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PubMed1993

Processing of endogenously synthesized hen egg-white lysozyme retained in the endoplasmic reticulum or in secretory form gives rise to a similar but not identical set of epitopes recognized by class II-restricted T cells.

To study the processing and presentation of endogenously synthesized Ag to class II MHC-restricted T cells, hen egg lysozyme (HEL), either tagged with a peptide that confers retention in the endoplasmic reticulum (HEL.KDEL), or in the secretory form (HELs), was stably expressed in LK-35.2 B hybridoma cells. Presentation of HEL peptides bound to class II molecules was assessed by activation of specific T cell hybridomas recognizing seven different epitopes derived from exogenous HEL. The presentation of endogenously synthesized HEL was not caused by reuptake of secreted of shed Ag. All the HEL epitopes examined were efficiently presented after processing of endogenous HEL by HELs-transfected LK-35.2 cells. Processing of HEL tagged with KDEL, however, gave rise to presentation of only six of the seven HEL epitopes. The epitope included in the HEL sequence 112-124 was not presented by HEL.KDEL-transfected B cells. In addition, two of the four T cell hybridomas recognizing HEL 116-129 together with I-Ak molecules were not activated by HEL.KDEL, and three other epitopes were presented with lower efficiency as compared with HELs. Thus, endogenously synthesized HEL in secretory form gives rise to a set of class II-binding epitopes indistinguishable from exogenous HEL, whereas endoplasmic reticulum-retained HEL generates a similar but not identical set of epitopes. The endosomal protease inhibitor leupeptin prevented presentation of the epitope 108-116, but not 46-61, both by HELs and HEL.KDEL transfected cells, indicating a requirement for endosomal processing in both cases. In addition, the presentation of peptides derived from endogenously synthesized, either secretory or endoplasmic reticulum-retained HEL, could be inhibited by lysosomotropic amines, further indicating that the intracellular route of class II molecules presenting peptides derived from endogenous Ag intersects the acidic endosomal compartment.

Amino Acid Sequence↗

PubMed1994

Myasthenia gravis. Residues of the alpha and gamma subunits of muscle acetylcholine receptor involved in formation of immunodominant CD4+ epitopes.

We propagated from myasthenia gravis (MG) patients by stimulation in vitro with synthetic sequences (alpha 48-67, alpha 304-322, gamma 75-94 and gamma 321-340) of the human muscle acetylcholine receptor (AChR), CD4+ lines against four 20-residue sequence regions of the AChR alpha and gamma subunits that are recognized by Th cells of most MG patients. Most lines secreted IL-2 and not IL-4, suggesting that they comprise Th1 cells. For three lines we verified that, as reported previously, AChR epitopes are presented by DR molecules: their response to the relevant peptide was abolished by anti-DR Abs. The DR molecules presenting AChR epitopes were identified by testing the response of the lines to the relevant peptide, using APC from donors homozygous for the different DR alleles of the line. We tested the lines with single residue-substituted analogues of the epitope sequence. The results of these experiments indicated that the lines were polyclonal and recognized overlapping epitopes. Their response was abolished by some substitutions, identifying residues common to all epitopes within a given region, whereas other substitutions reduced but did not obliterate the response, indicating residues included in some but not all epitopes recognized by the line. Comparison of the residues involved in epitope formation for different lines supported the conclusion that within the 20-residue immunodominant regions investigated here, the same sequence segment is involved in formation of epitopes, even in DR-discordant patients.

Adult↗

PubMed1995

[The relationship between 4-hydroxynonenal-derived epitopes on apolipoprotein B and coronary heart disease].

