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Journal articles on the topic 'Immunoglobulin gamma-Chains'
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1
Kikutani, H., T. Taga, S. Akira, H. Kishi, Y. Miki, O. Saiki, Y. Yamamura, and T. Kishimoto. "Effect of B cell differentiation factor (BCDF) on biosynthesis and secretion of immunoglobulin molecules in human B cell lines." Journal of Immunology 134, no. 2 (February 1, 1985): 990–95. http://dx.doi.org/10.4049/jimmunol.134.2.990.
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Abstract Stimulation of human B lymphoblastoid cell lines, CESS and SKW6-CL4 with BCDF induced an increase in IgG- and IgM-secreting cells, as well as a slight increase in IgG and IgM expression on their respective surfaces. Biosynthetic labeling demonstrated that BCDF stimulation induced an increase in synthesis of secretory gamma- and mu-chains, as well as their precursors. A slight but significant increase in synthesis of membrane-bound gamma- and mu-chains and their precursors was also observed by BCDF stimulation. However, an increase in synthesis of secretory heavy chains was much higher than that in membrane-bound heavy chains in both cell lines. Pulse-chase experiments showed that increased synthesis of secretory heavy chains was not due to a decrease in degradation. BCDF stimulation induced a preferential increase in mRNA specific for secretory gamma- and mu-chains in CESS and SKW6-CL4 cells, respectively. These results suggest that BCDF induces an increase in the level of mRNA specific for secretory heavy chains, and then induces final maturation of B cells into immunoglobulin-secreting cells.
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Kurosaki, T., I. Gander, U. Wirthmueller, and J. V. Ravetch. "The beta subunit of the Fc epsilon RI is associated with the Fc gamma RIII on mast cells." Journal of Experimental Medicine 175, no. 2 (February 1, 1992): 447–51. http://dx.doi.org/10.1084/jem.175.2.447.
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Fc epsilon RI is a tetrameric receptor, composed of a ligand recognition subunit, alpha, a beta chain, and dimeric gamma chains. Previous studies have indicated that the dimeric gamma chain is associated with Fc gamma RIIIA (CD16) on natural killer cells and macrophages as well as the clonotypic T cell receptor. Here we show that in mast cells, in addition to the dimeric gamma chains, the beta subunit is associated not only with Fc epsilon RI, but also with Fc gamma RIIIA. Functional reconstitution studies with a mastocytoma cell line indicate that Fc gamma RIIIA composed of alpha, beta, and gamma subunits has the capacity for signal transduction. These studies suggest that through the association of alternative ligand recognition subunits (alpha epsilon, alpha gamma), a common signal transduction complex (beta gamma 2) mediates similar biochemical and effector functions in response to immunoglobulin G (IgG) and IgE.
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Knight, K. L., R. C. Burnett, and J. M. McNicholas. "Organization and polymorphism of rabbit immunoglobulin heavy chain genes." Journal of Immunology 134, no. 2 (February 1, 1985): 1245–50. http://dx.doi.org/10.4049/jimmunol.134.2.1245.
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Abstract Germline genes encoding C mu, C gamma, C alpha, and C epsilon heavy chains of rabbit immunoglobulins have been isolated from recombinant phage and cosmid libraries. The JH, C mu, C gamma, and C epsilon are found in a 5'-JH-C mu-C gamma-C epsilon-3' orientation on a 90kb stretch of DNA. Four C alpha genes have been cloned and presumably reside 3' to the other CH genes. Southern blot analysis of rabbit sperm DNA indicates that the rabbit genome contains a single C gamma gene, one C mu gene, and as many as 10 C alpha genes. Restriction site polymorphism is found for C mu, C gamma, and C alpha genes of rabbits of various heavy chain haplotypes. The organization of the rabbit CH genes differs from that of mouse and human CH genes in that the rabbit has multiple C alpha genes, whereas mouse and human have one or two C alpha genes, respectively. In addition, mouse and human have four C gamma genes, whereas rabbit has only one C gamma gene. The presence of a single C gamma gene indicates that at least in the rabbits examined, no germline gene encoding latent or unexpected, C gamma allotypes is present. The genetic control of the expression of latent C gamma allotypes is discussed.
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Lee, J. K., A. Flowers, J. Williams, S. Li, X. Yi, and R. Huang. "Immunoglobulin D Multiple Myeloma with a “Hidden” Lambda Light Chain." American Journal of Clinical Pathology 156, Supplement_1 (October 1, 2021): S31—S32. http://dx.doi.org/10.1093/ajcp/aqab191.061.
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Abstract Introduction/Objective In rare cases, the conventional immunofixation gel electrophoresis technique fails to detect the light chain of an M-protein. We report a case of immunoglobulin (Ig) D multiple myeloma with a hidden lambda (λ) light chain. Methods/Case Report Capillary electrophoresis (CE) (Sebia CAPILLARYS 2) was used to detect and quantify M- proteins in serum specimens. Immunosubtraction (IS) on the CAPILLARYS 2 systems was used to identify the classes of M-proteins. Conventional gel immunofixation electrophoresis (IFE) was performed, using monospecific antisera for IgD, IgE, kappa (κ) or λ in the Sebia HYDRASYS system, and IgG, IgA, IgM, κ or λ in the Helena SPIFE3000 system. Beta-mercaptoethanol (BME) with Fluidil were used as reduction agents. Results (if a Case Study enter NA) Results of serum CE showed two abnormal peaks in beta 2 and gamma regions, suspected to be positive for M-proteins. IS results showed subtraction for λ light chain only in both peaks, suggesting two monoclonal λ light chains. In contrary, no monoclonal λ light chain was detected in gamma region by IFE (Sebia). Epitope masking in the folded monoclonal protein was suspected to cause the “hidden λ light chain” and was further investigated by two laboratory approaches. IFE performed on the Helena SPIFE3000 system found two λ bands in beta 2 and gamma regions, which was consistent with the results from IS. The treatment of BME with Fluidil helped unmasking the hidden epitope and revealed the λ band in gamma region on IFE (Sebia). Conclusion The medical laboratories should be aware of the described scenario. The failure to detect light chains of certain intact M-proteins is most likely due to the structurally inaccessibility of light chains. It is recommended that treatment with reduction agents or use of an alternative methodology or IS might be helpful for investigating suspected heavy chain only cases, due to the limitation of conventional methodology.
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Shibata, Sho, and Akiko Fukunaga. "Gamma heavy chain disease complicated by pulmonary hypertension, which was successfully treated with lenalidomide." BMJ Case Reports 13, no. 11 (November 2020): e236162. http://dx.doi.org/10.1136/bcr-2020-236162.
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Heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. Gamma HCD is a subgroup of HCD. A 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema. Based on the results of heart catheterisation, he was diagnosed with pulmonary hypertension. Laboratory tests revealed an elevated level of IgG, and serum immunoelectrophoresis showed that IgG was a monoclonal gamma heavy chain without light chains. Finally, he was diagnosed with gamma HCD complicated by pulmonary hypertension. Bortezomib and dexamethasone therapy was initiated, but became refractory within 8 months. Therefore, the treatment was switched to lenalidomide and dexamethasone therapy, and the disease has been stably controlled for more than 2 years. To the best of our knowledge, this is the first case of gamma HCD being successfully treated by lenalidomide and dexamethasone therapy.
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Bachhawat, A. K., and S. Pillai. "Distinct intracellular fates of membrane and secretory immunoglobulin heavy chains in a pre-B cell line." Journal of Cell Biology 115, no. 3 (November 1, 1991): 619–24. http://dx.doi.org/10.1083/jcb.115.3.619.
