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PubMed2003

Resting CD8 T cells recognize beta-galactosidase expressed in the immune-privileged retina and mediate autoimmune disease when activated.

Although the expression of class II major histocompatibility complex (MHC) in retina is extremely low, it is an established fact that activated CD4 T cells, specific for retinal antigens (Ags), mediate experimental autoimmune uveoretinitis (EAU). Conversely, CD8 T cells have not been shown to recognize Ag in the retina. This study investigated whether retinal-specific Ags are detected by class I MHC-restricted CD8 T cells. Using a CD8 T-cell clone (beta3) specific for an immunodominant epitope of beta-galactosidase (beta-gal), local Ag recognition was shown by transfer of activated beta3 cells into beta-gal transgenic (Tg) mice expressing beta-gal in the retina (hi-arr-beta-gal mice), or in the brain and eye (GFAP-beta-gal mice). Beta-gal-positive photoreceptor cells were damaged in the retina of hi-arr-beta-gal mice, and anterior segment disease was found in the eyes of GFAP-beta-gal mice. Ag recognition by resting CD8 T cells was also evaluated. Recovery of 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CFSE)-labelled beta3 cells from hi-arr-beta-gal mice was slightly decreased compared to recovery from B10.A mice, while recovery from GFAP-beta-gal mice was transiently increased. Conversely, recovery of CFSE- cells increased in hi-arr-beta-gal mice, consistent with an Ag-dependent response. The CFSE content of the CFSE+ population was unchanged relative to beta3 cells recovered from controls. Intracellular cytokine responses of beta3 cells recovered from hi-arr-beta-gal and GFAP-beta-gal mice correlated with the number of cells recovered, regardless of CFSE content. Even though their production of interferon-gamma and tumour necrosis factor-alpha was affected little by transfer into hi-arr-beta-gal recipients, the ability of beta3 cells to mediate delayed-type hypersensitivity was inhibited in hi-arr-beta-gal mice. These results show that resting CD8 T cells are affected by the presence of Ag that originates in retina and, when activated prior to transfer, mediate pathogenic autoimmunity against retinal and other ocular targets.

Adoptive Transfer↗
PubMed1996

Mucin-1-related T cell infiltration in colorectal carcinoma.

Mucins (MUC) are highly glycosylated molecules widely expressed on epithelia of different origins, including colonic mucosa. Altered glycosylation processes in tumour cells result in the exposure of normally cryptic peptide epitopes, which may then be recognized as tumour-specific antigens. Recently, MUC1-specific antibodies were detected in the serum of a broad range of cancer patients, and from different tumours tumour-specific cytotoxic T lymphocytes (CTL) were isolated that recognized MUC1. Absence of HLA restriction in the recognition has been ascribed to the highly repetitive sequence of the polypeptide core, allowing simultaneous recognition of multiple identical epitopes and cross-linking and aggregation of T cell receptor on mucin-specific T cells. We investigated the expression of MUC1 epitopes in 56 cell suspensions from Dukes' B to D colorectal carcinomas using antibodies that recognize distinct peptide sequences on the glycosylated or deglycosylated MUC1 protein backbone. No relation was observed between MUC1 expression, or the extent of its glycosylation, and Dukes' stage, tumour location and tumour differentiation, but a positive correlation was detected between the percentages of tumour cells expressing mucin-1 and the numbers of CD3+ infiltrating cells. These tumour-infiltrating lymphocytes contained, however, only a few MUC1-specific T lymphocytes, as CTL showing preferential killing of MUC1-expressing target cells were only obtained from one tumour. Since, in addition, the majority of colorectal carcinomas were found to express the fully glycosylated MUC1 glycoprotein, its potential role as a target antigen for T-lymphocyte-mediated immunotherapy in this tumour type is probably limited.

Antibodies, Monoclonal↗
PubMed2002

A Renilla luciferase-Aequorea GFP (ruc-gfp) fusion gene construct permits real-time detection of promoter activation by exogenously administered mifepristone in vivo.