When lipid peroxidation takes place in plasma low density lipoprotein (LDL), a lot of aldehydes-derived epitopes are generated. To explore the relationship between these aldehydes-derived epitopes on apolipoprotein B (apo B) and coronary heart disease (CHD), we used both antibody against 4-hydroxynonenal (HNE)-derived epitopes and antibody against apo B to establish a sandwich enzyme-linked immunoassay (ELISA). The sera from 160 normal controls as well as from 103 patients with CHD were tested by ELISA for the expression of HNE-derived epitopes on apo B. The measurements showed that the mean expression of HNE-epitopes in the patients with CHD (183.5 +/- 63.6 mg/L, n = 103) was higher than that of normal controls (133.3 +/- 47.5 mg/L, n = 160). The difference of the expression of HNE-epitopes on serum apo B between the patients and normal controls was statistically significant. The results analysed by a multiple regression demonstrated that the expression of HNE-epitopes, levels of LDL-cholesterol and age were positively related to CHD, while the levels of HDL-cholesterol and female were negatively related to CHD. Thus, it was proven for the first time that the enhanced expression of HNE-epitopes on apo B might be an independent risk factor of CHD.

Aldehydes↗

PubMed1996

The B cell response to autologous type II collagen: biased V gene repertoire with V gene sharing and epitope shift.

Collagen-induced arthritis is an autoimmune model disease induced in the DBA/1 mouse immunized with type II collagen (CII). Both T and B cells play a critical role for the induction of arthritis. Draining lymph nodes from CII-immunized mice contain high numbers of CII-specific B cells, which are isotype switched and V gene selected. In the present study we analyze the V region gene usage and epitope specificity of CII-reactive B cell hybridomas, randomly isolated from the primary and the secondary response in mice immunized with rat CII we make the following conclusions. 1) There are major epitopes in the native CII molecule to which the B cells preferentially respond. 2) B cells specific for the same epitope show a preferential pairing of certain VH/VK genes or a biased usage of individual VH (VHJ558 and VHX24) or VK genes (VK21). 3) The V genes are germ line encoded in the primary response and somatically mutated in the secondary response. Somatic mutations give the Abs cross-reactivity between CII epitopes, and epitope shift, i.e., another epitope within the CII molecule is recognized. 4) There is a sharing of certain V genes in B cell clones specific for different epitopes, indicating structural similarities of the different CII epitopes.

Amino Acid Sequence↗

PubMed1996

Flanking residues alter antigenicity and immunogenicity of multi-unit CTL epitopes.

CD8+ CTL responses constitute a critical component for vaccines developed to eliminate intracellular pathogens. One approach to achieve broad CTL diversity is based on genetically linking immunogenic peptides from multiple proteins to form poly-epitope Ags. To address the influence of flanking residues on class I Ag presentation, H-2d-restricted HIV-1 and mouse hepatitis virus CTL epitopes were linked via various spacer residues. The resulting 20 to 31 amino acid peptides were expressed using recombinant vaccinia viruses to monitor both CTL recognition and induction. Our data indicate that recognition is profoundly influenced by the nature of intervening residues forming carboxyl-terminal flanks for one and amino-terminal flanks for the other epitope. Flanking amino acids with aromatic (tyrosine), basic (lysine), and small aliphatic side chains (alanine) supported efficient CTL recognition of both epitopes. By contrast, acidic and helix breaking residues (glycine, proline) specifically inhibited recognition of the adjacent amino-terminal epitope. Flanking residues inhibitory for recognition were also detrimental for CTL induction, suggesting similar processing mechanisms in vitro and in vivo. The ratios of peptide-specific CTL precursors primed by the tandem epitopes varied up to 50-fold depending on molecular context. These data demonstrate a substantial role of carboxyl-flanking residues in governing the efficiency of class I Ag presentation both in vitro and in vivo. The dramatic influence of flanking residues on the hierarchy of CTL responses indicates that CTL induction by poly-epitope Ags can be optimized by strategically linking epitopes via selection of appropriate spacer residues.

Animals↗

PubMedDate not supplied

Neutralization epitope patterns of poliovirus strains isolated from cases of acute spinal paralysis and from healthy vaccinated children.