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The intracellular fates of membrane and secretory immunoglobulin heavy chains were examined in a pre-B cell line that has switched to the gamma isotype. The membrane form of the heavy chain (gamma m) was rapidly degraded while the secretory form (gamma s) was retained intracellularly in association with BiP. The degradation of gamma m could not be inhibited by ammonium chloride, chloroquine, or monensin suggesting that it occurred in a nonlysosomal compartment. The inability to detect any Endo H-resistant form of gamma m before its degradation suggested that degradation occurs before entry into the Golgi compartment. Degradation of gamma m could be inhibited by incubation at 24 degrees C. In a derivative of this cell line expressing a transfected kappa gene, gamma s formed disulfide linked tetramers with kappa and was secreted, while gamma m, although associated with kappa, continued to be rapidly degraded. These observations suggest that membrane and secretory heavy chain proteins are retained by distinct intracellular mechanisms. Although masking of the CH1 domain abrogates gamma s retention, this domain does not influence the intracellular fate of gamma m.
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Cuilliere, M. L., P. Montagne, Th Bessou, R. el Omari, D. Riochet, P. Varcin, P. Laroche, et al. "Microparticle-enhanced nephelometric immunoassay (Nephelia) for immunoglobulins G, A, and M." Clinical Chemistry 37, no. 1 (January 1, 1991): 20–25. http://dx.doi.org/10.1093/clinchem/37.1.20.
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Abstract Covalent binding of gamma chains of IgG, whole IgA, and mu chains of IgM on polyfunctional hydrophilic microspheres (MS) yields MS-Ig conjugates, usable as reagents in new microparticle-enhanced nephelometric immunoassays (Nephelia). The principle of the assays is inhibition by free analyte (IgG, IgA, and IgM) of agglutination of the MS-Ig conjugate with specific antiserum, the light scattered by the aggregates being measured with a nephelometer. The immunoglobulin assays developed are easy to perform (single-step assays, no washing or phase separation) and sensitive (high dilution of biological samples to exclude interferences and pretreatment). Analytical recovery results (95.4-101.2%) and correlations with generally used commercial assays (r = 0.86-0.98) indicate that the assays are accurate for large concentration ranges of immunoglobulins. Precision sxtudy gives CVs = 2.8-9.6%. Nephelia appears to be useful for quantifying a large variety of biological molecules.
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Wiederkehr, F., A. Ogilvie, and D. J. Vonderschmitt. "Two-dimensional gel electrophoresis of cerebrospinal fluid proteins from patients with various neurological diseases." Clinical Chemistry 31, no. 9 (September 1, 1985): 1537–42. http://dx.doi.org/10.1093/clinchem/31.9.1537.
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Abstract We subjected cerebrospinal fluid (CSF) samples from over 200 patients with various neurological diseases to two-dimensional electrophoresis. The series included non-inflammatory diseases such as epilepsy, amyotrophic lateral sclerosis, and polyneuropathy; and inflammatory diseases such as multiple sclerosis and neurolues. In the resulting electrophoretograms we considered mainly the region of CSF-specific proteins and the area corresponding to the immunoglobulin light chains. The former, at Mr 35 000-38 000, shows some interesting variations from one CSF to another. Samples from patients with various brain tumors show a specific change. A zone of oligoclonal immunoglobulin light chains appeared in all CSF samples with above-normal gamma-globulin content. These oligoclonal patterns remained constant and characteristic during the course of different diseases for several patients so examined. As expected, differences appeared in the patterns of immunoglobulin light chains from one individual to another, even among a group of patients with the same disease. The extent of the correlation of certain basic patterns with certain diseases cannot yet be determined.
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Wagner, Bettina, Irene Greiser-Wilke, Anja Wege, Andreas Radbruch, and Wolfgang Leibold. "Evolution of the six horse IGHG genes and corresponding immunoglobulin gamma heavy chains." Immunogenetics 54, no. 5 (August 1, 2002): 353–64. http://dx.doi.org/10.1007/s00251-002-0458-4.
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Roth, P. E., L. Doglio, J. T. Manz, J. Y. Kim, D. Lo, and U. Storb. "Immunoglobulin gamma 2b transgenes inhibit heavy chain gene rearrangement, but cannot promote B cell development." Journal of Experimental Medicine 178, no. 6 (December 1, 1993): 2007–21. http://dx.doi.org/10.1084/jem.178.6.2007.
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Transgenic mice with a gamma 2b transgene were produced to investigate whether gamma 2b can replace mu in the development of B lymphocytes. Transgenic gamma 2b is present on the surface of B cells. Young transgenic mice have a dramatic decrease in B cell numbers, however, older mice have almost normal B cell numbers. Strikingly, all gamma 2b-expressing B cells in the spleen also express mu. The same is true for mice with a hybrid transgene in which the mu transmembrane and intracytoplasmic sequences replace those of gamma 2b (gamma 2b-mumem). The B cell defect is not due to toxicity of gamma 2b since crosses between gamma 2b transgenic and mu transgenic mice have normal numbers of B cells. Presence of the gamma 2b transgene strongly enhances the feedback inhibition of endogenous heavy chain gene rearrangement. Light chain genes are expressed normally, and the early expression of transgenic light chains does not improve B cell maturation. When the endogenous mu locus is inactivated, B cells do not develop at all in gamma 2b transgenic mice. The data suggest that gamma 2b cannot replace mu in promoting the developmental maturation of B cells, but that it can cause feedback inhibition of heavy chain gene rearrangement. Thus, the signals for heavy chain feedback and B cell maturation appear to be different.
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Davodeau, F., M. A. Peyrat, J. Gaschet, M. M. Hallet, F. Triebel, H. Vié, D. Kabelitz, and M. Bonneville. "Surface expression of functional T cell receptor chains formed by interlocus recombination on human T lymphocytes." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1685–91. http://dx.doi.org/10.1084/jem.180.5.1685.
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Structural diversity of lymphocyte antigen receptors (the immunoglobulin [Ig] of B cells and the alpha/beta or gamma/delta T cell receptor [TCR] of T cells) is generated through somatic rearrangements of V, D, and J gene segments. Classically, these recombination events involve gene segments from the same Ig or TCR locus. However, occurrence of "trans" rearrangements between distinct loci has also been described, although in no instances was the surface expression of the corresponding protein under normal physiological conditions demonstrated. Here we show that hybrid TCR genes generated by trans rearrangement between V gamma and (D) J beta elements are translated into functional antigen receptor chains, paired with TCR alpha chains. Like classical alpha/beta T cells, cells expressing these hybrid TCR chains express either CD4 or CD8 coreceptors and are frequently alloreactive. These results have several implications in terms of T cell repertoire selection and relationships between TCR structure and specificity. First, they suggest that TCR alloreactivity is determined by the repertoire selection processes operating during lymphocyte development rather than by structural features specific to V alpha V beta regions. Second, they suggest the existence of close structural relationships between gamma/delta and alpha/beta TCR and more particularly, between V gamma and V beta regions. Finally, since a significant fraction of PBL (at least 1/10(4)) expressed hybrid TCR chains on their surface, these observations indicate that trans rearrangements significantly contribute to the combinatorial diversification of the peripheral immune repertoire.
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Sheoran, Abhineet S., D. Paul Lunn, and Mark A. Holmes. "Monoclonal antibodies to subclass-specific antigenic determinants on equine immunoglobulin gamma chains and their characterization." Veterinary Immunology and Immunopathology 62, no. 2 (March 1998): 153–65. http://dx.doi.org/10.1016/s0165-2427(97)00162-1.
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BRIDGES, S. LOUIS, BJÖRN E. CLAUSEN, JOHN C. LAVELLE, PRISCILLA G. FOWLER, WILLIAM J. KOOPMAN, and HARRY W. SCHROEDER. "Analysis of Immunoglobulin Gamma Heavy Chains from Rheumatoid Arthritis Synovium Evidence of Antigen-Driven Selection." Annals of the New York Academy of Sciences 764, no. 1 (June 28, 2008): 450–60. http://dx.doi.org/10.1111/j.1749-6632.1995.tb55862.x.
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Van Keer, Jan, Björn Meijers, Michel Delforge, Gregor Verhoef, and Koen Poesen. "Two Cases of Heavy Chain MGUS." Case Reports in Oncological Medicine 2016 (2016): 1–4. http://dx.doi.org/10.1155/2016/8749153.
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Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.
