo and in vitro characterization. Using LHM2, a monoclonal antibody reacting with a high molecular weight melanoma-associated proteoglycan core protein, a subset of basal keratinocytes in both the interfollicular epidermis and the hair follicle has been identified. Coexpression of melanoma-associated chondroitin sulfate proteoglycan with keratins 15 and 19 as well as beta 1 and alpha 6 integrins has been examined in adult and fetal human skin from hair bearing, nonhair bearing, and palmoplantar regions. Although melanoma-associated chondroitin sulfate proteoglycan coexpression with a subset of beta 1 integrin bright basal keratinocytes within the epidermis suggests that melanoma-associated chondroitin sulfate proteoglycan colocalizes with epidermal stem cells, melanoma-associated chondroitin sulfate proteoglycan expression within the hair follicle was more complex and multiple subpopulations of basal outer root sheath keratinocytes are described. These data suggest that epithelial compartmentalization of the outer root sheath is more complex than interfollicular epidermis and further supports the hypothesis that more than one hair follicle stem cell compartment may exist.

Animals↗
PubMed2004

GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter.

Sonic hedgehog (Shh) binds to its receptor patched (PTCH), leading to the activation and repression of target genes via the GLI family of zinc-finger transcription factors. Deregulation of the Shh pathway is associated with basal cell carcinoma (BCC) due to upregulation of GLI1 and GLI2. We recently demonstrated a positive feedback loop between GLI1 and GLI2, which revealed that GLI1 may be a direct target of GLI2. Using band shift and luciferase reporter assays, we now show that GLI2 binds the GLI-binding consensus sequence in the GLI1 promoter. These data suggest that GLI2 directly activates GLI1 and that retrovirally expressed GLI2 induces expression of endogenous GLI1 in human primary keratinocytes. Finally, using in situ hybridization, we show that GLI2 is expressed in the interfollicular epidermis and the outer root sheath of hair follicles in normal skin as well as in BCC tumor islands. These results suggest an important role for GLI2 in regulating epidermal proliferation and skin tumorigenesis.

Base Sequence↗
PubMed2004

Therapeutic potential of targeting IL-1 and IL-18 in inflammation.

Interleukin (IL)-1 and IL-18 are cytokines that play a major role in autoimmune and inflammatory human disease. Both cytokines drive a wide range of pro-inflammatory effector networks in many cell types and use common signal transduction cascades. IL-1, IL-18 and other members of the IL-1 superfamily are expressed at elevated levels in tissue and fluid samples isolated from patients with many chronic inflammatory diseases. These cytokines are primary drivers in acute and chronic animal models of inflammation and their blockade has been shown to ameliorate disease in preclinical studies. Biological agents that target IL-1 have demonstrated efficacy in patients with rheumatoid arthritis, and further agents targeting IL-1 or IL-18 neutralisation are in clinical development. The potential for such agents spans human disease where tissue destruction is a primary end point of cytokine action.

Antibodies↗
PubMed2002

Induction of myocarditis and valvulitis in lewis rats by different epitopes of cardiac myosin and its implications in rheumatic carditis.

Immune responses against cardiac myosin and group A streptococcal M protein have been implicated in the pathogenesis of rheumatic heart disease. Although cardiac myosin is known to produce myocarditis in susceptible animals, it has never been investigated for its role in production of valvular heart disease, the most serious sequelae of group A streptococcal infection in acute rheumatic fever. In our study, cardiac myosin induced valvulitis in the Lewis rat, and epitopes responsible for production of valvulitis were located in the rod region. Human and rat cardiac myosins induced severe myocarditis in the Lewis rats as expected. A purified S2 fragment (amino acid sequences 842 to 1295) produced the most severe myocarditis as well as valvulitis. Different regions of light meromyosin produced valvulitis (residues 1685 to 1936) or myocarditis (residues 1529 to 1611). Because streptococcal M proteins produced valvular heart disease in Lewis rats and have been linked to anti-cardiac myosin responses, we reacted myosin-sensitized lymphocytes isolated from the hearts of Lewis rats with peptides of streptococcal M5 protein in tritiated thymidine assays. Infiltrating lymphocytes responded most strongly to peptides within the B repeat region of streptococcal M protein. These data show direct evidence that immune responses against cardiac myosin lead to valvular heart disease and the infiltration of the heart by streptococcal M protein reactive T lymphocytes.

Animals↗
PubMed2002

Effect of Honan balloon compression on peribulbar anesthesia adequacy in cataract surgery.

PURPOSE: To ascertain whether a Honan balloon is necessary to produce effective peribulbar anesthesia in routine cataract surgery by evaluating its effect on intraocular pressure (IOP), surgeon assessment of the anesthesia's effectiveness, and patients' analgesic experience. SETTING: West of England Eye Unit, Royal Devon and Exeter Hospital, England. METHOD: Fifty eyes of 50 patients having routine phacoemulsification cataract extraction and intraocular lens implantation were randomized to have 10-minute ocular compression with the Honan balloon or no compression after peribulbar anesthesia. A single investigator gave all the peribulbar injections using a standard technique. The IOP was measured immediately before and 10 minutes after the injections. Two surgeons who were blinded to the randomization process performed the surgeries and completed an assessment questionnaire on various aspects of the peribulbar block. The patients also scored their level of analgesia during surgery. RESULTS: In the 26 patients who had Honan balloon compression, there was a significant reduction in IOP (mean 6.2 mm Hg; P <.05). In the 24 patients with no balloon compression, there were no significant changes in IOP 10 minutes after the peribulbar injections. There was no statistically significant difference in the surgeons' scores in any aspect of the peribulbar anesthesia (P >.05). All patients experienced a good level of analgesia. CONCLUSIONS: There was a significant reduction in IOP after Honan balloon ocular compression. However, there was no significant increase in IOP without balloon compression. The use of a Honan balloon did not appear to make a significant difference in the effectiveness of the peribulbar anesthesia to the surgeons or patients.

Aged↗
PubMed2002

Strain-dependent effect of nasal instillation of antigen on the immune response in mice.

BACKGROUND: Nasal instillation is an effective method for inducing antigen-specific immune tolerance. However, it is not clear how a tolerization scheme established in one mouse strain will perform when used in a mouse of a different haplotype. OBJECTIVES: To compare the antigen-specific recall responses in four mouse strains--BALB/c, C57BL/6, NOD, and B10.PL--that were pretreated nasally with 50 micrograms of hen egg-white lysozyme prior to parenteral immunization with homologous antigen. METHODS: Mice were nasally treated with a prototype antigen, HEL, and then immunized with the same antigen emulsified in complete Freund's adjuvant. Spleens and lymph nodes were assayed for T cell proliferation measured by tritiated thymidine incorporation. Cytokine production was measured using ELISPOT assay. Serum antibody response to HEL was measured using an enzyme-linked immunosorbent assay. RESULTS: Proliferative recall responses to HEL in B10.PL, C57BL/6, and BALB/c were greatly reduced compared to control mice, but non-obese diabetic mice were resistant to the tolerization regime. Despite their susceptibility to nasally induced suppression, the mechanisms responsible for tolerance induction differed in BALB/c and C57BL/6 mice. CONCLUSIONS: Our findings demonstrate that while mucosal contacts with specific antigen consistently affect the outcome of subsequent exposure to the same antigen, the observed response will vary non-predictably, depending on the genetic background of the animal.

Animals↗