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At least 145 records · Page 8Linked to original sources
PubMed1994

Cellular adhesion antigen modulation in purpura pigmentosa chronica.

BACKGROUND: Purpura pigmentosa chronica is an inflammatory skin disorder probably caused by an allergic reaction. Delayed-type hypersensitivity or immunocomplex vasculitis has been considered as a possible mechanism. OBJECTIVE: Detailed analysis of cell adhesion molecule (CAM) modulation may give further insights into the pathogenesis and underlying immune reaction of this disease. METHODS: By immunohistochemical techniques we investigated the in situ expression of integrins, selectins, and CAMs of the immunoglobulin superfamily. RESULTS: Infiltrating lymphocytes expressed LFA-1, LFA-2, VLA-4, and VLA-5, whereas some of the macrophages were also positive for p150/95 and MAC-1. VLA-1 was found on lymphocytes near the basement membrane of the epidermis. Compared with uninvolved or healthy skin endothelial cells showed upregulation of ICAM-1, VCAM-1, and, focally, E-selectin. Some fibroblasts were positive for ICAM-1. ICAM-1 was also upregulated on lesional keratinocytes that also expressed alpha 2, alpha 3, and alpha 6 integrin chains on basal and suprabasal epidermal layers. CONCLUSION: Our findings demonstrate characteristic modifications in the expression of CAMs in purpura pigmentosa chronica and indicate the involvement of the epidermis in this disease. This modulation shows close parallels to those described for chronic delayed-type immune reactions of the skin.

Cell Adhesion Molecules↗
PubMed2001

N-linked glycosylation in the V3 region of HIV type 1 surface antigen modulates coreceptor usage in viral infection.

The V3 hypervariable region of HIV-1 surface protein has been identified as a major determinant for viral tropism and coreceptor usage. However, the role of the highly conserved N-linked glycan at the V3 loop remains controversial. To further examine its role in viral infection, we introduced a conservative amino acid substitution (asparagine to glutamine) in the V3-proximal glycosylation motif (Asn-X-Ser/Thr) in the surface glycoprotein of a CXCR4-using virus (BRU), a CCR5-using virus (SF162), and a dual-tropic virus (89.6). The effect of the mutation was determined by complementation assays, and by infectivity on CEMx174 and U373-MAGI cells expressing either CXCR4 or CCR5. The mutation resulted in decreased CXCR4 usage by SHIV89.6, but increased usage by BRU. Similarly, it abrogated CCR5 usage by SHIV89.6, but had no effect on SF162. This effect was not dependent on the specific amino acid substitution used, because a threonine-toalanine mutation in the same motif in 89.6 Env yielded identical results as the asparagine-to-glutamine mutation. These findings support the notion that multiple factors, including glycosylation at V3, contribute to coreceptor usage and that the particular effects exerted by the N-linked glycan itself appear to be isolate dependent.

Amino Acid Motifs↗
PubMed1976

Effects of contact sensitization and delayed hypersensitivity reactions on immune responses to non-related antigens. Modulation of Immune responses.

Guinea pigs were immunized intracutaneously into the ears with sheep red blood cells (SRBC). Application of a sensitizing dose of the contact allergen dinitrochlorobenzene (DNCB) onto the same ears was shown to suppress or enhance the humoral response to SRBC depending on the time of application. When guinea pigs were sensitized to a contact allergen, application of a sensitizing dose of a non-related allergen on the same ears either had no effect or caused a clear enhancement of the development of delayed type hypersensitivity (DTH). Strongest enhancement was found when both sensitizations were performed on the same day. Further experiments on the effects of a concomitant DTH reaction elicited at the site of application of a contact allergen showed a strong potentiation of DTH when B-cell suppression was minimized by pretreatment with cyclophosphamide (CY). It was considered that CY-DTH-immunopotentiation might be a useful tool for achieving a higher level of sensitivity after epicutaneous sensitization.

Allergens↗
PubMed1996

Can immunoglobulin C(H)1 constant region domain modulate antigen binding affinity of antibodies?

