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PubMed1985

Systemic lupus erythematosus with deficiency of the T4 epitope on T helper/inducer cells.

Three black Jamaicans with systemic lupus erythematosus (SLE) were identified whose T helper/inducer cells lacked the T4 epitope (T4 epitope-deficient phenotype). All three patients had lymphadenopathy as part of their syndromes. The asymptomatic and otherwise healthy T4 epitope-deficient brother of one of these patients also had lymphadenopathy in a distribution identical to that of his sister with SLE. Family studies pointed to an autosomal codominant mode of inheritance not linked to the HLA locus for the T4 epitope phenotype. Cultures of peripheral-blood mononuclear cells revealed impaired B-cell differentiation upon stimulation with pokeweed mitogen in cells originating from the T4 epitope-deficient family members as compared with those originating from their T4 epitope-intermediate relatives. Ratios of T helper/inducer cells to T suppressor/cytotoxic cells, the presence of various autoantibodies, and proliferation in response to mitogens and in the mixed lymphocyte reactions did not correlate with T4 epitope phenotype. We suggest that SLE in association with the T4 epitope-deficient phenotype may represent a unique subset of patients with SLE that has distinct clinical and immunologic properties.

B-Lymphocytes↗
PubMed2005

Cell membrane-specific epitopes on CD30: Potentially superior targets for immunotherapy.

Because CD30 is highly expressed on Hodgkin's lymphoma and anaplastic large cell lymphoma, it is a promising target for immunotherapy. Soluble CD30, the extracellular domain of CD30 that is shed from the cells, can reduce the effects of CD30-targeting agents by competitive binding. In this study, we identified two epitopes on membrane-associated CD30 that are missing on soluble CD30 probably because of a conformational change upon shedding. These epitopes are potentially superior targets for immunotherapy because targeting them should be free from the competitive effects of soluble CD30. We studied 27 anti-native CD30 mAbs that were assigned to 8 different topographical epitopes. Soluble CD30 was prepared from culture supernatants of L540 cells or Karpas 299 cells. In an ELISA, the mAbs to two epitopes, Ep2 (amino acids 107-153) and Ep7 (amino acids 282-338), showed less than a 2% average cross-reactivity to soluble CD30 compared with a CD30-Fc fusion protein. In addition, these mAbs bound to CD30 on cells in the presence of an excess of soluble CD30. These epitopes (Ep2 and Ep7) are, therefore, more efficiently presented on cell-associated CD30 than on soluble CD30 (membrane-specific epitopes). Also, soluble CD30 in the sera of mice bearing L540 tumors did not form immune complexes with the membrane-specific mAbs analyzed by size-exclusion chromatography. In contrast, mAbs to the other epitopes reacted with both soluble CD30 and membrane CD30. Our results suggest that it may be possible to find membrane-specific epitopes on other immunotherapy target molecules.

Animals↗
PubMed1998

T cell-independent type I antibody response against B cell epitopes expressed repetitively on recombinant virus particles.

Recombinant viral or virus-like particles offer new tools for vaccine development. This study investigated hepatitis B core antigen (HBcAg) capsids and RNA phage Qbeta coats as carriers of a foreign epitope to induce antibody responses in mice. HBcAg capsids were shown to induce T cell-independent (TI) antibodies. We found that these particles behave as antigen-specific TI type 1 (TI-1) Ag comparable to other rigidly structured viruses. When a 5-aa long epitope of the pre-S1 domain of hepatitis B surface antigen (HBsAg) was introduced into the optimal position of the HBc molecule, it also behaved as a TI-1 Ag. Best efficiency of the antibody response to the foreign epitope was achieved by a compensatory deletion after the epitope to retain the regular structure of the HBcAg capsid with a highly repetitive superficial exposition of the foreign epitope. For recombinant Qbeta phage coats, a much more efficient antibody response to the foreign epitope was achieved when the foreign epitope was expressed repetitively on a particulate derivate of Qbeta phage coats. Thus, recombinant virus particles are suitable vaccine carriers for the introduction of foreign B cell epitopes, if precise structural requirements are fulfilled.

Amino Acid Sequence↗
PubMed1998

Differential exposure of surface epitopes in the beta-strand region of LOOP1 of the yeast H+-ATPase during catalysis.