By using a battery of poliovirus neutralizing monoclonal antibodies received from the Pasteur Institute, Paris, we carried out the study of the patterns of neutralization epitopes of more than 300 poliovirus strains isolated from cases of acute spinal paralysis and from healthy vaccinated children. We tried to find out the utility of this test for establishing the origin (wild or Sabin) of a poliovirus strain and the possible evolution of the pattern of neutralization epitopes. The study of the neutralization epitopes was carried out by neutralization index assay (NI). The neutralization index represents the difference between the titers of poliovirus strain determined in parallel in the absence, as well as in the presence of constant concentration (predetermined) for each monoclonal antibody. An epitope was considered to be present for a NI > or = 2 and absent for a NI < or = 1.5. For types 1 and 3 polioviruses, Sabin-like epitopes have never been found to be present simultaneously with wild type epitopes on the same virus particle. Therefore, examination of the epitope pattern of these strains is very useful for intratypic differentiation. On the other hand, in type 2 poliovirus strains, Sabin and wild type epitopes sometimes coexist, in various combinations, thus rendering the interpretation of the results rather difficult.

Antibodies, Monoclonal↗

PubMed1997

Induction of melanoma reactive T cells by stimulator cells expressing melanoma epitope-major histocompatibility complex class I fusion proteins.

Several epitopes in the human melanoma antigens recognized by HLA-A2-restricted CTLs have a relatively low MHC-binding affinity and as a result may be expressed at very low densities on the cell surface, indicating that these epitopes may not be efficient immunogens. To express these epitopes at higher densities on the surface of antigen-presenting cells and therefore improve their immunogenicity, a DNA construct in which a cDNA fragment encoding the melanoma epitope MART-1(27-35) or gp100(280-288) was inserted between sequences encoding the leader and the HLA-A*0201 protein. Cells transfected with these epitope-HLA fusion constructs were recognized by HLA-A2-restricted melanoma-reactive CTLs specific for the MART-1 or gp100 epitope. In addition, tumor-reactive CTLs could be induced from PBMCs of patients with metastatic melanoma by in vitro stimulation with HMY-C1R B-cell lines expressing the MART-1 or gp100 epitope-HLA-A*0201 fusion protein. These epitope-HLA fusion constructs may be useful for the development of immunotherapies for patients with melanoma.

Animals↗

PubMed1998

Intercellular and intracellular events following the MHC-unrestricted TCR recognition of a tumor-specific peptide epitope on the epithelial antigen MUC1.

We examined the functional and molecular parameters involved in direct TCR recognition of a tumor-specific peptide epitope on the tumor Ag MUC1. This peptide epitope is tandemly repeated and recognized on the native molecule rather than processed and bound to the MHC. Even though the TCR was not MHC restricted, intercellular interactions found to facilitate this recognition included intercellular adhesion molecule-1/LFA-1, LFA-3/CD2, and class I/CD8. Intracellular parameters of MHC-unrestricted CTL activation were examined to compare the recognition of the MUC1 epitope presented on synthetic microspheres, with the recognition of the native epitope in the context of other molecules on the target cells. The epitope on microspheres induced a transient influx of Ca2+ that was not accompanied by detectable tyrosine phosphorylation of the zeta-associated protein ZAP-70, whereas recognition of MUC1 epitopes on tumor cells caused a sustained Ca2+ influx and ZAP-70 phosphorylation. The transient influx of Ca2+ was not sufficient to cause translocation of the nuclear factor of activated T cells (NF-AT) into the nucleus or CTL proliferation. In contrast, recognition of the MUC1 epitope on tumor cells resulted in full activation of the CTL, nuclear translocation of NF-AT, and proliferation. MHC-unrestricted TCR triggering, therefore, involves similar intercellular and intracellular events that participate in the conventional, MHC-restricted Ag recognition. Direct recognition of the MUC1 peptide epitope by the TCR in the absence of presentation by the MHC induces a partial signal that is completed by further interactions of other receptor/ligand pairs on the surface of the CTL and their target cells.

Amino Acid Sequence↗

PubMed1995

A 10-amino-acid linear sequence of VP1 of foot and mouth disease virus containing B- and T-cell epitopes induces protection in mice.