In this study, we used a steroid-induced promoter activation system as a molecular switch to study the exogenous activation of transgene expression. This promoter activation system consists of three components: (1) a steroidal inducer drug, mifepristone (RU486), which binds to (2) a chimeric transcription factor complex, consisting of the mutant human progesterone receptor fused to the yeast GAL4 DNA-binding domain and the activation domain of the herpes simplex virus protein VP16, and (3) a synthetic promoter, consisting of a series of GAL4 recognition sequences upstream of the adenovirus major late E1B TATA box, linked to a gene construct (ruc-gfp) encoding a Renilla luciferase- Aequorea green fluorescent protein (GFP) fusion protein. Transcription of the promoter-marker gene cassette is activated by the drug (mifepristone)-bound chimeric transcription factor complex. Monitoring of induced gene expression was carried out using a low-light video camera and a UV microscope to detect luciferase and GFP, respectively. Using this activation system, we observed a 10- to 25-fold activation, depending on the inducer dose, of both luciferase and GFP expression in transiently transfected cells in comparison to cells that were not exposed to mifepristone. We further demonstrated activation of gene expression from the promoter activation system in live animals. The plasmids PAP CMV-GL914VPc'SV, carrying the chimeric transcription factor cassette, and plasmid p17x4-TATA-ruc-gfp, carrying the ruc-gfp reporter gene construct, were co-injected into limb muscles of nude mice. Following DNA injection, mifepristone (50 micro g/kg) was delivered by intraperitoneal injection. Thirty-six hours after DNA and mifepristone injection, significant Renilla luciferase activity was detectable in the limb muscles. The promoter activation system was also demonstrated in limb muscles and livers of nude mice that had received transplants of ex vivo-modified cells, which were transiently transformed with both the chimeric activator plasmid and the ruc-gfp reporter plasmid prior to implantation. Significant Renilla activity and GFP fluorescence were detected externally in limb muscles and in the livers of anesthetized animals that had received an intraperitoneal injection of inducer. This external monitoring method for observing inducible gene expression in live animals will facilitate experimental studies of fundamental questions of biological and therapeutic relevance. It will be especially valuable for the analysis of gene function at specific stages of animal development. The method should also be of general use in gene therapy, since it permits simultaneous monitoring of the expression levels of light-emitting proteins and therapeutic proteins originating from the activation of identical promoters.

Animals↗
PubMed2000

Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin.

An association between oncogenic transformation and repression of different components of the MHC class I antigen processing machinery (APM) have been described in murine model systems. In order to discover whether a similar correlation exists, human tumor cell lines of distinct histology with altered ras protein were analyzed for the expression of APM components utilizing RT-PCR and Western blot analyses. A heterogeneous expression pattern of MHC class I antigens, TAP peptide transporter, proteasome subunits, proteasome activator PA28 and the chaperones calnexin, calreticulin as well as tapasin was displayed by these tumor cell lines. Single or combined deficiencies in the expression and/or function of TAP, LMP2, LMP10 and tapasin were demonstrated in 11 of 12 cell lines studied, whereas the expression of calnexin, calreticulin, beta2-microglobulin, LMP7 and PA28alpha was unaltered or only weakly decreased. The impaired expression of TAP, LMP subunits and tapasin was not associated with altered ras, but resulted in reduced MHC class I surface expression. In particular, a significant allele- and locus-specific downregulation of the HLA-A and HLA-B haplotypes was found. IFN-gamma treatment corrected the TAP, LMP and tapasin deficiencies and enhanced the constitutive PA28alpha, LMP7, calnexin and calreticulin expression which was accompanied with increased levels of MHC class I antigens. Thus, dysregulation rather than structural alterations of different APM components might be one mechanism of colon carcinoma, small cell lung carcinoma and pancreatic carcinoma cell lines to evade immune recognition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Neurotensin receptors: binding properties, transduction pathways, and structure.

Neurotensin is a 13-amino acid peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) originally isolated from hypothalami (Carraway and Leeman, 1973) and later from intestines (Kitabgi et al., 1976) of bovine. The peptide is present throughout the animal kingdom, suggesting its participation to important processes basic to animal life (Carraway et al., 1982). Neurotensin and its analogue neuromedin-N (Lys-Ile-Pro-Tyr-Ile-Leu) (Minamino et al., 1984) are synthesized by a common precursor in mammalian brain (Kislauskis et al., 1988) and intestine (Dobner et al., 1987). The central and peripheral distribution and effects of neurotensin have been extensively studied. In the brain, neurotensin is exclusively found in nerve cells, fibers, and terminals (Uhl et al., 1979), whereas the majority of peripheral neurotensin is found in the endocrine N-cells located in the intestinal mucosa (Orci et al., 1976; Helmstaedter et al., 1977). Central or peripheral injections of neurotensin produce completely different pharmacological effects (Table I) indicating that the peptide does not cross the blood-brain barrier. Many of the effects of centrally administered neurotensin are similar to those of neuroleptics or can be antagonized by simultaneous administration of TRH (Table I). The recently discovered nonpeptide antagonist SR 48692 (Gully et al., 1993) can inhibit several of the central and peripheral effects of neurotensin (Table I). Like many other neuropeptides, neurotensin is a messenger of intracellular communication working as a neurotransmitter or neuromodulator in the brain (Nemeroff et al., 1982) and as a local hormone in the periphery (Hirsch Fernstrom et al., 1980). Thus, several pharmacological, morphological, and neurochemical data suggest that one of the functions of neurotensin in the brain is to regulate dopamine neurotransmission along the nigrostriatal and mesolimbic pathways (Quirion, 1983; Kitabgi, 1989). On the other hand, the likely role of neurotensin as a parahormone in the gastrointestinal tract has been well documented (Rosell and Rökaeus, 1981; Kitabgi, 1982). Both central and peripheral modes of action of neurotensin imply as a first step the recognition of the peptide by a specific receptor located on the plasma membrane of the target cell. Formation of the neurotensin-receptor complex is then translated inside the cell by a change in the activity of an intracellular enzyme. This paper describes the binding and structural properties of neurotensin receptors as well as the signal transduction pathways that are activated by the peptide in various target tissues and cells.