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Fung-Leung, W. P., J. De Sousa-Hitzler, A. Ishaque, L. Zhou, J. Pang, K. Ngo, J. A. Panakos, E. Chourmouzis, F. T. Liu, and C. Y. Lau. "Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor alpha chain respond to human IgE in mast cell degranulation and in allergic reactions." Journal of Experimental Medicine 183, no. 1 (January 1, 1996): 49–56. http://dx.doi.org/10.1084/jem.183.1.49.
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The high-affinity receptor for immunoglobulin (Ig) E (Fc epsilon RI) on mast cells and basophils plays a key role in IgE-mediated allergies. Fc epsilon RI is composed of one alpha, one beta, and two gamma chains, which are all required for cell surface expression of Fc epsilon RI, but only the alpha chain is involved in the binding to IgE. Fc epsilon RI-IgE interaction is highly species specific, and rodent Fc epsilon RI does not bind human IgE. To obtain a "humanized" animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human Fc epsilon RI alpha chain were generated. The human Fc epsilon RI alpha chain gene with a 1.3-kb promoter region as a transgene was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human Fc epsilon RI alpha chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic Fc epsilon RI on bone marrow-derived mast cells was 4.7 x 10(4)/cell, and the human IgE-binding affinity was Kd = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human Fc epsilon RI alpha chain was complexed with the mouse beta and gamma chains in immunoprecipitation studies. Cross-linking of the transgenic Fc epsilon RI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the Fc epsilon RI beta and gamma chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by beta-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human Fc epsilon RI alpha chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse beta and gamma chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice "humanized" in IgE-mediated allergies may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.
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Tosato, G., G. E. Marti, R. Yarchoan, C. A. Heilman, F. Wang, S. E. Pike, S. J. Korsmeyer, and K. Siminovitch. "Epstein-Barr virus immortalization of normal cells of B cell lineage with nonproductive, rearranged immunoglobulin genes." Journal of Immunology 137, no. 6 (September 15, 1986): 2037–42. http://dx.doi.org/10.4049/jimmunol.137.6.2037.
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Abstract Most continuous cell lines derived by EBV immortalization of peripheral blood cells are composed of phenotypically mature B lymphocytes, and secrete Ig. Occasionally, EBV-immortalized cell lines have failed to secrete Ig. Expansion and characterization of one of these EBV-induced cell lines, VDS-O, showed that in addition to a lack of Ig secretion, surface and intracytoplasmic Ig were absent. Cell surface phenotyping revealed that VDS-O belongs to the B cell lineage, because it expresses the B cell restricted antigens B1 and B4, while it lacks T cell and monocyte-associated determinants. Analysis of the Ig gene organization in VDS-O revealed that the Ig genes are rearranged for both heavy (gamma) and light (kappa) chains. However, the expected gamma-heavy chain and/or kappa-light chain RNA species were not detected. These findings demonstrate the existence in normal peripheral blood of cells of B cell lineage susceptible to EBV immortalization that have Ig genes that are rearranged but are nonproductive.
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Hudson, N. W., M. Mudgett-Hunter, D. J. Panka, and M. N. Margolies. "Immunoglobulin chain recombination among antidigoxin antibodies by hybridoma-hybridoma fusion." Journal of Immunology 139, no. 8 (October 15, 1987): 2715–23. http://dx.doi.org/10.4049/jimmunol.139.8.2715.
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Abstract Conditions necessary for in vitro chain recombination of high affinity (10(9) to 10(12) M-1) antidigoxin monoclonal antibodies resulted in decreased affinity for both intact "native" and chain recombinant molecules. Chain recombination by somatic cell fusion was used instead to study the effects on antigen specificity and idiotypy of recombinants in which an homologous light (L) chain substituted for the parental L chain. The antidigoxin antibody 26-10 utilizes a VL sequence highly homologous to that of antibody 40-20, an antidigoxin antibody which uses a different VH gene than does 26-10 and lacks significant reactivity with an anti-26-10 idiotypic serum. The drug-marked antidigoxin cell line 26-10 (gamma 2a, kappa) and a drug-marked light chain producing variant of antidigoxin hybridoma 45-20 (lambda 1) which lacks both digoxin binding and idiotypy were fused. The fusion progeny (gamma 2a, kappa, lambda 1) which binds digoxin and is idiotype-positive, was selected for kappa loss (resulting in loss of digoxin and idiotype binding) and then fused with a heavy (H) chain loss variant of antidigoxin hybridoma 40-20 (kappa, digoxin nonbinding, idiotype negative). The resultant cell line CR-57 (gamma 2a, kappa, lambda) secretes antibodies which assemble the 26-10 H chain with both the 40-20 kappa-chain and the 45-20 lambda 1-chain. The affinity purified recombinant species consisting of 26-10 H chain and 40-20 kappa-chain expresses complete 26-10 idiotypic determinants. However, this recombinant antibody binds digoxin with decreased affinity and altered specificity relative to native 26-10. The binding specificity pattern nonetheless is most similar to the H chain donor. Amino acid and nucleotide sequence analyses of the respective light chains demonstrate six variable region differences between them, two of which are in complementarity-determining regions and the remainder in the framework. Hybridoma-hybridoma fusion provides an alternative to in vitro chain recombination for studying the contribution of chain combinational diversity to antibody diversity, antigen binding, and idiotypy.
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Pesando, J. M., L. S. Bouchard, and B. E. McMaster. "CD19 is functionally and physically associated with surface immunoglobulin." Journal of Experimental Medicine 170, no. 6 (December 1, 1989): 2159–64. http://dx.doi.org/10.1084/jem.170.6.2159.
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The pan-B and B cell-specific sIg and CD19 antigens are functionally and physically associated in the presence of anti-Ig mAb. Incubation of B cells with anti-Ig antibodies causes rapid, specific, reversible, concentration-dependent, and unidirectional comodulation of CD19 on every mature B cell studied. Comodulation is produced by mAbs specific for the gamma, mu, kappa, and lambda chains of Ig, and by at least one idiotype-specific mAb. Comodulation is observed using 15 CD19-specific mAbs that detect at least three different CD19 epitopes. Of 18 surface antigens studied, only CD19 is comodulated. Loss of sIg and CD19 occurs concurrently during anti-Ig modulation and demonstrates a comparable dependence on anti-Ig concentration, suggesting that these are parallel rather than serial events. Incubation with anti-Ig specifically cocaps and suggests internalization of anti-CD19 mAb. Comodulation of sIg and CD19 by anti-Ig but not anti-CD19 mAbs suggests that ligand binding enables sIg to then interact with CD19. We propose that CD19 is a component of the B cell antigen receptor and suggest that it could facilitate signal transduction by sIg-antigen complexes.
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Chari, Ajai, Andrew Eisenberger, and Michael Pesce. "Monoclonal Immunoglobulins of Alpha-2 Mobility on Protein Electrophoresis: A Case Series." Blood 110, no. 11 (November 16, 2007): 4753. http://dx.doi.org/10.1182/blood.v110.11.4753.4753.
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Abstract Protein electrophoresis (PEP) separates proteins based on mobility through support media such as agarose into five general regions: albumin, alpha-1, alpha-2, beta, and gamma. Monoclonal and polyclonal immunoglobulins typically migrate in the gamma or beta regions. Between April 1990 and July 2007 at Columbia University Medical Center, we identified and then retrospectively reviewed 15 patients with monoclonal proteins of alpha-2 mobility repeatedly on serum PEP (see figure). Immunofixation identified the paraprotein as IgA kappa in 7 patients, IgA lambda in 2, IgG lambda in 2, free kappa light chain in 4, free lambda light chain in 2, and one IgG lambda. In the urine, of the 14 patients who had PEP performed, 6 patients had serum concordant light chains (5 kappa and 1 lambda) also migrating in the alpha 2 region, however, for 5 other patients migration was either in the beta or gamma regions. Published case reports of monoclonal proteins with atypical mobility patterns are reviewed. The median age of our patients was 66 years and there were 9 males. 10 patients had multiple myeloma, 5 had monoclonal gammopathy of undetermined significance (MGUS), and 1 had lambda AL amyloidosis. This is the largest case series ever described of patients with monoclonal proteins migrating in alpha 2 region and illustrates the importance of immunofixation in screening patients for plasma cell dyscrasias. Possible explanations for this unusual migration pattern include protein complex formation with other plasma components, high carbohydrate content, or given the IgA predominance noted, properties of the IgA immunoglobulin such as polymerization. Figure Figure
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Mizuguchi, J., W. Tsang, S. L. Morrison, M. A. Beaven, and W. E. Paul. "Membrane IgM, IgD, and IgG act as signal transmission molecules in a series of B lymphomas." Journal of Immunology 137, no. 7 (October 1, 1986): 2162–67. http://dx.doi.org/10.4049/jimmunol.137.7.2162.