The area of foot and mouth disease virus (FMDV) comprising residues 140 and 160 of capsid protein VP1 has been used extensively as an immunogen in natural and experimental hosts. A detailed epitope mapping of this region, however, has not been reported. For this purpose a synthetic peptide containing the residues 135 to 160 (p135-160) of VP1 of FMDV O1 Campos was analyzed for its T- and B-cell epitopes. The p135-160 is highly immunogenic, either by itself or coupled to a carrier protein (BSA), elicits a long-lasting neutralizing antibody response in mice, and provides solid protection against virulent challenge. By using a set of synthetic 10mer overlapping peptides, which cover the entire sequence 135-160 of VP1, we have shown that at least four discrete B epitopes are regularly distributed along the peptide. Although immunization with each of the 10mers coupled with BSA as a carrier protein induced peptide-specific antibody responses, individually none of the 10mers was able to induce neutralizing antibodies. However, anti-135-160 antibodies sorted by immunoaffinity chromatography using each of the 10mers revealed the existence of at least four discrete neutralizing sites: one spanning residues 135-144, at least two more between residues 140 and 154, and another in the region 150-160. Moreover, T-cell epitopes were identified, both by antigen-dependent proliferation assays and by adoptive cell transfer. By both methods, a T-cell epitope was located in the area comprising residues 135-144; the cell transfer experiment, which seems to be more sensitive, also identified a second T-cell epitope between residues 150 and 160. Interestingly, when the region 135-144, which contains both B- and T-cell epitopes, was in a tandem repeat configuration it induced a strong neutralizing antibody response in mice and solid protection against the challenge.

Amino Acid Sequence↗

PubMed2001

Identification and characterization of B-cell epitopes of a 53-kDa outer membrane protein from Porphyromonas gingivalis.

We have previously reported that Porphyromonas gingivalis FDC 381 possesses a 53-kDa protein antigen (Ag53) on its outer membrane that evokes a strong humoral immune response in many patients with periodontal disease and that the humoral immune responses to Ag53 differ greatly among patients. To understand how the individual humoral immune system against Ag53 was determined, the regions of Ag53 recognized by specific antibody (B-cell epitopes) and dominant subclasses of serum immunoglobulin G (IgG) against major B-cell epitopes were examined by enzyme-linked immunosorbent assay. This study used sera from six patients with periodontitis, which all reacted strongly with sonic extracts of P. gingivalis 381 and with purified Ag53, and sera from six periodontally healthy children, which did not react with either sonic extracts of P. gingivalis 381 or Ag53. The epitopes were identified using synthetic 5-residue overlapping decapeptides covering the entire Ag53. Thirteen of 89 synthetic decapeptides showed a strong reaction with sera from the periodontal patients, but no reaction with those from the healthy children. Four peptides of 13 exerted different immune responses among patients. Furthermore, restriction analyses of the highly antigenic regions revealed that three sequences, RAAIRAS, YYLQ and MSPARR, were identified as major B-cell epitopes. Additionally, these epitopes were recognized mainly by the IgG2 isotype. These data suggest that the difference of B-cell epitopes might influence individual differences in antibody titer against Ag53 and also that the epitopes recognized commonly by multiple antibodies are quite valuable for peptide vaccine development against P. gingivalis infection.

Adolescent↗

PubMed2005

Cytolytic T lymphocytes (CTLs) from HIV-1 subtype C-infected Indian patients recognize CTL epitopes from a conserved immunodominant region of HIV-1 Gag and Nef.