Amino Acid Sequence↗
PubMed2006

A convolutional neural network approach for objective video quality assessment.

This paper describes an application of neural networks in the field of objective measurement method designed to automatically assess the perceived quality of digital videos. This challenging issue aims to emulate human judgment and to replace very complex and time consuming subjective quality assessment. Several metrics have been proposed in literature to tackle this issue. They are based on a general framework that combines different stages, each of them addressing complex problems. The ambition of this paper is not to present a global perfect quality metric but rather to focus on an original way to use neural networks in such a framework in the context of reduced reference (RR) quality metric. Especially, we point out the interest of such a tool for combining features and pooling them in order to compute quality scores. The proposed approach solves some problems inherent to objective metrics that should predict subjective quality score obtained using the single stimulus continuous quality evaluation (SSCQE) method. This latter has been adopted by video quality expert group (VQEG) in its recently finalized reduced referenced and no reference (RRNR-TV) test plan. The originality of such approach compared to previous attempts to use neural networks for quality assessment, relies on the use of a convolutional neural network (CNN) that allows a continuous time scoring of the video. Objective features are extracted on a frame-by-frame basis on both the reference and the distorted sequences; they are derived from a perceptual-based representation and integrated along the temporal axis using a time-delay neural network (TDNN). Experiments conducted on different MPEG-2 videos, with bit rates ranging 2-6 Mb/s, show the effectiveness of the proposed approach to get a plausible model of temporal pooling from the human vision system (HVS) point of view. More specifically, a linear correlation criteria, between objective and subjective scoring, up to 0.92 has been obtained on a set of typical TV videos.

Algorithms↗
PubMed1989

Antigenic properties and cellular localization of herpes simplex virus glycoprotein H synthesized in a mammalian cell expression system.

Herpes simplex virus type 1 glycoprotein H (HSV-1 gH) was synthesized in an inducible mammalian cell expression system, and its properties were examined. The gH coding sequence, together with the stable 5' untranslated leader sequence from xenopus beta-globin, was placed under control of the strong promoter from the human cytomegalovirus major immediate-early gene in an amplifiable plasmid which contains the simian virus 40 (SV40) virus origin for replication (ori). This expression vector was transfected into ts COS cells constitutively expressing a temperature-sensitive SV40 T antigen which allows utilization of the SV40 ori at permissive temperatures. The results of transient expression assays at the permissive temperature showed that HSV-1 gH could be synthesized in greater amounts than those produced by a high-multiplicity virus infection. The proteins produced were detected in Western blots (immunoblots) with a HSV-1 gH-specific polyclonal serum raised against a TrpE-gH fusion protein. The transfected gH had an apparent molecular weight of approximately 105,000, intermediate in size to those of the precursor (100,000) and fully processed forms (110,000) of HSV-1 gH from infections. Antigenicity was investigated by reactions with three virus-neutralizing monoclonal antibodies specific for conformational epitopes on gH. Only one of these monoclonal antibodies could immunoprecipitate the synthesized gH. However, equal recognition of the transfected gH was achieved by superinfection with virus. In addition, detectable amounts of gH were not expressed on the cell surface unless the cells were superinfected with virus. Studies with a temperature-sensitive mutant, ts1201, defective in encapsidation showed that the changes in antigenic structure and cell surface expression caused by superinfection with virus were not due simply to incorporation of gH into virions. These results suggest that gH requires additional virus gene products for cell surface localization and formation of an antigenic structure important for its function in mediating infectivity.