The plasma membrane H+-ATPase of yeast assumes distinct conformational states during its catalytic cycle. To better understand structural changes in the LOOP1 domain, a catalytically important cytoplasmic loop segment linking transmembrane segments 2 and 3, surface epitopes were examined at different stages of catalysis. A polyclonal rabbit antibody was prepared to a fusion protein consisting of LOOP1 and the maltose binding protein. This antibody was affinity-purified to produce a LOOP1-specific fraction that could be used in competition enzyme-linked immunosorbent assays to assess surface exposure of the LOOP1 epitopes. It was found that in an E1 conformation stabilized with either adenosine 5'-(beta,gamma -imino)triphosphate (AMP-PNP) or ADP, less than 10% of the LOOP1 epitopes were accessible on native enzyme. However, when the enzyme was stabilized in an E2-state with ATP plus vanadate, approximately 40% of the surface epitopes on LOOP1 became accessible to antibody. The remaining 60% of the LOOP1 epitopes were fully occluded in the native enzyme and never showed surface exposure. Enzyme-linked immunosorbent assays utilizing fusion proteins consisting of LOOP1 subdomains demonstrated that all of the available epitopes were contained in the beta-strand region (Glu-195-- Val-267) of LOOP1. The epitopes that were differentially exposed during catalysis were included in regions upstream and downstream of the highly conserved TGES sequence. Our results suggest that during catalysis either the beta-strand region of LOOP1 or an interacting domain undergoes substantial structural rearrangement that facilitates epitope exposure.

Adenylyl Imidodiphosphate↗
PubMed2000

The goodpasture autoantigen. Identification of multiple cryptic epitopes on the NC1 domain of the alpha3(IV) collagen chain.

Goodpasture (GP) disease is an autoimmune disorder in which autoantibodies against the alpha3(IV) chain of type IV collagen bind to the glomerular and alveolar basement membranes, causing progressive glomerulonephritis and pulmonary hemorrhage. Two major conformational epitope regions have been identified on the noncollagenous domain of type IV collagen (NC1 domain) of the alpha3(IV) chain as residues 17-31 (E(A)) and 127-141 (E(B)) (Netzer, K.-O. et al. (1999) J. Biol. Chem. 274, 11267-11274). To determine whether these regions are two distinct epitopes or form a single epitope, three GP sera were fractionated by affinity chromatography on immobilized NC1 chimeras containing the E(A) and/or the E(B) region. Four subpopulations of GP antibodies with distinct epitope specificity for the alpha3(IV)NC1 domain were thus separated and characterized. They were designated GP(A), GP(B), GP(AB), and GP(X), to reflect their reactivity with E(A) only, E(B) only, both regions, and neither, respectively. Hence, regions E(A) and E(B) encompass critical amino acids that constitute three distinct epitopes for GP(A), GP(B), and GP(AB) antibodies, respectively, whereas the epitope for GP(X) antibodies is located in a different unknown region. The GP(A) antibodies were consistently immunodominant, accounting for 60-65% of the total immunoreactivity to alpha3(IV)NC1; thus, they probably play a major role in pathogenesis. Regions E(A) and E(B) are held in close proximity because they jointly form the epitope for Mab3, a monoclonal antibody that competes for binding with GP autoantibodies. All GP epitopes are sequestered in the hexamer configuration of the NC1 domain found in tissues and are inaccessible for antibody binding unless dissociation of the hexamer occurs, suggesting a possible mechanism for etiology of GP disease. GP antibodies have the capacity to extract alpha3(IV)NC1 monomers, but not dimers, from native human glomerular basement membrane hexamers, a property that may be of fundamental importance for the pathogenesis of the disease.

Anti-Glomerular Basement Membrane Disease↗
PubMed2006

Major histocompatibility complex and T cell interactions of a universal T cell epitope from Plasmodium falciparum circumsporozoite protein.