Analysis of the human immunodeficiency virus type 1 (HIV-1) cytolytic T lymphocyte (CTL) epitopes recognized by the targeted population is critical for HIV-1 vaccine design. Peripheral blood mononuclear cells from 47 Indian subjects at different stages of HIV-1 infection were tested for HIV-1 Gag-, Nef-, and Env-specific T cell responses by interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) assay, using pools of overlapping peptides. The Gag and Nef antigens were targeted by 83% and 36% of responders. Five immunodominant regions, 4 in Gag and 1 in Nef, were identified in the study; these regions are conserved across clades, including the African subtype C clade. Three antigenic regions were also found to be recognized by CTLs of the study participants. These regions were not identified as immunodominant regions in studies performed in Africa, which highlights the importance of differential clustering of responses within HIV-1 subtype C. Twenty-six putative epitopes--15 Gag (10 in p24 and 5 in p17), 10 Nef, and 1 Env (gp 41)--were predicted using a combination of peptide matrix ELISPOT assay and CTL epitope-prediction software. Ninety percent of the predicted epitopes were clustered in the conserved immunodominant regions of the Gag and Nef antigens. Of 26 predicted epitopes, 8 were promiscuous, 3 of which were highly conserved across clades. Three Gag and 4 Nef epitopes were novel. The identification of conserved epitopes will be important in the planning of an HIV-1 vaccine strategy for subtype C-affected regions.

AIDS Vaccines↗

PubMed2002

Analysis of a conformational B cell epitope of human thyroid peroxidase: identification of a tyrosine residue at a strategic location for immunodominance.

Thyroid peroxidase (TPO) is involved in autoimmune thyroid diseases and high titers of TPO autoantibodies directed to various conformational B cell epitopes are frequently present in patients' sera. Deciphering these epitopes is a difficult task, but can give insight into the structural basis of autoimmune recognition. TPO is a membrane-bound enzyme with the extracellular part organized in three protein domains, but of unknown three-dimensional structure. We previously localized a TPO B cell epitope within amino acid residues 742-848, a region encompassing the two C-terminal, extracellular domains of the protein. We found that at least one of the three tyrosine residues of the peptide 742-848 might be involved in autoantibody binding. In this study, we show by site-directed mutagenesis that the autoepitope contains tyrosine 772 located near the hinge area between the two protein domains, suggesting they are both involved in the epitope structure. The B cell epitopes of TPO are clustered in two overlapping immunodominant regions. To map the newly localized epitope with respect of these regions, competition experiments were performed using a reference panel of TPO mAb and a further mAb previously found to be specific for the TPO peptide 742-848 at variance with all the other ones. Here, we show that the tyrosine 772-bearing epitope in the peptide 742-848 maps in a region that partly overlaps the reported two immunodominant regions. These results are suggestive of a complex TPO folding that involves all the three TPO protein domains to form a highly conformational immunodominant region.

Animals↗

PubMed2002

Epitope analysis of the FanC subunit protein of the K99 (F5) fimbriae of enterotoxigenic Escherichia coli using a recombinant fusion technique.

We have used a recombinant approach to characterise the B- and T-cell epitopes of FanC, the major subunit polypeptide of K99 (F5) fimbriae of enterotoxigenic Escherichia coli strains. This involved the fusion of FanC and its carboxy-terminal truncated derivatives to a reporter, the E. coli alkaline phosphatase (PhoA), generating stable, recombinant fusions. The B-cell epitopes of FanC were characterised by Western blotting of FanC::PhoA fusion proteins with a polyclonal mouse antiserum directed against K99 fimbrial antigen, and with a panel of monoclonal antibodies generated to the K99 antigen. An attempt to characterise the T-cell epitopes of the fimbrial subunit was made by standard in vitro T-cell proliferation assay. Our results suggest that the B-cell epitopes of FanC are likely to be continuous, with a potentially immunodominant epitope at the carboxy-terminus. However, T-cell proliferation assays with the FanC::PhoA fusion proteins did not indicate any immunodominant T-cell epitope(s). We hypothesise that fusion of FanC peptides to PhoA had resulted in altered folding of the peptides for antibody and T-cell recognition, highlighting the potential problems and drawbacks of the recombinant fusion technique in defining the epitopes of certain proteins.

Alkaline Phosphatase↗

PubMed2004

Epitope mapping of Porphyromonas gingivalis heat-shock protein and human heat-shock protein in human atherosclerosis.