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Abstract Increases in intracellular free calcium concentration ((Ca2+)i) were observed in response to anti-immunoglobulin (Ig) antibodies in each of six B cell tumors or B cell hybridomas bearing mu or delta chains on their cell surface. The BAL17 cell line, bearing mu and delta chains on its surface, behaved similarly to mature B cells in the following respects. Anti-IgM and anti-IgD antibodies caused increases in (Ca2+)i and inositol phospholipid metabolism; the initial increases in (Ca2+)i were derived partly from an intracellular Ca2+ pool; lipopolysaccharide, phorbol myristate acetate (PMA), B cell stimulatory factor-1, and antibodies to class I and class II major histocompatibility molecules and to the Fc gamma receptor failed to cause increases in (Ca2+)i or in inositol phospholipid metabolism; and increases in (Ca2+)i and inositol phospholipid metabolism in response to anti-Ig were inhibited by pretreatment with PMA. Furthermore A20, an IgG2a bearing lymphoma, showed increases in (Ca2+)i in response to anti-IgG2a, and a lymphoma cell line (6G8-2E10) expressing membrane IgG2b as a result of DNA-mediated transfer of the gamma 2b H chain gene, showed increases in (Ca2+)i in response to anti-IgG2b. These results indicate that Ig-bearing lymphomas display early events in B cell activation after receptor cross-linkage and can be used for detailed studies of the activation process.
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McCool, D., B. K. Birshtein, and R. H. Painter. "Structural requirements of immunoglobulin G for binding to the Fc gamma receptors of the human tumor cell lines U937, HL-60, ML-1, and K562." Journal of Immunology 135, no. 3 (September 1, 1985): 1975–80. http://dx.doi.org/10.4049/jimmunol.135.3.1975.
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Abstract Fc receptors (FcR) on U937, HL-60, ML-1, and K562 cells were characterized by using competitive binding assays and EA rosette inhibition studies. Like human monocytes, U937, HL-60, and ML-1 cells bound monomeric human IgG Fc with high affinity and mildly reduced and alkylated human IgG and Fc with a somewhat diminished affinity. In contrast, K562 cells had a much lower affinity for monomeric human IgG or Fc. Concentrations of these proteins as high as 10(-5) M were needed to completely block EA rosette formation. There was no binding of reduced and alkylated IgG and Fc. We assessed the influence of various segments of IgG on FcR interactions by using human pFc', rabbit Facb, mouse IgG2b-IgG2a hybrid Ig, and also studied the effect of reduction of the interchain disulfide bonds. The FcR on all four cell types bound rabbit IgG but not rabbit Facb or human pFc', suggesting that rabbit C gamma 3 domains are required for FcR interaction and that isolated human C gamma 3 domains do not have a human FcR binding site. Murine IgG2a, but not IgG2b, was cytophilic for U937, HL-60, and ML-1 cells. Binding studies with the use of several mouse myeloma variant Ig molecules having hybrid gamma 2b-gamma 2a heavy chains showed that variants with a complete gamma 2a Fc region bound to these FcR-like IgG2a, whereas those having gamma 2a sequences only in the C gamma 3 region and in a short adjacent segment of the C gamma 2 region behaved like IgG2b and did not bind. These results suggested that additional murine gamma 2a sequences are required for FcR binding. Interestingly, the Fc fragments from murine proteins with a complete gamma 2a Fc region bound only to a limited extent. These fragments are shorter than the human IgG1 Fc fragments, and they lack that segment of the hinge region that includes the interchain disulfide bonds. Cleavage of the interchain disulfide bonds of murine Ig having a complete gamma 2a Fc region diminished binding to a similar extent as that observed with human IgG. Together, these findings provide additional insight into the roles of the hinge, C gamma 2, and C gamma 3 regions of human, rabbit, and mouse IgG in their interaction with the FcR of human tumor cells.
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Nakarai, T., M. J. Robertson, M. Streuli, Z. Wu, T. L. Ciardelli, K. A. Smith, and J. Ritz. "Interleukin 2 receptor gamma chain expression on resting and activated lymphoid cells." Journal of Experimental Medicine 180, no. 1 (July 1, 1994): 241–51. http://dx.doi.org/10.1084/jem.180.1.241.
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The interleukin 2 receptor (IL-2R) is known to be comprised of at least three genetically distinct subunits termed alpha, beta, and gamma. These chains can be expressed individually or in various combinations resulting in distinct receptors with different affinities for IL-2. In contrast to alpha and beta, the cell surface expression of the gamma chain protein previously has not been well-characterized. To examine cell surface expression of IL-2R gamma on hematopoietic cells, we developed two new monoclonal antibodies (mAbs) specific for this protein. Both 1A11 (immunoglobulin [IgG1]) and 3G11 (IgM) specifically reacted with murine cells transfected with IL-2R gamma cDNA, and immunoprecipitation studies indicated that both antibodies precipitated a protein of approximately 62-65 kD. Scatchard analysis of IL-2 binding to murine cells transfected with cDNA-encoding combinations of IL-2R components demonstrated that neither beta nor gamma chain bind IL-2 with measurable affinity, but coexpression of both beta and gamma is sufficient to form an intermediate affinity receptor. In the absence of gamma chain, beta chain interacts with alpha chain to form a "pseudo-high" affinity receptor. In contrast, gamma chain does not appear capable of interacting with alpha in the absence of beta chain. Thus, gamma chain appears to interact only with beta, but beta chain is capable of interacting with both alpha and gamma. Using the newly developed mAbs to examine cell surface expression by immunofluorescence, resting T cells were found to express low levels of gamma chain without detectable alpha or beta. Early after mitogen stimulation, T cells expressed higher levels of alpha, beta, and gamma. However, at later time points, T cells expressed alpha and gamma in marked excess over beta. Thus, formation of high affinity IL-2R on activated T cells was primarily limited by beta chain expression. In contrast, resting natural killer (NK) cells constitutively expressed IL-2R beta without detectable alpha or gamma. After activation with either IL-2 or IL-12, expression of both alpha and gamma transiently increased and then returned to very low levels. Expression of functional IL-2R on resting and activated NK cells, therefore, appeared to be primarily limited by the expression of gamma chain. IL-2 binding studies with resting NK cells confirmed the results of immunofluorescence studies indicating the presence of very low numbers of intermediate affinity (beta gamma) receptors for IL-2 on these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Fujita, K., I. Sakurabayashi, M. Kusanagi, and T. Kawai. "A lactate dehydrogenase-immunoglobulin G1 complex, not blocked by anti-idiotype antibody, in a patient with IgG1-lambda type M-proteinemia." Clinical Chemistry 33, no. 8 (August 1, 1987): 1478–83. http://dx.doi.org/10.1093/clinchem/33.8.1478.
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Abstract The serum of a patient with IgG1-lambda type M-proteinemia showed an abnormal isoenzyme pattern for lactate dehydrogenase (LDH, EC 1.1.1.27). By affinity chromatography, we showed that four isoenzymes (LDH2, LDH3, LDH4, and LDH5) were bound to the M-protein. This complex formation was not blocked by anti-idiotype antibody, even though the binding capacity of IgG was exclusively located in the Fab region of the molecule. Moreover, heavy and light chains of the patient's IgG, obtained by reduction, separately had affinities for each of the LDH isoenzymes. LDH-IgG complex was easily dissociated by affinity chromatography on 5'-AMP-Sepharose 4B or by added NADH. We propose the following hypothesis for the LDH-IgG complex formation: LDH can recognize the gamma-Fab region of IgG at the NAD+ binding site of the molecule, but the affinity of the LDH molecule for immunoglobulin is much weaker than that for NADH or 5'-AMP.