A 20-residue sequence from the C-terminal region of the circumsporozoite protein of the malaria parasite Plasmodium falciparum is considered a universal helper T cell epitope because it is immunogenic in individuals of many major histocompatibility complex (MHC) haplotypes. Subunit vaccines containing T* and the major B cell epitope of the circumsporozoite protein induce high antibody titers to the malaria parasite and significant T cell responses in humans. In this study we have evaluated the specificity of the T* sequence with regard to its binding to the human class II MHC protein DR4 (HLA-DRB1*0401), its interactions with antigen receptors on T cells, and the effect of natural variants of this sequence on its immunogenicity. Computational approaches identified multiple potential DR4-binding epitopes within T*, and experimental binding studies confirmed the following two tight binding epitopes: one located toward the N terminus (the T*-1 epitope) and one at the C terminus (the T*-5 epitope). Immunization of a human DR4 volunteer with a peptide-based vaccine containing the T* sequence elicited CD4+ T cells that recognize each of these epitopes. Here we present an analysis of the immunodominant N-terminal epitope T*-1. T*-1 residues important for interaction with DR4 and with antigen receptors on T*-specific T cells were mapped. MHC tetramers carrying DR4/T*-1 MHC-peptide complexes stained and efficiently stimulated these cells in vitro. T*-1 overlaps a region of the protein that has been described as highly polymorphic; however, the particular T*-1 residues required for anchoring to DR4 were highly conserved in Plasmodium sequences described to date.

Amino Acid Sequence↗
PubMed2003

ELDKWA-epitope-specific monoclonal antibodies inhibit HIV env-mediated syncytium formation.

Recent studies demonstrated that the N- and C-domains of HIV-1 gp41 are involved in virus-mediated membrane fusion resulting in HIV-entry into target cells. Synthetic N- and C-domain peptides, such as DP107 and DP178, potently inhibit membrane fusion induced by both laboratory-adapted strains and primary isolates of HIV-1. Monoclonal antibody (mAb) 2F5 recognizing ELDKWA-epitope on the gp41 C-domain has shown broad neutralizing activity to many HIV stains even primary isolates. To test the neutralizing mechanism of the ELDKWA-epitope-specific antibody, mAbs with predefined ELDKWA-epitope-specificity were induced by synthetic epitope-peptide instead of a natural or recombinant gp41 bearing this epitope. All of five mAbs were identified to recognize ELDKWA-epitope on recombinant soluble gp41 in ELISA-assay. In flow cytometry analysis, four out of five mAbs could bind to HIV-Env+ CHO-WT cells and such binding could be inhibited by ELDKWA-epitope peptide, which suggests that these mAbs could recognize native envelope protein expressed on cell membranes. Interestingly, two out of five mAbs could inhibit membrane fusion between the CXCR4- and CD4-expressing 3T3.T4.CXCR4 cells and HIV-Env+ CHO-WT cells in a dose-dependent manner, consistent with their potent binding capability to HIV-Env+ CHO-WT cells. Parren et al. (1998) suggested that neutralization of HIV-1 by antibody may be determined primarily by occupancy of sites and spatial obstruction which blocks virus entry. Based on this theory, a model was suggested to explain the neutralizing activities of mAbs against the epitope ELDKWA.

3T3 Cells↗
PubMed2002

Searching for the cartilage-associated mimicry epitope in adjuvant arthritis.

Adjuvant arthritis (AA) is a T cell mediated disease which can be induced in genetically susceptible rats by immunization with heat-killed Mycobacterium tuberculosis (Mt) suspended in incomplete Freund's adjuvant. The critical mycobacterial T cell epitope for the induction of AA was previously identified as residues 178-186 of the mycobacterial 65 kDa heat shock protein (Mt. hsp65(178-186)). It was suggested that the development of AA was due to molecular mimicry between a mycobacterial epitope and a cartilage-associated self-antigen. However, until now such cartilage-associated mimicry epitope has not been identified. In this study we designed a computer search profile to predict mimicry self-epitopes, and investigated whether one or more of these self-epitopes could serve as mimicry epitopes in AA. Although several of these self-epitopes were recognized by arthritogenic T cells, no cross-reactivity was found between T cells specific for these self-epitopes and Mt. hsp65(178-186) specific T cells.

Amino Acid Sequence↗
PubMed1988

An immunodominant epitope present in multiple class I MHC molecules and recognized by cytotoxic T lymphocytes.