To identify T- and/or cross-reactive B-cell epitopes of P. gingivalis and human heat-shock protein (HSP)60 in atherosclerosis patients, we synthesized 104 overlapping synthetic peptides spanning whole molecules of P. gingivalis HSP60 and human HSP60, respectively. T-cell epitopes of P. gingivalis HSP were identified with the use of previously established P. gingivalis HSP-reactive T-cell lines. B-cell epitopes of P. gingivalis HSP60 and human HSP60 were identified by the use of patients' sera. Anti-P. gingivalis, anti-P. gingivalis HSP60, or anti-human HSP60 IgG antibody titers were higher in the atherosclerosis patients compared with the healthy subjects. Five immunodominant peptides of P. gingivalis HSP60, identified as T-cell epitopes, were also found to be B-cell epitopes. Moreover, 6 cross-reactive B-cell epitopes of human HSP60 were identified. It was concluded that P. gingivalis HSP60 might be involved in the immunoregulatory process of atherosclerosis, with common T- and/or B-cell epitope specificities and with cross-reactivity with human HSP60.

Aged↗

PubMed2002

Enhanced immunogenicity of a functional enzyme by T cell epitope modification.

BACKGROUND: T helper epitopes are necessary for the induction of high titers of antigen-specific IgG antibodies. We are interested in the epitope modification of intact proteins as a method to enhance their immunogenicity for the generation of recombinant protein-based vaccines. RESULTS: Hartley strain guinea pig T cell epitopes were mapped for two related bacterial proteases. Two T cell epitopes were found in one of the proteases, while a comparatively reduced immunogenicity protease had no detectable T cell epitopes. A T cell epitope sequence homologous to the immunogenic protease was created in the less immunogenic protease by changing a single amino acid. Proliferative responses to the whole protein parent enzyme were two-fold higher in splenocyte cultures from variant-immunized animals. We found that the single amino acid change in the variant resulted in a protein immunogen that induced higher titers of antigen-specific IgG antibody at low doses and at early time points during the immunization protocol. The serum from parent- and variant-immunized guinea pigs cross-reacted at both the protein and the peptide level. Finally, animals primed to the variant but boosted with the parent enzyme had higher levels of antigen-specific IgG than animals immunized with the parent enzyme alone. CONCLUSIONS: With a single amino acid change we have introduced a T cell epitope into a comparatively low-immunogenic enzyme and have increased its immunogenicity while retaining the enzyme's original proteolytic function. The ability to immunomodulate proteins while leaving their function intact has important implication for the development of recombinant vaccines and protein-based therapeutics.

Amino Acid Substitution↗

PubMed2025

In silico identification of Leishmania GP63 protein epitopes to generate a new vaccine antigen against leishmaniasis.

BACKGROUND: The surface of Leishmania spp. presents glycoprotein 63 (GP63), a metalloprotease that acts as one of the parasite's major antigens. A vaccine against leishmaniasis has not yet been developed and stationary phase promastigotes have utmost importance in transmitting Leishmania spp. from phlebotomine sand fly to humans or reservoirs. Therefore, this study aimed to analyze GP63 protein in three different Leishmania spp. to determine new vaccine candidate antigen against leishmaniasis using sequencing data of locally detected Leishmania strains and in silico approaches. METHODOLOGY/PRINCIPAL FINDINGS: The GP63 protein sequences of the stationary phase/amastigote form of L. infantum, L. major, and L. tropica were identified and then the gene encoding GP63 protein in Leishmania positive samples (n:59) was amplified and sequenced for variation analysis. According to the results, 4, 6, 19 GP63 variants were found within L. infantum, L. major, and L. tropica isolates, respectively. The most prevalent variants within each species were selected for further analysis using in silico approaches. Accordingly, all selected GP63 proteins were antigenic and the amount of B and T cell epitopes were 23 for L. infantum, 10 for L. major, and 9 for L. tropica. The analysis of each epitope showed that all of them were non-toxic, non-allergen, and soluble but had different antigenicity values. Among these epitopes, EMEDQGSAGSAGS associated with L. major, STHDSGSTTC and AEDILTDEKRDILRK epitopes associated with L. infantum had the highest antigenicity values for B cell, MHC-I, and MHC-II epitopes, respectively. Moreover, conserved epitopes were detected among two or three Leishmania species. CONCLUSIONS/SIGNIFICANCE: This study detected many epitopes that could be used in vaccine studies and the development of serological diagnostic assays.