Animals↗
PubMed1984

Interaction between genes of chromosome 12 and I-region genes in the control of the arsonate-specific T cell repertoire.

The T lymphocyte repertoire consists of clones recognizing foreign antigens together with self histocompatibility molecules. Diversification of the receptor is believed to arise by somatic mechanisms during ontogeny. MHC gene products are essential for this process as well as for antigen recognition and expression of T cell functions. Yet, the antigen-specific T cell receptor is not encoded by MHC genes. Little is still known concerning the nature and the genetic origin of this receptor despite numerous experimental approaches. Although the T cell repertoire is mainly determined, in a single individual, by the alleles expressed at the MHC locus, one can postulate that it could also be influenced by the existence of alleles of the germ line gene(s) encoding the T cell receptor. If so, an analysis of the T cell fine specificity in mice of the same H-2 haplotype with different background genes might permit the mapping of the genes coding for this receptor. Such an experimental approach requires the use of an antigen consisting of only one major determinant. Several recent observations suggested to us that the hapten p-azobenzenearsonate (ABA) was a suitable model for such investigations. Thus, we decided to compare the specific pattern of responses to ABA-tyrosine, ABA-histidine and to free ABA in different inbred mouse strains. We report here that the lymph node T cell proliferative response to these molecules is under the control of an ABA-specific Ir gene. The ABA-Tyr conjugate is the most potent immunogen of the three in vivo as well as in vitro. High responder strains to ABA-His or ABA are included in the group of high responders to ABA-Tyr suggesting that the response to the three molecules is under the control of the same Ir-gene. The pattern of the response is also influenced by background gene(s). One of these can be localized on chromosome 12 using congenic mice. No close linkage to IgCH markers or VH idiotypes can be demonstrated but a linkage of this gene(s) to the Pre-1 locus seems possible. B lymphocytes do not seem to account for the involvement of Chr.12-genes in the response since; in our experimental system, they do not present ABA to T cells nor do they proliferate in the assays. Similarly, ABA-Tyr-antibody complexes do not enhance macrophages presentation of ABA to T cells, which supports the conclusion that IgCH or VH gene products are not involved in the control of the response.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Autologous activated natural killer cells suppress primitive chronic myelogenous leukemia progenitors in long-term culture.

A graft-versus-leukemia effect has been well documented to prevent relapse in chronic myelogenous leukemia (CML) after allogeneic marrow transplantation. One type of lymphocytes that may contribute to this effect are natural killer cells (NK), which after activation with interleukin (IL)-2, exhibit a broad range of cytolytic activity against allogeneic and autologous cells. We have previously demonstrated that IL-2-activated NK (ANK) can be generated from blood of patients with CML and are benign in origin. Their proliferation and function, however, diminish with disease progression in CML, suggesting a role in tumor surveillance. We studied the effect of IL-2-activated NK (ANK) on normal and malignant primitive and committed progenitors in a novel long-term bone marrow culture (LTBMC) assay. Because ANK destroy marrow stromal layers, the use of classic stroma-dependent long-term cultures is not possible. Therefore, we used the stroma noncontact LTBMC system developed in our laboratory to analyze the effect of autologous ANK cells on primitive hematopoietic progenitors. Autologous ANK (CD56+/CD3-) were generated from the peripheral blood of 10 patients with chronic phase CML and from six normal individuals by culturing CD5/CD8-depleted mononuclear cells for 14 days in 1,000 U/mL IL-2. At the same time ANK cultures were initiated, sorted normal (CD34+/DR+) marrow populations were plated in Transwell inserts of the stroma noncontact culture. On day 15, hydrocortisone, which rapidly inhibits ANK function, was removed, and autologous ANK were added to the Transwell inserts with fresh LTBMC medium without hydrocortisone but supplemented with 1,000 U/mL IL-2. After 48 hours, the number of colony-forming cells (CFC) was enumerated in methylcellulose culture. To determine the effect of ANK on more primitive long-term culture-initiating cells (LTCIC), the IL-2-supplemented LTBMC medium was replaced with fresh hydrocortisone containing LTBMC medium, and cultures were maintained for an additional 5 weeks. We demonstrate that autologous ANK did not suppress normal CFC or LTCIC. In contrast, ANK from eight patients with CML with potent cytotoxicity against NK-sensitive (K562) NK-resistant (Raji) tumor targets exhibited an ANK dose-dependent suppression of both CFC and LTCIC. Interestingly, ANK from two patients with CML who exhibited diminished cytotoxicity also did not suppress autologous CFC and LTCIC. These studies indicate that ANK with potent major histocompatibility complex unrestricted cytotoxic activity suppress malignant hematopoiesis. This effect was not mediated by soluble factors and was absolutely dependent on direct cell-to-cell contact. We further demonstrate that the beta2 integrin receptor is involved in ANK recognition of CML targets. These observations support the use of autologous ANK therapy to prevent relapse of CML after autologous marrow transplantation or use of ANK to purge CML marrow for autologous transplantation.