CTL derived from (C3H x B6.K1)F1 animals were sensitized against L cells that express the transfected gene product Q10d/Ld. These CTL were highly crossreactive against three other class I molecules, H-2Kbm1, H-2Ld, and H-2Kd. In an attempt to define this crossreactive epitope it was noted that between 25 and 39% of amino acids in the alpha helices and central beta strands of these three molecules vary from Q10d. These amino acids represent residues that have been proposed to potentially interact with a peptide antigen or TCR (21). However, all four molecules share the amino acid tyrosine at positions 155 and 156. Additionally, Q10d, H-2Kbm1, and H-2Ld share alanine at position 152, while H-2Kd has an aspartic acid. We showed that these residues were important in controlling this epitope by the finding that anti-Q10d CTL did not recognize H-2Kbm1 revertant molecules that had either the position 152 alanine changed back to the wild-type H-2Kb residue (glutamic acid) or position 155 and 156 tyrosines changed back to wild-type residues arginine and leucine. Further evidence that these molecules share a crossreactive epitope was noted by the failure of (C3H x H-2Kbm1)F1 animals to generate CTL that recognized H-2Ld or H-2Kd, and the inability of (C3H x BALB/c)F1 animals to generate CTL reactive against H-2Kbm1. CTL from these mice were still able to recognize Q10d/Ld indicating that other epitopes could be detected if natural tolerance prevented recognition of the crossreactive epitope. To further define the epitope, CTL clones were generated against Q10d/Ld and maintained on either H-2Kbm1 or BALB/c feeder cells. In addition to testing these clones on the target cells described above, mutant molecules derived from H-2Ld, which have amino acid substitutions in their alpha 1 domain, were analyzed. It was noted that some anti-Q10 clones that did not crossreact on H-2Ld did react against H-2Ld mutant antigens that had H-2Dd amino acid substitutions in the alpha 1 domain at positions 63, 65, 66, and 70. Other clones had differential reactivities on these H-2Ld mutants further substantiating that alpha 1 domain amino acids play a role in controlling the expression of the crossreactive epitope. Thus, four class I molecules with multiple amino acid differences in their alpha 1 and alpha 2 domains share a crossreactive epitope readily recognized by alloreactive CTL.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed mutants and anti-idiotypes.

The CD4 molecule, a differentiation marker expressed primarily by T lymphocytes, plays an important role in lymphocyte activation. CD4 is also the receptor for HIV. A number of recent studies have localized the high affinity binding site of the HIV envelope glycoprotein, gp120, to the NH2-terminal (V1) domain of CD4, a region with sequence and predicted structural homology with Ig kappa chain V domains (V kappa). In this report, we show that V1 bears structural similarities with V kappa regions through detailed epitope mapping of 26 CD4 mAbs. The binding sites of these mAbs were initially defined relative to one another by crossblocking analysis and were then localized to specific domains of CD4 in blocking studies with truncated, soluble CD4 proteins. The epitopes within the V1 domain were mapped in detail with a panel of 17 substitution mutants, and the specificities of several mAbs that appear to recognize very similar epitopes were examined in crossblocking studies with anti-idiotype antibodies. The location of the epitopes is consistent with a V kappa-like structure of V1. Most of the epitopes lie within regions of predicted exposed loops. A number of these epitopes span discontinuous residues in the linear sequence that lies in close proximity in an Ig fold. Alignment of CD4 V1 with the Ig V kappa chains places these epitopes within stretches corresponding to the complimentarity-determining regions. This epitope analysis is relevant for a vaccine strategy for HIV based on anti-idiotype antibodies to CD4 mAbs and for studies with CD4 antibodies on the role of CD4 in T lymphocyte activation.

Amino Acid Sequence↗
PubMed1996

B7-CD28 costimulation unveils the hierarchy of tumor epitopes recognized by major histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes.