Although the switch process is frequently associated with affinity maturation, the constant region is not assumed to play a role in Ag-Ab binding. In the present work, we demonstrate that two clonally related human monoclonal Igs sharing identical V(H) and V(L) sequences, but expressing different isotypes (IgA1kappa(PER) and IgG1kappa(PER)), bind tubulin with significantly different affinities. This difference was mainly accounted for by a disparity in the association rate constants. These results suggest that affinity maturation of this clone could be achieved through class switching in the absence of further somatic mutations. Since the differences observed were found at the Fab level, they also suggest a role for the C(H)1 domain in structuring the Ag-binding site into a more kinetically competent form.

Amino Acid Sequence↗
PubMed2003

Amino acid residue substitution at T-cell determinant-flanking sites in beta-lactoglobulin modulates antigen presentation to T cells through subtle conformational change.

We compared T-cell responses to regions in residues 21-40 of A and B variants of bovine milk beta-lactoglobulin (beta-LG) that vary by two different amino acid residues at 64 and 118. Results showed that T cells from C57/BL6 and C3H/HeN mice immunized with peptide 21-40 or BALB/c mice immunized with peptide 21-32 or 25-40 responded more vigorously to beta-LG B than to beta-LG A. This difference in response to 25-40 in BALB/c mice was not observed when beta-LGs B and A were denatured, suggesting that the conformation difference affects display of the determinant 25-40. Reactivity of anti-beta-LG monoclonal antibodies and molecular modeling using molecular dynamics calculations revealed subtle differences in the three-dimensional structure of these two variants. Furthermore, substitution of two amino acid residues at sites distant from the T-cell determinant induced differential determinant display on antigen-presenting cells, possibly due to subtle conformational changes in beta-LG.

Amino Acid Substitution↗
PubMed1989

Expression and modulation of surface antigens in cultured rat glomerular visceral epithelial cells.

This study, using immunocytochemical light and electron microscopy techniques, characterizes the distribution of three antibodies bound to the surface of rat glomerular visceral epithelial cells (GEC) in culture, and tests their ability to redistribute corresponding antigens under conditions appropriate for antigenic modulation (antigen disappearance). At 4 degrees C or after fixation, anti-renal tubular brush border vesicle (BBV) IgG bound diffusely to the surface of GEC and to coated pits. Anti-gp330 IgG had a discrete distribution on the surface of GEC and reacted with coated pits. Anti-podocalyxin IgG was bound diffusely to the surface of GEC but not to coated pits. At 37 degrees C, anti-BBV IgG induced marked redistribution of immune complexes with both shedding and internalization. Anti-gp330 IgG induced weaker redistribution, with internalization of immune complexes predominating. Anti-podocalyxin IgG induced rapid redistribution of immune complexes and antigenic modulation but minimal internalization. Experiments of differential redistribution indicated that anti-BBV IgG modulated the expression of both gp330 and podocalyxin; anti-gp330 IgG had a weaker effect on BBV antigens and podocalyxin; and anti-podocalyxin failed to redistribute BBV antigens or gp330. The relevance of these immunocytochemical studies of antibody-cell surface antigen interaction in cultured GEC to understanding the pathogenesis of Heymann glomerulonephritis (HG) is discussed.

Animals↗
PubMed1987

Lung injury mediated by antibodies to endothelium. II. Study of the effect of repeated antigen-antibody interactions in rabbits tolerant to heterologous antibody.

The effect of repeated interactions of antibodies with cell surface antigens have been examined in in vitro, but not in in vivo systems. In this study are described the results of multiple antibody-cell surface antigen interactions in vivo. Rabbits were given repeated intravenous injections of goat antibodies to angiotensin converting enzyme (ACE), an antigen expressed on the surface of lung endothelial cells. For prevention of anaphylactic reactions, which would have been induced by multiple injections of heterologous immune or nonimmune IgG, the rabbits were made neonatally tolerant to goat IgG. Divalent immune IgG given daily for 21 days induced chronic antigenic modulation (antigen disappearance) with resistance to antibody-mediated inflammatory lesions. The rabbits, however, developed degenerative changes of alveolar endothelial and epithelial cells. Administration of immune IgG every other day for 43 days allowed partial reexpression of ACE and was associated with intravascular, but not interstitial, inflammatory changes. In contrast, repeated administration of monovalent immune Fab did not induce antigenic modulation but caused severe, lethal, interstitial pneumonitis. Thus, in this experimental model the development of acute interstitial inflammatory changes correlates with persistence of antigen and is abrogated by disappearance of antigen induced by divalent antibodies. Further, repeated endothelial antigen antibody interactions fail to induce chronic inflammatory or sclerosing lung lesions.