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Parvari, R., A. Avivi, F. Lentner, E. Ziv, S. Tel-Or, Y. Burstein, and I. Schechter. "Chicken immunoglobulin gamma-heavy chains: limited VH gene repertoire, combinatorial diversification by D gene segments and evolution of the heavy chain locus." EMBO Journal 7, no. 3 (March 1988): 739–44. http://dx.doi.org/10.1002/j.1460-2075.1988.tb02870.x.
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Peluso, A. L., I. Cozzolino, A. Bottiglieri, L. Lucchese, R. M. Di Crescenzo, M. Langella, C. Selleri, and P. Zeppa. "Immunoglobulin heavy and light chains and T-cell receptor beta and gamma chains PCR assessment on cytological samples. A study comparing FTA cards and cryopreserved lymph node fine-needle cytology." Cytopathology 28, no. 3 (December 22, 2016): 203–15. http://dx.doi.org/10.1111/cyt.12402.
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Lankester, A. C., G. M. van Schijndel, J. Frommé, J. L. Cordell, R. A. van Lier, and C. J. van Noesel. "Evidence for a direct physical interaction of membrane IgM, IgD, and IgG with the B29 gene product." Journal of Immunology 152, no. 5 (March 1, 1994): 2157–62. http://dx.doi.org/10.4049/jimmunol.152.5.2157.
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Abstract The B cell Ag-receptor complex is composed of membrane immunoglobulin (mIg) and the mb-1/B29 heterodimer. In order to obtain insight into the architecture of the B cell receptor complex, we have looked for conditions that disrupt all disulfide bridges in the complex without affecting the noncovalent interaction between the mIg heavy chain and one or both members of the associated heterodimer. We show that in the presence of the reducing agent beta-mercaptoethanol the m mu, m delta, and m gamma heavy chains remain selectively associated with the B29 members. Our findings implied that if isotype-related differences exist between the mIg-associated dimers, they may reside in B29 and not, as initially suggested, in mb-1. However, sequence analyses of B29 gene transcripts from B cells expressing mIgM, mIgD, or mIgG only revealed no differences in their nucleotide composition. Thus, in spite of their close physical interaction with mIg heavy chain classes, which are significantly distinct in the C-terminal regions, no isotype-specific forms of B29 seem to exist.
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Levinson, Stanley S. "kappa/lambda index for confirming urinary free light chain in amyloidosis AL and other plasma cell dyscrasias." Clinical Chemistry 37, no. 6 (June 1, 1991): 1122–26. http://dx.doi.org/10.1093/clinchem/37.6.1122.
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Abstract Primary systemic amyloidosis (AL), a disease involving the deposition of immunoglobulin light chains in tissue, is caused by a plasma cell dyscrasia. In the case of amyloidosis reported here, no monoclonal component was seen upon routine protein electrophoresis of serum or urine nor was a bone marrow analysis positive for AL. Immunofixation electrophoresis did not show a typical paraprotein band but did show, in the gamma region, two large diffuse bands and a lower concentration of oligoclonal-type bands, all of which stained for free lambda but not for free kappa chain. The ratio of kappa to lambda chains in urine was 0.178, much less than the ratio in serum (1.3). Six other urine samples from a group of patients with documented Bence Jones proteinuria also exhibited kappa/lambda ratios that differed manyfold from the ratios in their corresponding serum samples. On the other hand, the kappa/lambda ratios from seven controls (seven patients with generalized proteinuria unrelated to plasma cell dyscrasia) were similar in serum and urine. This difference between the kappa/lambda ratios from serum and urine can be expressed as a kappa/lambda index. The index was significantly different (P less than 0.01) between the two patient groups compared here, and was useful in confirming the presence of Bence Jones protein in this case with a difficult-to-interpret electrophoretic pattern. Although the kappa/lambda ratio has been widely used for confirmation and identification of monoclonal components in serum, its use in clinical laboratories has not been widely extended to urine. Comparison of serum and urine kappa/lambda ratios as a kappa/lambda index may help reduce the need for more complex immunoelectrophoresis techniques in identifying free light chains in urine.
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Franco-Martínez, Lorena, Andrea Gelemanović, Anita Horvatić, María Dolores Contreras-Aguilar, Roman Dąbrowski, Vladimir Mrljak, José Joaquín Cerón, Silvia Martínez-Subiela, and Asta Tvarijonaviciute. "Changes in Serum and Salivary Proteins in Canine Mammary Tumors." Animals 10, no. 4 (April 24, 2020): 741. http://dx.doi.org/10.3390/ani10040741.
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The aim of this study was to evaluate changes in serum and saliva proteomes in canine mammary tumors (CMT) using a high-throughput quantitative proteomic analysis in order to potentially discover possible biomarkers of this disease. Proteomes of paired serum and saliva samples from healthy controls (HC group, n = 5) and bitches with CMT (CMT group, n = 5) were analysed using a Tandem Mass Tags-based approach. Twenty-five dogs were used to validate serum albumin as a candidate biomarker in an independent sample set. The proteomic analysis quantified 379 and 730 proteins in serum and saliva, respectively. Of those, 35 proteins in serum and 49 in saliva were differentially represented. The verification of albumin in serum was in concordance with the proteomic data, showing lower levels in CMT when compared to the HC group. Some of the modulated proteins found in the present study such as haptoglobin or S100A4 have been related to CMT or human breast cancer previously, while others such as kallikrein-1 and immunoglobulin gamma-heavy chains A and D are described here for the first time. Our results indicate that saliva and serum proteomes can reflect physiopathological changes that occur in CMT in dogs and can be a potential source of biomarkers of the disease.
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Kholopov, L. S., N. B. Gubegrits, O. A. Dyadyk, Yu E. Chirkov, and Yu V. Tsohoyeva. "A Case of Primary Amyloidosis Involving Liver, Stomach, Intestines, and Heart without Evident Kidney Involvement." Russian Journal of Gastroenterology, Hepatology, Coloproctology 31, no. 6 (March 7, 2022): 47–55. http://dx.doi.org/10.22416/1382-4376-2021-31-6-47-55.
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Aim. Systemic amyloidosis caused by the synthesis and deposition of immunoglobulin light chains (AL amyloidosis) is a relatively rare disease that involves heart, kidneys, peripheral nervous system, gastrointestinal tract, and has a large number of various clinical manifestations. We present a clinical case of systemic AL amyloidosis with a predominant involvement of liver, stomach, intestines, and heart in a Caucasian female.Key points. A Caucasian woman presented to clinic with severe general weakness, abdominal pain, diarrhea, sudden weight loss, and palpitation. Initial examination revealed a duodenal bulb ulcer complicated by bleeding and polyps in the retrobulbar part of duodenum. Decreased hemoglobin levels, elevated levels of alkaline phosphatase, gamma-glutamyltransferase, and N-terminal prohormone of brain natriuretic peptide, signs of heart failure with preserved ejection fraction, and hepatomegaly became the basis for a clinical suspicion of AL amyloidosis and puncture liver biopsy. Histochemical and immunohistochemical studies of liver, stomach, and duodenum biopsy specimens confirmed AL amyloidosis. Timely diagnosis made it possible to conduct a specific therapy with melphalan plus dexamethasone, get a satisfactory response and improve the patient’s condition.Conclusion. A thorough examination of patients along with a pathomorphological and immunohistochemical study of the biopsy specimens is the basis for confirming the diagnosis of AL amyloidosis, selecting the proper therapy, improving the condition of patients and their survival.