Immunization of mice with tumors genetically engineered to express the B7 costimulatory molecules amplifies the antitumor immune response mediated by CD8+ cytolytic T lymphocytes (CTL). In this report, we examined the effect of B7-CD28 costimulation on the hierarchy of tumor epitopes. Using a combination of affinity chromatography/reversed-phase high performance liquid chromatography and CTL cloning, we show that major histocompatibility complex (MHC) class I molecules from EL4 lymphoma cells can present at least six distinct CTL epitopes presented by MHC class I molecules. Nevertheless, mice immunized with wild-type B7-negative EL4 cells develop CTL only to one immunodominant epitope. In contrast, immunization with B7-transduced EL4 cells led to not only the amplification of the CTL response to this immunodominant epitope, but also to the recognition of five otherwise silent subdominant epitopes. The adoptive transfer of a CTL clone against such a subdominant epitope cured mice bearing EL4 lymphoma growing as an ascites tumor. The fact that CTL response can be spread to normally silent epitopes as a result of B7-CD28 costimulation suggests a novel approach to manipulate the hierarchy of CTL epitopes and offers an opportunity to explore novel targets for T cell-mediated cancer therapy.

Animals↗
PubMed1996

Patr-A and B, the orthologues of HLA-A and B, present hepatitis C virus epitopes to CD8+ cytotoxic T cells from two chronically infected chimpanzees.

Common chimpanzees (Pan troglodytes) infected with hepatitis C virus (HCV) show a disease progression similar to that observed for human patients. Although most infected animals develop a chronic hepatitis, virus persistence is associated with an ongoing immune response, for which the beneficial or detrimental effects are uncertain. Lines of virus-specific cytotoxic CD8+ T lymphocytes (CTL) have been previously established from liver biopsies of two common chimpanzees chronically infected with HCV-1. The viral epitopes recognized by six lines of CTL have been defined using synthetic peptides and shown to consist of 8 to 9-residue peptides derived from various viral proteins. Five of the epitopes derive from sequences that vary among strains of HCV. The majority of the corresponding variant epitopes from different HCV strains were either recognized less efficiently or not at all by the CTL, suggesting their response may have limited potential for controlling replication of HCV variants. Complementary DNAs encoding class I alleles of the two common chimpanzees, Patr-A, -B, and -C were cloned, sequenced, and transfected individually into a class I-deficient human cell line. Analysis of peptide presentation by the class I transfectants to CTL identified the Patr class I allotypes that present the six epitopes defined here and an additional epitope defined previously. The assignment of epitopes to class I allotypes based upon analysis of the transfected cells correlates precisely with the segregation of antigen-presenting function within a panel of common chimpanzee cell lines and the expression of class I heavy chains as defined by isoelectric focusing. Five of the HCV-1 epitopes are presented by Patr-B allotypes, two epitopes are presented by a Patr-A allotype, and none is presented by Patr-C allotypes.

Amino Acid Sequence↗
PubMed2002

Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection.

Primary virus infection often elicits a large CD8(+) T cell response which subsequently contracts to a smaller memory T cell pool; the relationship between these two virus-specific populations is not well understood. Here we follow the human CD8(+) T cell response to Epstein-Barr virus (EBV) from its primary phase in infectious mononucleosis (IM) through to the persistent carrier state. Using HLA-A2.1 or B8 tetramers specific for four lytic cycle and three latent cycle epitopes, we find marked differences in the epitope-specific composition of the T cell populations between the two phases of infection. The primary response is dominated by lytic epitope specificities which are severely culled (and in one case extinguished) with resolution of the acute infection; in contrast latent epitope specificities are less abundant, if present at all, in acute IM but often then increase their percentage representation in the CD8 pool. Even comparing epitopes of the same type, the relative size of responses seen in primary infection does not necessarily correlate with that seen in the longer term. We also follow the evolution of phenotypic change in these populations and show that, from a uniform CD45RA(-)RO(+)CCR7(-) phenotype in IM, lytic epitope responses show greater reversion to a CD45RA(+)RO(-) phenotype whereas latent epitope responses remain CD45RA(-)RO(+) with a greater tendency to acquire CCR7. Interestingly these phenotypic distinctions reflect the source of the epitope as lytic or latent, and not the extent to which the response has been amplified in vivo.

Adolescent↗
PubMed2004

B cell memory is directed toward conformational epitopes of parvovirus B19 capsid proteins and the unique region of VP1.