Bone Marrow↗
PubMed1991

Interleukin-2-activated murine cell lines with macrophage- and B-lymphoblast-lytic activity.

Interleukin-2 (IL-2)-activated murine killer cell lines with macrophage- and B-lymphoblastic-lytic activity were established, and their target specificity, surface markers, recognition-related structures, and requirements for optimal cell growth were characterized. Sustained growth of IL-2-activated lymphocytes was supported by the combination of IL-2 and IL-4-enriched T cell conditioned medium (CM), but was not supported by IL-2 alone or the combination of IL-2 and IL-3-containing CM in the presence of macrophages (M phi). The established line required continuous contact with M phi to maintain anti-M phi cytolytic activity. Flow cytometric analysis showed that the original line isolated by the first cloning was Thyl+, CD4-, and weakly CD8+, FcR+. The majority of these cells were CD3+ and TCR-V beta 8+. From this line, the CD3+, TCR-V beta 8+ and CD3-, TCR-V beta 8- clones were isolated by subcloning. The former clone showed Thyl+, CD3+, CD4-, CD8-, TCR-V beta 8+, FcR(+)-phenotype, and the latter clone showed Thyl+, CD3-, CD4-, CD8-, TCR-V beta 8-, FcR- phenotype. The original line and subclones showed a similar target specificity and killed resident or thioglycollate (TG)-induced peritoneal M phi and B-lymphoblasts, but did not kill T-lymphoblasts. Allogeneic M phi, M phi-like cell line P388D1, and B cell hybridoma were sensitive, whereas fresh lymphocytes, T cell lymphoma BW5147, natural killer (NK)-sensitive YAC-1, and NK-resistant P815 tumor cells were resistant to lysis by these cytotoxic lines. The addition of anti-H-2 heteroserum, anti-MHC class 1, anti-MHC class II, anti-CD3, or anti-TCR-V beta 8 monoclonal antibody (mAb) to assay cultures did not inhibit the anti-M phi cytolysis by these killer cells. In addition, the CD3- TCR-V beta 8- clone killed M phi and B lymphoblasts better than the CD3+, TCR-V beta 8+ clone. These results suggest that cytotoxic lines established in this study do not use the T cell receptor (TCR) molecules to recognize target cells and the MHC molecules are not involved in recognition. Anti-LFA-1 mAb partially inhibited anti-M phi-lysis, suggesting that the cell contact between targets and effectors is important in cytolysis. Our present data suggest that the culture condition containing IL-2, IL-4, and M phi may support the continuous growth of non-MHC-restricted killer cells with relative target specificity against M phi and B-lymphoblasts.

Animals↗
PubMed1995

Anti-cruciform monoclonal antibody and cruciform DNA interaction.

Cruciform DNA structure, as a structural feature, has been associated with regulation of transcription, recombination and replication. Previously used to successfully modify DNA replication and affinity-purify origins and autonomously replicating sequences. Using enzyme protection assays, their binding activity has been localized to the base (elbow) of the cruciform stem. We report here the hydroxyl radical footprinting of 2D3 (kappa IgG1) anti-cruciform monoclonal antibody on a stable cruciform structure created by heteroduplexing fragments from two plasmids, identical except for two centrally located palindromes of different sequence. The footprinting was performed at near-physiological salt concentrations, conditions favouring the stacked X-structure of the cruciform. Our data show that binding by the antibody occurs at the four-way junction (elbows) of the stable cruciform. The binding of the antibody seems also to cause associated structural distortions in the heteroduplex, which generally result in greater sensitivity to hydroxyl radicals at the tips of the cruciforms. The data are consistent to hydroxyl radicals at the tips of the cruciforms. The data are consistent with the binding of a single antibody to an antigen-combining site. The results of this study compare favourably with the hydroxyl radical footprinting studies reported recently for a human cruciform binding protein (CBP), which binds at the base of the stem-loop structure and causes similar distortions of the stable cruciform structure. These studies indicate that the four-way junction of the cruciform possesses certain unique structural qualities that are antigenic; the association of this structural determinant with DNA replication and the existence of a novel cellular protein, CBP, of similar binding specificity as the antibody specificity support a role for cruciforms as important regulatory recognition signals in replication.