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Melarkode Vattekatte, Akhila, Nicolas Ken Shinada, Tarun J. Narwani, Floriane Noël, Olivier Bertrand, Jean-Philippe Meyniel, Alain Malpertuy, Jean-Christophe Gelly, Frédéric Cadet, and Alexandre G. de Brevern. "Discrete analysis of camelid variable domains: sequences, structures, and in-silico structure prediction." PeerJ 8 (March 6, 2020): e8408. http://dx.doi.org/10.7717/peerj.8408.
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Antigen binding by antibodies requires precise orientation of the complementarity- determining region (CDR) loops in the variable domain to establish the correct contact surface. Members of the family Camelidae have a modified form of immunoglobulin gamma (IgG) with only heavy chains, called Heavy Chain only Antibodies (HCAb). Antigen binding in HCAbs is mediated by only three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain. This feature of the VHH, along with their other important features, e.g., easy expression, small size, thermo-stability and hydrophilicity, made them promising candidates for therapeutics and diagnostics. Thus, to design better VHH domains, it is important to thoroughly understand their sequence and structure characteristics and relationship. In this study, sequence characteristics of VHH domains have been analysed in depth, along with their structural features using innovative approaches, namely a structural alphabet. An elaborate summary of various studies proposing structural models of VHH domains showed diversity in the algorithms used. Finally, a case study to elucidate the differences in structural models from single and multiple templates is presented. In this case study, along with the above-mentioned aspects of VHH, an exciting view of various factors in structure prediction of VHH, like template framework selection, is also discussed.
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Marolleau, JP, T. Henni, P. Gaulard, JP Le Couedic, MF Gourdin, M. Divine, A. Katz, M. Tulliez, M. Goossens, and F. Reyes. "Hairy cell leukemia associated with large granular lymphocyte leukemia: immunologic and genomic study, effect of interferon treatment." Blood 72, no. 2 (August 1, 1988): 655–60. http://dx.doi.org/10.1182/blood.v72.2.655.655.
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Abstract The authors describe a patient who presented an association of hairy cell leukemia (HCL) and large granular lymphocyte (LGL) leukemia. An eventual relationship between these two rare entities is analyzed. Hairy cells (HCs) were present in the blood, bone marrow, and spleen. An excess of LGLs was found only in the blood and bone marrow. After splenectomy the patient received an alpha 2-interferon (alpha 2-IFN) treatment. The HCs surface phenotype was mu+delta+kappa+, CD20+, and CD25+. The LGLs consisted in CD3+, CD8+, HNK1+, WT31+ T lymphocytes. These were absent in the spleen. alpha 2-IFN treatment resulted in the disappearance of the HCs in the blood and bone marrow, whereas the LGLs remained unchanged. Before alpha 2-IFN treatment, peripheral blood cells, predominantly LGLs, exerted low cytotoxicity that increased up to a normal level after treatment. Using Southern blotting the authors studied the rearrangements of the T-cell receptor beta--chain (C beta) and gamma-chain (J gamma) genes and immunoglobulin heavy (JH)- and light (C kappa, C lambda)- chain genes. An unique JH and C kappa gene rearrangement was found in the blood and spleen, whereas C beta and J gamma gene rearrangements were present in the blood, not in the spleen. Under alpha 2-IFN treatment, the JH gene rearrangement fainted dramatically, in contrast to that of the C beta gene. The study of messenger RNA (mRNA) of the T cell receptor alpha and beta chains evidenced the 1.3-kilobase (kb) and 1.6-kb bands in the blood and their absence in the spleen. The patient was human T-cell leukemia virus (HTLV)-II negative by Southern analysis of blood and spleen cells. It is concluded that the LGL expansion was clonal and not reactive to the HCL. Although the authors cannot definitely exclude that both HC and LGL proliferations stem in a common leukemic precursor, their findings support an association of the two entities.
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Marolleau, JP, T. Henni, P. Gaulard, JP Le Couedic, MF Gourdin, M. Divine, A. Katz, M. Tulliez, M. Goossens, and F. Reyes. "Hairy cell leukemia associated with large granular lymphocyte leukemia: immunologic and genomic study, effect of interferon treatment." Blood 72, no. 2 (August 1, 1988): 655–60. http://dx.doi.org/10.1182/blood.v72.2.655.bloodjournal722655.
Full textAbstract:
The authors describe a patient who presented an association of hairy cell leukemia (HCL) and large granular lymphocyte (LGL) leukemia. An eventual relationship between these two rare entities is analyzed. Hairy cells (HCs) were present in the blood, bone marrow, and spleen. An excess of LGLs was found only in the blood and bone marrow. After splenectomy the patient received an alpha 2-interferon (alpha 2-IFN) treatment. The HCs surface phenotype was mu+delta+kappa+, CD20+, and CD25+. The LGLs consisted in CD3+, CD8+, HNK1+, WT31+ T lymphocytes. These were absent in the spleen. alpha 2-IFN treatment resulted in the disappearance of the HCs in the blood and bone marrow, whereas the LGLs remained unchanged. Before alpha 2-IFN treatment, peripheral blood cells, predominantly LGLs, exerted low cytotoxicity that increased up to a normal level after treatment. Using Southern blotting the authors studied the rearrangements of the T-cell receptor beta--chain (C beta) and gamma-chain (J gamma) genes and immunoglobulin heavy (JH)- and light (C kappa, C lambda)- chain genes. An unique JH and C kappa gene rearrangement was found in the blood and spleen, whereas C beta and J gamma gene rearrangements were present in the blood, not in the spleen. Under alpha 2-IFN treatment, the JH gene rearrangement fainted dramatically, in contrast to that of the C beta gene. The study of messenger RNA (mRNA) of the T cell receptor alpha and beta chains evidenced the 1.3-kilobase (kb) and 1.6-kb bands in the blood and their absence in the spleen. The patient was human T-cell leukemia virus (HTLV)-II negative by Southern analysis of blood and spleen cells. It is concluded that the LGL expansion was clonal and not reactive to the HCL. Although the authors cannot definitely exclude that both HC and LGL proliferations stem in a common leukemic precursor, their findings support an association of the two entities.
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Eshhar, Z., T. Waks, G. Gross, and D. G. Schindler. "Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors." Proceedings of the National Academy of Sciences 90, no. 2 (January 15, 1993): 720–24. http://dx.doi.org/10.1073/pnas.90.2.720.
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Linsley, P. S., W. Brady, L. Grosmaire, A. Aruffo, N. K. Damle, and J. A. Ledbetter. "Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation." Journal of Experimental Medicine 173, no. 3 (March 1, 1991): 721–30. http://dx.doi.org/10.1084/jem.173.3.721.
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A successful immune response requires intercellular contact between T and B lymphocytes. We recently showed that CD28, a T cell surface protein that regulates an activation pathway, could mediate intercellular adhesion with activated B cells by interaction with the B7 antigen. Here we show that CD28 is the primary receptor for B7 on activated peripheral blood T cells, that CD28 binds to B7 in the absence of other accessory molecules, and that interaction between CD28 and B7 is costimulatory for T cell activation. To characterize the binding of CD28 to B7, we have produced genetic fusions of the extracellular portions of B7 and CD28, and immunoglobulin (Ig) C gamma 1 chains. 125I-labeled B7 Ig bound to CD28-transfected Chinese hamster ovary (CHO) cells, and to immobilized CD28 Ig with a Kd approximately 200 nM. B7 Ig also inhibited CD28-mediated cellular adhesion. The function of CD28-B7 interactions during T cell activation was investigated with soluble fusion proteins and with B7-transfected CHO cells. Immobilized B7 Ig and B7+ CHO cells costimulated T cell proliferation. Stimulation of T cells with B7+ CHO cells also specifically increased levels of interleukin 2 transcripts. These results demonstrate that the CD28 signaling pathway could be activated by B7, resulting in increased T cell cytokine production and T cell proliferation. Cellular interactions mediated by B7 and CD28 may represent an important component of the functional interactions between T and B lymphoid cells.