BACKGROUND: Loss of antibody reactivity against linear epitopes of parvovirus B19 (B19) capsid proteins VP1 and VP2 occurs after infection; however, it is unclear whether B cell memory is established against linear epitopes. METHODS: B cell enzyme-linked immunospot assay was used to evaluate B19-specific B cell memory in volunteer donors (n=22). RESULTS: B cell memory is maintained against conformational epitopes of VP2 and is absent against linear epitopes of VP2. Individuals seronegative for IgG against the unique region of VP1 have detectable B cell memory, with the potential to mount a humoral response on reexposure to B19. Conversely, in mice immunized with VP2, long-lasting IgG against linear epitopes of VP2 and a strong B cell-memory response are observed. CONCLUSIONS: B cell memory is established and maintained against conformational epitopes of VP2 and against linear epitopes of VP1 but not against linear epitopes of VP2. These findings further our understanding of the immune response to B19 and suggest that analysis of B19-specific B cell memory merits consideration for future B19-vaccine studies.

Adult↗
PubMed1990

Mouse monoclonal antibody 5-21-3 recognizes a contiguous, conformation-dependent epitope and maps to a hydrophilic region in HIV-1 gp41.

Mouse monoclonal antibody 5-21-3 is mapped to an epitope within a hydrophilic region of HIV-1 gp41 between amino acids 642 and 665 (numbering by Meyers et al. based on HXB2 isolate). The epitope is formed from amino acids within the sequence IHSLIEESQNQQEKNEQELLELDK; however, antibody 5-21-3 is unable to recognize the epitope-forming sequence when it is presented to the antibody in the form of a short (642-665) synthetic polypeptide. The epitope apparently is partially formed when additional native sequence of varying length is added to the amino and/or carboxy ends of the epitope-forming sequence, and 5-21-3 binds these larger synthetic polypeptides to varying degrees depending on the position and length of the flanking sequences. The 5-21-3 epitope apparently is formed from contiguous amino acids which require a specific, conformation-dependent, secondary structure for proper epitope formation. Binding preferences exhibited by 5-21-3 toward synthetic polypeptides and recombinant proteins may reflect the conformational nature of the epitope in disrupted HIV which elicited formation of the monoclonal.

Amino Acid Sequence↗
PubMed1997

Epitopes for thyroid stimulating and blocking autoantibodies on the extracellular domain of the human thyrotropin receptor.

The majority (97%) of functional epitopes for stimulating thyrotropin receptor (TSHR) antibodies (stimulating TSHRAbs) in a large cohort (n = 59) of Japanese Graves' patients exists on the N-terminal region of the extracellular domain of TSHR, between residues 25 and 165 numbering from the methionine start site. This was determined by measuring the loss of stimulating activity in the Cos-7 cells transfected with TSHR/lutropin-choriogonadotropin receptor (LH-CGR) chimeras wherein TSHR residues 89-165 (Mc2) or 8-165 (Mc1 + 2) are replaced by comparable LH-CGR residues. There is no comparable loss when stimulating TSHRAb activity is measured in an Mc4 chimera, wherein TSHR residues 261 to 370 are replaced. In contrast, immunoglobulin (IgG) preparations from 35 patients with Hashimoto's disease or idiopathic myxedema, who have blocking TSHRAbs causing hypothyroidism, loose blocking TSHRAb activity in the Mc4 chimera, but not the Mc2 or Mc1 + 2 chimeras. Thus, in a large population of Japanese patients with autoimmune thyroid disease caused by TSHR autoantibodies, the major functional epitope for stimulating TSHRAbs is on the N-terminal portion of the TSHR extracellular domain, whereas that for blocking TSHRAbs is on the C-terminal portion of the extracellular domain. To further evaluate the nature of the critical functional epitope between residues 90 to 165, we divided this region approximately in half, creating chimeras Mc2a and Mc2b with, respectively, residues 90-124 or 125-165 replaced by comparable LH-CGR residues. IgGs from all patients tested lost significant stimulating activity using the Mc2a and Mc2b chimeras; however, when present, residual stimulating TSHRAb activity was evident on one or the other half of the region or on both halves, indicating that both segments are required for expression of the stimulating TSHRAb epitope within residues 90-165. Finally, we have identified a complex epitope involving both the N- and C-terminal portion of the extracellular domain that appears to account for the small fraction of stimulating TSHRAbs whose activity is not solely dependent on residues 25 to 165. Thus, using chimeras Mc1 + 2 + 4, with TSHR residues 8-165 and 261-370 substituted, or chimera Mc1 + 2 + 3 + 4, with residues 8-370 substituted, as well as Mc2, Mc1 + 2, and Mc4, we show that the Graves' IgGs which maintain stimulating TSHRAb activity when residues 8-165 of the TSHR are replaced by LH-CGR residues have an epitope involving residues 90-165 and the immunogenic 15mer peptide (YYVFFEEQEDEIIGF), residues, 352-366. Because that peptide can decrease the stimulating TSHRAb activity of these Graves IgGs in assays with the Mc2 chimera alone, we speculate that this complex epitope may be important in an epitope spreading process involved in the formation of stimulating TSHRAbs.