Antibodies, Monoclonal↗
PubMed1983

Honored guest presentation: abulia minor vs. agitated behavior.

The neurological analysis of complex behavioral states associated with serious brain disease not infrequently is a difficult task. In many such cases, the signs of minor degrees of akinetic mutism were found when deliberately looked for. Recognition of this feature greatly facilitated interpretation. The ancient term abulia is suggested for the specific neurological syndrome comprising slowness, decreased responsiveness, apathy, etc. Akinetic mutism is its extreme form. A lesser degree of abulia is here termed abulia minor. The attributes of abulia minor are described, and the neurological conditions with which it had been found associated are listed. Preliminary conclusions as to the anatomical localization of the syndrome are presented. The literature on akinetic mutism is reviewed, and a few special observations are commented on--paradoxical activity, the telephone effect, and reflex attention. The application of the newer knowledge of cerebral neurotransmitters to akinetic mutism is illustrated. At the beginning of the study the focus was on abulia, but it was natural that sooner or later the contrasting state of behavioral hyperactivity or agitation would have to come under equal scrutiny. A list of conditions in which psychomotor agitation was a feature has been compiled from personal files. The localization of the disease process in hyperactive states is compared with that in abulia. A few special observations on hyperactive states are presented, along with a note on a unique syndrome termed anideation. There has gradually emerged a concept of a continuum of behavioral activity extending from abulia at one end through eukinesia to hyperactivity at the other end. Involvement of specific fundamental integrative circuits is postulated. This morning we have been enthralled by Computers in Neurosurgery, Neurobiology in Neurosurgery, and Humanism in Neurosurgery. What could be more natural for a neurologist than to talk about Neurology in Neurosurgery. And how best to pay homage to the great lady of Medicine than by offering a modest example of her handiwork. Thus, I am led to discuss a neurological theme which has recently occupied my attention. To anticipate a little, I shall be talking about two somewhat opposite states: on the one hand there is abulia--slowness, apathy, and lack of spontaneity--and on the other hand, agitation and hyperactivity. By way of explanation, this study originated during the bedside examination of patients with brain damage and serious impairment of analysis appeared not only formidable but even impossible.(ABSTRACT TRUNCATED AT 400 WORDS)

Akinetic Mutism↗
PubMedDate not supplied

Immunogenetic aspects of clinical and experimental uveitis.

Genetic association of some immune-mediated human uveitic diseases with histocompatibility antigens, ethnic origin, familial background, or gender have suggested the presence a hereditary component in susceptibility. Experimental autoimmune uveoretinitis (EAU) can be induced in inbred rodents by immunization with evolutionarily conserved retinal proteins, and mimics many features of human uveitis. Susceptibility to EAU is genetically controlled, and the model is being used to study mechanisms that might affect susceptibility to ocular autoimmune disease. EAU expression in mice and in rats requires the presence of both a susceptible MHC haplotype and a "permissive" genetic background. MHC control of susceptibility in H-2k mice was tentatively mapped to the I-A subregion (HLA-DR equivalent), implicating epitope recognition as a major mechanism in susceptibility. In contrast, expression of the I-Ek gene product (HLA-DQ equivalent) appeared to have an ameliorating effect on disease. Susceptible H-2 haplotypes exhibited highest disease scores on the B10 background, and disease was reduced, or even absent, on some other (nonpermissive) backgrounds. Factors which may determine "permissiveness" or "nonpermissiveness" of a particular genetic background, as studied in mice and rats, may include regulation of responses to lymphokines, hypothalamic-adrenal-pituitary axis hormones, mast cell/vascular effects, and possibly the T cell repertoire. The data are interpreted to suggest that, in individuals susceptible to uveitis by virtue of their MHC, the final expression of disease will be determined by the genetic background. These results might help to explain why only a minority of individuals with a susceptible HLA type develop uveitis, as well as the variable incidence of disease in HLA-identical populations of different ethnic backgrounds.

Animals↗
PubMed2006

A multiscale expectation-maximization semisupervised classifier suitable for badly posed image classification.