Antigens, Protozoan↗

PubMed2004

Rescuing melanoma epitope-specific cytolytic T lymphocytes from activation-induced cell death, by SP600125, an inhibitor of JNK: implications in cancer immunotherapy.

Activation-induced cell death (AICD) as well as programmed cell death (PCD) serve to control the expansion of activated T cells to limit untoward side effects of continued effector responses by T cells and to maintain homeostasis. AICD of T cells in tumor immunotherapy can be counterproductive particularly if the activated T cells undergo apoptotic death after the very first secondary encounter of the specific epitope. We examined the extent to which tumor epitope-specific CTLs that are activated and expanded in an in vitro-matured dendritic cell-based primary stimulation protocol undergo AICD following their first secondary encounter of the cognate epitope. Using the MART-1(27-35) epitope as a prototype vaccine epitope, we also examined whether these CTLs could be rescued from AICD. Our results demonstrate that a substantial fraction of MART-1(27-35) epitope-specific primary CTLs undergo AICD upon the very first secondary encounter of the cognate epitope. The AICD in these CTLs is neither caspase dependent nor is it triggered by the extrinsic death signaling pathways (Fas, TNFR, etc.). These CTLs, interestingly, could be rescued from AICD by the JNK inhibitor, SP600125. We also found that SP600125 interferes with their IFN-gamma response but does not block their cytolytic function. The rescued CTLs, however, regain their capacity to synthesize IFN-gamma if continued in culture without the inhibitor. These observations have implications in tumor immunotherapy and in further studies for regulation of AICD in CTLs.

Anthracenes↗

PubMed1996

Fine tuning of epitopic dominance induced by lung cancer on the IgG response to bovine betalactoglobulin: towards a paraneoplastic immune marker.

BACKGROUND: Investigating the humoral immune response to mucosal antigens in patients with lung cancer, we have documented a preferential immunoglobulin G (IgG) binding to cryptic epitopes unmasked by the proteolysis of bovine beta-lactoglobulin (BLG). In contrast, IgG from healthy controls and patients with chronic bronchitis (COPD) bind preferentially to continuous epitopes presented on both native (n) and denaturated (d) forms of this antigen. The present study further characterized the differences in the epitope profiles recognized on BLG. METHODS: The capacity of individual sera from 65 lung cancer patients, tested before and after cancer removal for the patients with early stage lung carcinoma, 65 healthy controls, and 52 patients with COPD, to prevent the binding of pooled IgG fractions from each population as well as murine monoclonal antibodies (MoAb), specific for BLG, to solid phase bound antigen was evaluated in enzyme-linked immunoadsorbent assay using streptavidin-biotin technology. Some of these experiments were also performed with sera from 42 patients diagnosed with other cancers. RESULTS: Compared with control sera and sera from patients with other solid tumors, lung cancer patient sera showed distinct capacities to prevent the binding of murine MoAb as well as human pooled IgG fractions to n- and d-BLG. The inhibition capacities of lung cancer sera changed as soon as five weeks after cancer removal. CONCLUSIONS: The results indicate that the difference in epitope specificity exhibited by lung cancer sera is not restricted to cryptic epitopes, but also affects continuous and discontinuous epitopes, accessible only on the native antigen. A high level of binding discrimination between antibodies from the study populations is also observed at the level of the epitope. This deviation in the epitope specificity of antibodies changes soon after cancer removal, suggesting a tumor-dependent disturbance. Also documented in the Dermatophagoides pteronyssinus model, it opens the way to a new class of paraneoplastic immune markers for this malignancy, with, at first glance, a high specificity level.

Adenocarcinoma↗