Amino Acid Sequence↗
PubMed2000

Various stages of schistosoma express Lewis(x), LacdiNAc, GalNAcbeta1-4 (Fucalpha1-3)GlcNAc and GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAc carbohydrate epitopes: detection with monoclonal antibodies that are characterized by enzymatically synthesized neoglycoproteins.

We report here that fucosylated epitopes such as Lewis(x), LacdiNAc, fucosylated LacdiNAc (LDN-F) and GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAc (LDN-DF) are expressed by schistosomes throughout their life cycle. These four epitopes were enzymatically synthesized and coupled to bovine serum albumin to yield neoglycoproteins. Subsequently these neoglycoproteins were used to probe a panel of 188 monoclonal antibodies obtained from infected or immunized mice, in ELISA and surface plasmon resonance analysis. Of these antibodies, 25 recognized one of the fucosylated structures synthesized, indicating that these structures are immunogenic during infection. The MAbs identified could be subdivided in four different groups based on the recognition of either the Lewis(x)-, the LacdiNAc-, the LDN-DF-, or both the LDN-F- and LDN-DF epitope. These monoclonal antibodies were then used to investigate the localization of the fucosylated epitopes in various stages of Schistosoma mansoni using indirect immunofluorescence. Lewis(x)epitopes were mainly found in the gut and on the tegument of adult worms, on egg shells, and on the oral sucker of cercariae. The LacdiNAc epitope was expressed on the tegument of adult worms, on miracidia, and on the oral sucker of cercariae. In contrast, LDN-DF epitopes were mainly present in the excretory system of adult worms, on miracidia and on whole cercariae. These also stained positive with the LDN-F/LDN-DF epitope antibodies, while whole parenchyma reacted characteristically only with the latter antibodies. The identification of different carbohydrate structures in various stages of schistosomes may lead to a better understanding of the function of glycans in the immune response during infection.

Animals↗
PubMed1998

Serological responses of patients with ectopic pregnancy to epitopes of the Chlamydia trachomatis 60 kDa heat shock protein.

Clinical and histopathological correlations of immunoreactivity to Chlamydia trachomatis and to epitopes of the C. trachomatis 60 kDa heat shock protein (hsp60) among women with ectopic pregnancy were evaluated in a case-control study. Serological responses to 13 synthetic peptides corresponding to major epitopes of the chlamydial hsp60 were determined in 67 women treated for ectopic pregnancy and 45 women with uncomplicated pregnancy in utero. Plasma cell salpingitis was detected in 29 (43.3%) of the ectopic patients. Its presence correlated with antibodies to two hsp60 epitopes, encompassing amino acids 260-271 and 411-422 (P = 0.02). Antibodies to these two epitopes, along with five other epitopes, also correlated with peritubal adhesion formation in ectopic pregnant patients (P < 0.01). Antibodies to epitopes 260-271 and 188-199 also correlated with a history of pelvic inflammatory disease (PID; P = 0.05). Patients with ectopic pregnancy were also more likely than their intrauterine pregnant controls to have present anti-chlamydial immunoglobulin G (P < 0.005). Women positive for both C. trachomatis and hsp60 epitope antibodies had an increased prevalence over controls of salpingitis, pelvic adhesions or history of PID (P < 0.05). In contrast, patients who were positive for only C. trachomatis antibodies or only hsp60 epitope antibodies did not differ from antibody-negative patients in each of these categories.

Adult↗