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Sheridan, W., EF Winton, WC Chan, DS Gordon, WR Vogler, C. Phillips, KF Bongiovanni, and TA Waldmann. "Leukemia of non-T lineage natural killer cells." Blood 72, no. 5 (November 1, 1988): 1701–7. http://dx.doi.org/10.1182/blood.v72.5.1701.1701.
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Abstract An unusual case of an aggressive leukemia of natural killer (NK) cells occurred in a 65-year-old male. Clinical characteristics of this case included hepatosplenomegaly, ascites, marrow infiltrate with leukemic cells, and a WBC up to 82.8 X 10(9) before therapy. One year before his presentation he had been noted to have a WBC of 12.1 X 10(9) with 78% lymphocytes, and 6 months before had noted intermittent fever and weight loss. He and his brother had well documented hereditary cold urticaria. The patient was treated with a modification of ProMACE CYTABOM regimen and had prompt regression of the leukemia with associated acute tumor lysis. Renal, hepatic, and marrow failure predominated during a terminal course that ended 22 days after therapy was commenced, and at autopsy there was no evidence for leukemic cell infiltrate in the liver, spleen or marrow. The leukemic cells were large granular lymphocytes by light and electron microscopic criteria, and had the following immunophenotype: CD2+, DR+, Leu7+, NKH1+, CD11+, CD3-, CD5-, CD4-, CD8-, CD16-. The cells displayed high antibody- dependent cell-mediated cytotoxicity (ADCC) and NK activity, and had a high rate of spontaneous proliferation in vitro that was not augmented by phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). Southern analysis of DNA from leukemic cells revealed normal germline arrangements for the beta and gamma chains of the T cell antigen receptor and immunoglobulin heavy chain genes. The majority of metaphases were clonally abnormal revealing consistent rearrangements involving extra material attached to the long arms of chromosomes 5 and 11.
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Sheridan, W., EF Winton, WC Chan, DS Gordon, WR Vogler, C. Phillips, KF Bongiovanni, and TA Waldmann. "Leukemia of non-T lineage natural killer cells." Blood 72, no. 5 (November 1, 1988): 1701–7. http://dx.doi.org/10.1182/blood.v72.5.1701.bloodjournal7251701.
Full textAbstract:
An unusual case of an aggressive leukemia of natural killer (NK) cells occurred in a 65-year-old male. Clinical characteristics of this case included hepatosplenomegaly, ascites, marrow infiltrate with leukemic cells, and a WBC up to 82.8 X 10(9) before therapy. One year before his presentation he had been noted to have a WBC of 12.1 X 10(9) with 78% lymphocytes, and 6 months before had noted intermittent fever and weight loss. He and his brother had well documented hereditary cold urticaria. The patient was treated with a modification of ProMACE CYTABOM regimen and had prompt regression of the leukemia with associated acute tumor lysis. Renal, hepatic, and marrow failure predominated during a terminal course that ended 22 days after therapy was commenced, and at autopsy there was no evidence for leukemic cell infiltrate in the liver, spleen or marrow. The leukemic cells were large granular lymphocytes by light and electron microscopic criteria, and had the following immunophenotype: CD2+, DR+, Leu7+, NKH1+, CD11+, CD3-, CD5-, CD4-, CD8-, CD16-. The cells displayed high antibody- dependent cell-mediated cytotoxicity (ADCC) and NK activity, and had a high rate of spontaneous proliferation in vitro that was not augmented by phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). Southern analysis of DNA from leukemic cells revealed normal germline arrangements for the beta and gamma chains of the T cell antigen receptor and immunoglobulin heavy chain genes. The majority of metaphases were clonally abnormal revealing consistent rearrangements involving extra material attached to the long arms of chromosomes 5 and 11.
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Vremec, D., M. Zorbas, R. Scollay, D. J. Saunders, C. F. Ardavin, L. Wu, and K. Shortman. "The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells." Journal of Experimental Medicine 176, no. 1 (July 1, 1992): 47–58. http://dx.doi.org/10.1084/jem.176.1.47.
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A new procedure for rapid isolation of dendritic cells (DC) was devised, involving collagenase digestion of tissues, dissociation of lymphoid-DC complexes, selection of light-density cells, then depletion of lymphocytes and other non-DC by treatment with a mixture of lineage-specific monoclonal antibodies (mAbs) and removal with anti-immunoglobulin-coupled magnetic beads. This enriched population (approximately 80% DC) was further purified when required by fluorescence-activated cell sorting for cells expressing high levels of class II major histocompatibility complex (MHC). The isolated DC were characterized by immunofluorescent staining using a panel of 30 mAbs. Thymic DC were surface positive for a number of markers characteristic of T cells, but they were distinct from T-lineage cells in expressing high levels of class II MHC, in lacking expression of the T cell receptor (TCR)-CD3 complex, and having TCR beta and gamma genes in germline state. Splenic DC shared many markers with thymic DC, but were negative for most T cell markers, with the exception of CD8. A substantial proportion of DC from both thymus and spleen expressed CD8 at high levels, comparable with that on T cells. This appeared to be authentic CD8, and was produced by the DC themselves, since they contained CD8 alpha mRNA. Thymic DC presented both the CD8 alpha and beta chains on the cell surface (Ly-2+3+), although the alpha chain was in excess; the splenic DC expressed only the CD8 alpha chain (Ly-2+3-). It is suggested that the expression of CD8 could endow certain antigen-presenting DC with a veto function.
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Storb, U., C. Pinkert, B. Arp, P. Engler, K. Gollahon, J. Manz, W. Brady, and R. L. Brinster. "Transgenic mice with mu and kappa genes encoding antiphosphorylcholine antibodies." Journal of Experimental Medicine 164, no. 2 (August 1, 1986): 627–41. http://dx.doi.org/10.1084/jem.164.2.627.
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Transgenic mice were produced that carried in their germlines rearranged kappa and/or mu genes with V kappa and VH regions from the myeloma MOPC-167 kappa and H genes, which encode anti-PC antibody. The mu genes contain either a complete gene, including the membrane terminus (mu genes), or genes in which this terminus is deleted and only the secreted terminus remains (mu delta mem genes). The mu gene without membrane terminus is expressed at as high a level as the mu gene with the complete 3' end, suggesting that this terminus is not required for chromatin activation of the mu locus or for stability of the mRNA. The transgenes are expressed only in lymphoid organs. In contrast to our previous studies with MOPC-21 kappa transgenic mice, the mu transgene is transcribed in T lymphocytes as well as B lymphocytes. Thymocytes from mu and kappa mu transgenic mice display elevated levels of M-167 mu RNA and do not show elevated levels of kappa RNA, even though higher than normal levels of M-167 kappa RNA are detected in the spleen of these mice. Approximately 60% of thymocytes of mu transgenic mice produce cytoplasmic mu protein. However, despite a large amount of mu RNA of the membrane form, mu protein cannot be detected on the surface of T cells, perhaps because it cannot associate with T cell receptor alpha or beta chains. Mice with the complete mu transgene produce not only the mu transgenic mRNA but also considerably increased amounts of kappa RNA encoded by endogenous MOPC-167 like kappa genes. This suggests that B cells are selected by antigen (PC) if they coexpress the mu transgene and appropriate anti-PC endogenous kappa genes. Mice with the mu delta mem gene, however, do not express detectable levels of the endogenous MOPC-167 kappa mRNA. Like the complete mu transgene, the M-167 kappa transgene also causes amplification of endogenous MOPC-167 related immunoglobulins; mice with the kappa transgene have increased amounts of endogenous MOPC-167-like mu or alpha or gamma in the spleen, all of the secreted form. Implications for the regulation of immunoglobulin gene expression and B cell triggering are discussed.
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Gurtner, Kari M., Eslam Shosha, Sandra C. Bryant, Bruna D. Andreguetto, David L. Murray, Sean J. Pittock, and Maria Alice V. Willrich. "CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes." Clinical Chemistry and Laboratory Medicine (CCLM) 56, no. 7 (June 27, 2018): 1071–80. http://dx.doi.org/10.1515/cclm-2017-0901.