Animals↗
PubMed2001

Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response.

During infection, parasites evade the host immune system by modulating or exploiting the immune system; e.g., they suppress expression of major histocompatibility complex class II molecules or secrete cytokine-like molecules. However, it is not clear whether helminths disturb the immune responses of their hosts by controlling the antigen-processing pathways of the hosts. In this study, we identified a new cysteine protease inhibitor, nippocystatin, derived from excretory-secretory (ES) products of an intestinal nematode, Nippostrongylus brasiliensis. Nippocystatin, which belongs to cystatin family 2, consists of 144 amino acids and is secreted as a 14-kDa mature form. In vivo treatment of ovalbumin (OVA)-immunized mice with recombinant nippocystatin (rNbCys) profoundly suppressed OVA-specific proliferation of splenocytes but not non-antigen-specific proliferation of splenocytes. OVA-specific cytokine production was also greatly suppressed in rNbCys-treated mice. Although the serum levels of both OVA-specific immunoglobulin G1 (IgG1) and IgG2a were not affected by rNbCys treatment, OVA-specific IgE was preferentially downregulated in rNbCys-treated mice. In vitro rNbCys inhibited processing of OVA by lysosomal cysteine proteases from the spleens of mice. Mice with anti-nippocystatin antibodies became partially resistant to infection with N. brasiliensis. Based on these findings, N. brasiliensis appears to skillfully evade host immune systems by secreting nippocystatin, which modulates antigen processing in antigen-presenting cells of hosts.

Amino Acid Sequence↗
PubMed1976

Different mechanisms for the modulation of TL antigens on murine lymphoid cells.

An indirect radioimmunoassay has been used to study the antibody-induced changes in expression of TL antigens on mouse thymus and leukemia cells. The results obtained indicate that the incubation of TL+ cells in relatively high concentrations of anti-TL antisera results in a detectable, but not major, loss in the quantity of antigen detected in the plasma membranes. This decrease is not inhibited by azide. Although the antigen loss seems to coincide with the appearance of patching of membrane TL antigens on leukemia cells observed in indirect immunofluorescence microscopy, this is not the case when thymocytes are used as targets. Fab fragments prepared from anti-TL antibodies can also induce a quantitative decrease in antigen expression. The major mechanism involved in membrane antigen loss seems to be endocytosis, although some shedding may also occur. Resistance to immune cytolysis (antigenic modulation) occurs during incubation in anti-TL antibodies before either endocytosis or antigen redistribution has progressed enough to be directly responsible. Since antigenic modulation does not represent a depletion in TL antigens being expressed on the cell surfaces, another mechanism must account for the failure of guinea pig complement to achieve cell lysis.

Animals↗
PubMed1985

Antibody-induced redistribution of Heymann antigen on the surface of cultured glomerular visceral epithelial cells: possible role in the pathogenesis of Heymann glomerulonephritis.