This paper deals with the problem of badly posed image classification. Although underestimated in practice, bad-posedness is likely to affect many real-world image classification tasks, where reference samples are difficult to collect (e.g., in remote sensing (RS) image mapping) and/or spatial autocorrelation is relevant. In an image classification context affected by a lack of reference samples, an original inductive learning multiscale image classifier, termed multiscale semisupervised expectation maximization (MSEM), is proposed. The rationale behind MSEM is to combine useful complementary properties of two alternative data mapping procedures recently published outside of image processing literature, namely, the multiscale modified Pappas adaptive clustering (MPAC) algorithm and the sample-based semisupervised expectation maximization (SEM) classifier. To demonstrate its potential utility, MSEM is compared against nonstandard classifiers, such as MPAC, SEM and the single-scale contextual SEM (CSEM) classifier, besides against well-known standard classifiers in two RS image classification problems featuring few reference samples and modestly useful texture information. These experiments yield weak (subjective) but numerous quantitative map quality indexes that are consistent with both theoretical considerations and qualitative evaluations by expert photointerpreters. According to these quantitative results, MSEM is competitive in terms of overall image mapping performance at the cost of a computational overhead three to six times superior to that of its most interesting rival, SEM. More in general, our experiments confirm that, even if they rely on heavy class-conditional normal distribution assumptions that may not be true in many real-world problems (e.g., in highly textured images), semisupervised classifiers based on the iterative expectation maximization Gaussian mixture model solution can be very powerful in practice when: 1) there is a lack of reference samples with respect to the problem/model complexity and 2) texture information is considered negligible (i.e., a piecewise constant image model holds).

Algorithms↗
PubMed2006

Learning MHC I--peptide binding.

MOTIVATION AND RESULTS: Motivated by the ability of a simple threading approach to predict MHC I--peptide binding, we developed a new and improved structure-based model for which parameters can be estimated from additional sources of data about MHC-peptide binding. In addition to the known 3D structures of a small number of MHC-peptide complexes that were used in the original threading approach, we included three other sources of information on peptide-MHC binding: (1) MHC class I sequences; (2) known binding energies for a large number of MHC-peptide complexes; and (3) an even larger binary dataset that contains information about strong binders (epitopes) and non-binders (peptides that have a low affinity for a particular MHC molecule). Our model significantly outperforms the standard threading approach in binding energy prediction. In our approach, which we call adaptive double threading, the parameters of the threading model are learnable, and both MHC and peptide sequences can be threaded onto structures of other alleles. These two properties make our model appropriate for predicting binding for alleles for which very little data (if any) is available beyond just their sequence, including prediction for alleles for which 3D structures are not available. The ability of our model to generalize beyond the MHC types for which training data is available also separates our approach from epitope prediction methods which treat MHC alleles as symbolic types, rather than biological sequences. We used the trained binding energy predictor to study viral infections in 246 HIV patients from the West Australian cohort, and over 1000 sequences in HIV clade B from Los Alamos National Laboratory database, capturing the course of HIV evolution over the last 20 years. Finally, we illustrate short-, medium-, and long-term adaptation of HIV to the human immune system. AVAILABILITY: http://www.research.microsoft.com/~jojic/hlaBinding.html.

Algorithms↗
PubMed1999

PCR-based identification of individuals of Schistosoma japonicum representing different subpopulations using a genetic marker in mitochondrial DNA.

A mitochondrial NADH dehydrogenase I gene fragment (NDI) was sequenced for three laboratory maintained isolates of Schistosoma japonicum. Comparison of sequences representing the isolates (originally obtained from the Anhui and Zhejiang provinces of the People's Republic of China, and from the Philippines) revealed inter-isolate sequence variations of 0.2-0.6% and no intra-isolate variation was found. The sequences also indicated that while the amplification products of the Zhejiang and Philippine isolates contained a recognition site for the endonuclease RsaI, there was no such site in the Anhui isolate. This was tested by digesting amplification products from a number of individual worms with RsaI. Then an infection experiment was designed to test the value of this genetic marker for studies of the population biology of S. japonicum in the final host. For this, the two Chinese isolates were used. Three groups of mice (A-C) were exposed firstly to a primary infection and then challenge-infected at weeks 4 and 7 of the experiment. In group A the first infection was done with the Anhui isolate, and the two others with the Zhejiang isolate, thereby providing a specific, detectable cohort. In groups B and C the Anhui isolate was used for the second and third infection. All mice were perfused 5 weeks after the last challenge infection, and the NDI was subsequently amplified from DNA of the perfused worms and digested with RsaI. The digestion revealed that while infection groups A and B contained mixed populations of the Anhui and Zhejiang isolates, only Zhejiang worms were present in group C. We concluded that the absence/presence of the RsaI site in the NDI provides a useful marker for the delineation of cohorts of S. japonicum.

Amino Acid Sequence↗
PubMed1978

The role of H-2 linked genes in helper T-cell function. IV. Importance of T-cell genotype and host environment in I-region and Ir gene expression.