In this study we analyze the ability of antibodies that produce passive Heymann glomerulonephritis to induce antigen redistribution on the surface of cultured glomerular visceral epithelial cells (GEC). Polyclonal antibodies produced by immunization with membrane vesicles prepared from proximal tubule brush borders (BB) and polyclonal (rabbit) and monoclonal (mouse) antibodies to a membrane glycoprotein (gp 330) purified from epithelial cells of rat proximal tubule were used. The study by immunofluorescence of GEC kept at 4 degrees C or fixed with paraformaldehyde showed that the three antibody preparations reacted with the plasma membrane in a punctate pattern known to be due to staining of coated pits or coated vesicles on the cell surface. At 37 degrees C and, at a slower rate, at 22 degrees C, the two polyclonal antibodies induced a rapid clustering of antigen-antibody complexes on the nonadherent surface of living cultured GEC with subsequent formation of patches and caps and, after prolonged incubation, with temporary disappearance of Heymann antigen from the cell surface, so-called antigenic modulation. Antigen redistribution and modulation were inhibited by sodium azide, indicating that these processes are energy dependent. Monovalent Fab fragments of antibodies to BB vesicles did not alter the distribution of Heymann antigen unless they were subsequently cross-linked. Monoclonal anti-gp330 induced a modest degree of antigen redistribution, which was increased by subsequent cross-linking. Exposure of glomerular epithelial cells to cytochalasin B, colchicine, or ionophore A23187 prevented or altered antigen redistribution at 37 degrees C. Furthermore, the antibody-induced antigen redistribution was associated with changes in distribution of cytoplasmic actin, myosin, and tubulin, indicating that it is related to the contractile activity GEC. LEW rats, given i.v. injection of IgG directed against BB membrane vesicles, developed passive Heymann glomerulonephritis (i.e., immune deposits in the lamina rara externa of the glomerular basement membrane). In contrast, the glomeruli of rats exposed for longer periods to larger amounts of Fab fragments of the same antibodies failed to develop immune deposits. These studies show that the antibodies to the nephritogenic antigen of Heymann glomerulonephritis may induce a redistribution of immune complexes (IC) in the membrane of glomerular epithelial cells that is similar to that produced by other plasma membrane antigen-ligand interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Imaging and dosimetry determinations using radiolabeled antibodies.

Numerous studies using radiolabeled antibodies for imaging and therapy of lymphoma have been reported (Table 4). The targeting of lymphoma associated antigens with MoAb appears to be more favorable than the targeting of antigens on epithelial tumor. Antigen abundance may not be the overriding factor in this favorable targeting, since the number of antigenic sites per cell are often in the same range or lower than those targeted in epithelial tumors. This improved targeting is likely related to the greater access of antibody to the target antigen in lymph nodes, bone marrow, circulation, and other sites. With certain antibodies, trafficking of the cells targeted with the radiolabeled antibody may also result in favorable localization [19]. While the most frequently used isotope for imaging and therapy has been 131I, certain limitations have been observed, including its high-energy gamma rays and resulting lower resolution, and the frequent occurrence of dehalogenation [21,25,98]. Many of the antigens expressed by lymphomas undergo antigenic modulation. Antigens that undergo modulation may be targeted successfully, but once modulation occurs the antibody is broken down and the iodine is rapidly excreted from the cells. While this rapid release from normal organs is an advantage, it is an undesirable event at the tumor site. In contrast to the case of 131I MoAb, modulation may be an advantage for targeting with 111In labeled antibodies, since the radioactive metals are retained for longer periods at the tumor sites; even if the antibody is broken down, the 111In is not easily excreted from the cells [52]. Among the most consistent and favorable targeting observed to date is that seen with 111In T101 in CTCL. These studies have shown concentration of 111In in tumor of 10-100 times that seen in other tumor systems using iodinated antibodies. Unfortunately no studies have followed this lead and performed the necessary comparisons between 111In and 131I MoAb to determine if this is a consistent finding. The use of 99mTc labeled MoAb for imaging lymphomas is in its infancy, although preliminary reports appear promising [71]. While in epithelial tumors preferential tumor targeting may take more than 48 hours in lymphomas, targeting is usually seen within the first 24 hours, which is within the window of imaging time for 99mTc. Therefore, further evaluation of 99mTc antibodies should be performed. Determination of the optimum dose of antibody for imaging has been attempted. Studies using various anti-lymphoma directed antibodies have shown widely varying biodistribution and variable dose-response curves.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Anti-M monoclonal antibodies cross-reacting with variant Mg antigen: an example of modulation of antigenic properties of peptide by its glycosylation.