We have studied the properties of helper T cells specific for sheep erythrocytes (SRBC), keyhole limpet hemocyanin (KLH), or poly-L-(Tyr,Glu)-poly-DL-Ala-poly-L-Lys [(T,G)-A--L]. These T cells differentiated and were primed in vivo in irradiation chimeras constructed of various combinations of F1 and parental bone marrow donors and irradiated recipients. Primed T cells were then tested for helper activity in the in vitro response of B cells and macrophages (Mphi) of parental or F1 origin to the hapten trinitrophenol coupled to the priming antigen. When testing either SRBC or KLH-specific T cells of parental H-2 type which had differentiated in F1 hosts, we found that they cooperated equally well with B cells and Mphi of either parental H-2 type. On the other hand, when testing F1 T cells which had differentiated in parental hosts, we found that they cooperated well only with B cells and Mphi which had the K-IA region type of the parental host. In similar experiments we found that (T,G)-A--L-specific T cells of low responder H-2 type which had differentiated in (high responder X low responder) F1 hosts induced high responses in high responder B cells and Mphi (T,G)-A--L-specific F1 T cells which differentiated in high responder but not those which differentiated in low responder hosts induced high responses in high responder B cells and Mphi. Low responder B cells and Mphi yielded low responses in all cases regardless of the source of (T,G)-A--L-specific T cells with what they were tested. Our results support the conclusion that I-region and Ir genes function via their expression in B cells and Mphi and in the host environment during helper T-cell differentiation, but not, at least under the conditions of these experiments, via their expression in the helper T cell itself. These findings place constraints upon models which attempt to explain the apparent dual recognition of antigen and I-region gene products by helper T cells.

Animals↗
PubMed2001

Multivariate patterns of biochemical responses of Pinus ponderosa trees at field plots in the San Bernardino Mountains, southern California.

Most environmental stress conditions promote the production of potentially toxic active oxygen species in plant cells. Plants respond with changes in their antioxidant and photoprotective systems. Antioxidants and pigments have been widely used to measure these responses. Because trees are exposed to multiple man-made and natural stresses, their responses are not reflected by changes in single stress markers, but by complex biochemical changes. To evaluate such response patterns, explorative multivariate statistics have been used. In the present study, 12 biochemical variables (chloroplast pigments, state of the xanthophyll cycle, alpha-tocopherol, ascorbate and dehydroascorbate, glutathione and oxidized glutathione) were measured in previous-year needles of field-grown Pinus ponderosa Dougl. ex Laws. The trees were sampled in two consecutive years in the San Bernardino Mountains in southern California, where a pollution gradient is overlaid by gradients in natural stresses (drought, altitude). To explore irradiance effects, needle samples were taken directly in the field (sun exposed) and from detached, dark-adapted branches. A principal component analysis on this data set (n = 80) resulted in four components (Components 1-4) that explained 67% of the variance in the original data. Component 1 was positively loaded by concentrations of alpha-tocopherol, total ascorbate and xanthophyll cycle pools, as well as by the proportion of de-epoxides in the xanthophyll cycle. It was negatively loaded by the proportion of dehydroascorbate in the ascorbate pool. Component 2 was negatively loaded by chlorophyll concentrations, and positively loaded by the ratios of lutein and beta-carotene to chlorophyll and by the de-epoxidation state of the xanthophyll cycle. Component 3 was negatively loaded by GSH concentrations and positively loaded by the proportions of GSSG and tocopherol concentrations. Component 4 was positively loaded by neoxanthin and negatively loaded by beta-carotene. The four components could be assigned to the concerted action of the biochemical protection system: high scores on Component 1 represent highly activated antioxidative defense, changes in pigment composition are represented in Components 2 and 4, and the glutathione system, which is important for antioxidant regeneration, is represented in Component 2. Although Component 1 scores were generally higher (indicating activation of antioxidant defense) in light-adapted needles relative to dark-adapted needles, they were also site dependent with increased scores at sites with less pollution, but higher natural stress impacts. High scores of Components 2 and 3 at the highest elevation site, which was only moderately polluted, indicated an increase in photoprotection by pigments and activation of the glutathione system. Significant differences between light- and dark-adapted needles in Components 2 and 3 were only found at the site with the highest pollution. Use of accumulated variables (components) instead of single biochemical variables enabled recognition of response patterns at particular sites and a better comparison with results of other studies is expected. Typical response patterns could be assigned to particular environmental stress combinations, providing a means of assessing potential biological risks within individual forest stands.

Air Pollution↗