Some monoclonal antibodies (MoAbs) directed against blood group M-related epitope of glycophorin A (GPA) were found to agglutinate rare variant erythrocytes carrying GPA of Mg type. In contradistinction to normal GPA-M or -N, the N-terminal portion of GPA-Mg is not glycosylated. Therefore, the multipin peptide synthesis was used for testing the specificity of the cross-reacting MoAbs. Among several anti-M and anti-N MoAbs tested, only three anti-M (E3, E6, 425/2B) agglutinated Mg erythrocytes and showed binding to the synthetic octapeptides corresponding to N-terminal sequences of GPA-M (SSTTGVAM), GPA-N (LSTTEVAM), and GPA-Mg (LSTNEVAM). Testing multiple peptide analogs (window and replacement analysis) showed that these MoAbs were specific for peptidic epitope in which Met8 and Val6 were the most essential amino acid residues. The amino acid replacements Ser<-->Leu1 or Gly<-->Glu5 (M v N) and Thr4<-->Asn4 (M and N v Mg) had no or negligible effect on the reaction of synthetic peptides with the MoAbs. However, when Ser2, Thr3, and Thr4 carry O-linked sialooligosaccharides (normal GPA-M or -N), the MoAbs recognize Gly5- and sialic acid-dependent blood group M-related epitope. An interesting finding concerning anti-M/Mg MoAbs described here is the fact that glycosylation of amino acid residues adjacent to the most important part of peptidic epitope not only differentially modulates the proper exposure of peptidic epitope, but also alters the requirement for some amino acid residues present within the epitope. Pathologic conditions, including hematologic disorders, are often accompanied by alterations in protein glycosylation, resulting not only from differences in the structure of antigen polypeptide chain, but also from changes in specificity or expression of enzymes involved in glycosylation. Our present findings draw attention to possibility of the bidirectional modulation of protein antigenicity by glycosylation and may be helpful in interpretation of some results obtained with MoAb used for diagnostic or other purposes.

Amino Acid Sequence↗
PubMedDate not supplied

Modulation of CD4 antigen expression on the lymphocyte surface by immunosuppressive acidic protein in cancer patients.

The immunomodulatory effect of human immunosuppressive acidic protein (IAP) on lymphocyte surface antigens was investigated. IAP inhibited lymphocyte responses to phytohemagglutinin in a dose-dependent manner. By flow cytometry, using fluorescein-isothiocyanate-labelled antibodies, the mean fluorescence intensity on peripheral blood lymphocytes (PBLs) decreased for CD4, slightly decreased for CD3 but showed no change for the CD8 and T cell receptor alpha-beta antigens in the presence of IAP. This CD4 antigen modulation by IAP was observed in PBLs freshly isolated from patients with unresectable cancer but not in those isolated from patients with resectable tumor or from healthy volunteers. The modulation of the CD4 antigen by IAP on the lymphocyte surface was correlated with an increment of serum IAP levels in cancer patients. The CD4 modulation could be induced in PBLs from healthy volunteers by culturing them with IAP in vitro. It is suggested that IAP may play a role in cancer-related immunosuppression through the down-modulation of the CD4 antigen on the lymphocyte surface.

CD3 Complex↗
PubMed2005

Lead enhances CD4+ T cell proliferation indirectly by targeting antigen presenting cells and modulating antigen-specific interactions.

Although Pb is a well-known immunotoxicant, its mechanism of action is not well understood. Low levels of Pb (approximately 1 microM) markedly enhance the proliferative T cell response in mixed lymphocyte culture (MLC), a process we have termed allo-enhancement. As Pb allo-enhancement occurs whether alloantigen presenting cells (APC) are derived from C57BL/6 or BALB.B10, the allo-reactive T cells involved are likely to be specific for peptide in the context of the IA(b) molecule as the IE molecule is null in H-2(b) mice. Analysis of T cell division in MLC with Pb treatment indicated that there was no significant difference between Pb and non-Pb-treated cultures until day 4 when the frequency of proliferating T cells was much greater than in non-treated cultures. Our data suggest that this increased proliferation is not coupled with increased IL-2 levels in the media as these were actually decreased with Pb treatment and that Pb-induced enhancement in the allo-proliferative response is only partially dependent upon IL-2. Pb allo-enhancement is abrogated when stimulating allo-APCs are paraformaldehyde-fixed, and T cell proliferation stimulated by concanavalin A is not enhanced with Pb treatment, suggesting that the APC is the proximate target of Pb in allo-MLC. Pb allo-enhancement does not occur when T cells respond to irradiated allo-B cells, alone; however, it is restored when syngeneic CD11c-enriched cells are added. Of the CD11c-enriched splenocytes, the fraction that is adherent after 24 h, consistent with macrophages, appears to be the cell type targeted by Pb. Using T cells from DO11.10 transgenic mice, we determined that the effect of Pb is centered around specific p:MHC interactions and that enhanced costimulation is an unlikely mechanism for Pb allo-enhancement.

Animals↗