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Abstract Background: Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs. Methods: A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]–[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin]). Results: Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity. Conclusions: cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis.
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Gondek, Michał, Agnieszka Herosimczyk, Przemysław Knysz, Małgorzata Ożgo, Adam Lepczyński, and Krzysztof Szkucik. "Comparative Proteomic Analysis of Serum from Pigs Experimentally Infected with Trichinella spiralis, Trichinella britovi, and Trichinella pseudospiralis." Pathogens 9, no. 1 (January 11, 2020): 55. http://dx.doi.org/10.3390/pathogens9010055.
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Although the available proteomic studies have made it possible to identify and characterize Trichinella stage-specific proteins reacting with infected host-specific antibodies, the vast majority of these studies do not provide any information about changes in the global proteomic serum profile of Trichinella-infested individuals. In view of the above, the present study aimed to examine the protein expression profile of serum obtained at 13 and 60 days postinfection (d.p.i.) from three groups of pigs experimentally infected with Trichinella spiralis, Trichinella britovi, and Trichinella pseudospiralis and from uninfected, control pigs by two-dimensional gel electrophoresis (2-DE) followed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The comparative proteomic analysis of the T. spiralis group vs. the control group revealed 5 differently expressed spots at both 13 and 60 d.p.i. Experimental infection with T. britovi induced significant expression changes in 3 protein spots at 13 d.p.i. and in 6 protein spots at 60 d.p.i. in comparison with the control group. Paired analyses between the group infected with T. pseudospiralis and the uninfected control group revealed 6 differently changed spots at 13 d.p.i. and 2 differently changed spots at 60 d.p.i. Among these 27 spots, 15 were successfully identified. Depending on the Trichinella species triggering the infection and the time point of serum collection, they were IgM heavy-chain constant region, antithrombin III-precursor, immunoglobulin gamma-chain, clusterin, homeobox protein Mohawk, apolipoprotein E precursor, serum amyloid P-component precursor, Ig lambda chains, complement C3 isoform X1, and apolipoprotein A-I. Our results demonstrate that various Trichinella species and different phases of the invasion produce a distinct, characteristic proteomic pattern in the serum of experimentally infected pigs.
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Laurenti, Luca, Andrea Corbingi, Idanna Innocenti, Annamaria Tomasso, Raffaella Pasquale, Andrea Visentin, Marzia Varettoni, et al. "Impact of Serum Immunoglobulin Subsets and Levels on Chronic Lymphocytic Leukemia Natural History: A Retrospective Multicentric Italian Experience." Blood 134, Supplement_1 (November 13, 2019): 3026. http://dx.doi.org/10.1182/blood-2019-128351.
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Introduction: Chronic Lymphocytic Leukemia (CLL) is a clinically and biologically heterogeneous disorder that can be associated with immunological dysregulation. Several prognostic factors, such as IGHV status and chromosomal aberrations as trisomy 12, del11q, del13q or del17p have been detected so far. More recent genetic mutations, such as BIRC3, SF3B1, NOTCH1 and TP53 stratify even further the prognosis and the outcome in CLL patients (pts). However all data above reported, because of expensive techniques and experience typical of big laboratories, are not available to all medical centers. Therefore we considered necessary to identify more accessible and easy to perform parameters in all laboratories, as data concerning the presence of hypogammaglobulinemia, IgM or IgG monoclonal gammopathy, whose prevalence and impact on natural history of CLL in the medical literature are controversial, contradictory and not very significant because of few numbers in cohorts. Therefore the first aim of the study was to evaluate the prevalence of monoclonal IgM/CLL, IgG/CLL and hypogammaglobulinemia compared with CLL pts with normal immunoglobulins (Ig) levels and to establish the impact on clinical outcomes based on Ig levels. The second aim was to find a correlation between each group of pts and biological data. Methods: From four different Italian centers, we collected data from 1505 pts diagnosed with typical CLL from 1987 to 2017 and we divided them in four groups based on the presence of qualitative and quantitative alterations of serum immunoglobulins. Baseline assessment and levels of serum Ig, immunofixation, chromosomal aberrations and clinical features were collected. [Table 1]. We evaluated the impact of each immunoglobulin subset on progression free survival (PFS) and overall survival (OS). Results: Once assessment was made, we included in our study 1505 pts. Median age of 65.5 was similar in all groups and data gathered from the four centers showed an overlapping rate about prevalence and time-dependent parameters in CLL pts and their related subclasses. The overall prevalence of monoclonal gammopathy was 15%, of whom 149 pts (10%) with IgG/CLL and 73 pts (5%) with IgM/CLL. Hypogammaglobulinemia was detected in 200 pts (13%), while 1083 pts (72%) had no evidence of paraprotein or hypogammaglobulinemia. The worst outcome group was identified among CLL with IgM paraprotein; moreover, this group of pts showed more advanced stages at diagnosis according to Binet staging (p<0.002) and a higher frequency of del17p with a percentage of 15% (p<0.022). [Table 1]. The worse median PFS observed was in IgM/CLL group, compared to Hypogamma/CLL, IgG/CLL, and normal/CLL: 33, 54, 62, 96 months respectively (p<0.0001). At the same time, a projection at 150-months showed an estimated OS of 62% in IgM/CLL group, versus 68% in hypogamma/CLL, 81% in IgG/CLL and 86% in normal/CLL (p<0.0001). To evaluate if the specific deficit of IgG or IgM could have any unfavourable impact on each group's prognosis, we measured the serum levels of IgM and IgG in all pts. No statistically significant differences were observed among time-dependent parameters in IgG/CLL, IgM/CLL and hypogamma groups, based on IgM and IgG levels, if deficient or normal.Finally, in the group of pts who had normal gamma-level, median PFS and TTT was reached at 79 months (p=0.006 and 0.002, respectively) in the subgroup with IgM deficiency, while no statistical difference was observed regarding OS (p=0.785). Conclusions: Our study provides data about prevalence and impact of monoclonal gammopathy and hypogammaglobulinemia on the outcomes of CLL patients. In this study, we observed that the 28% pts had any qualitative or quantitative immunoglobulins alteration, of whom 15% had monoclonal gammopathy and 13% had hypogammaglobulinemia. The worst outcomes were observed in the IgM/CLL pts in terms of PFS and OS. In conclusion, the laboratory data of serum Ig could be used as predictive markers of clinical outcomes because, for their easy availability, they could direct the prognosis of CLL pts. As a future perspective, we would like to characterize pts with monoclonal IgM component from a biological view, to correlate the subset of somatic mutations of the heavy chains of surface immunoglobulins with the monoclonal component and its prognostic significance. Disclosures Varettoni: ABBVIE: Other: travel expenses; Roche: Consultancy; Gilead: Other: travel expenses; Janssen: Consultancy. Trentin:ABBVIE: Honoraria, Other: board; Janssen: Consultancy, Honoraria, Other: Board; gilead: Consultancy; Roche: Honoraria, Other: Board.
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Musso, Tiziana, Liliana Calosso, Mario Zucca, Maura Millesimo, Manuela Puliti, Silvia Bulfone-Paus, Chiara Merlino, et al. "Interleukin-15 Activates Proinflammatory and Antimicrobial Functions in Polymorphonuclear Cells." Infection and Immunity 66, no. 6 (June 1, 1998): 2640–47. http://dx.doi.org/10.1128/iai.66.6.2640-2647.1998.
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ABSTRACT Interleukin-15 (IL-15) is a recently discovered cytokine produced by a wide range of different cell types including fibroblasts, keratinocytes, endothelial cells, and macrophages in response to lipopolysaccharide or microbial infection. This suggests that IL-15 may play a crucial role in the activation of phagocytic cells against pathogens. We studied polymorphonuclear leukocyte (PMN) activation by IL-15, evaluated as enhancement of PMN anti-Candidaactivity as well as IL-8 production, following stimulation with the cytokine. The PMN response to IL-15 depends on binding to the IL-15 receptor. Our experiments show that binding of a biotinylated human IL-15–immunoglobulin G2b IgG2b fusion protein was competed by the addition of human recombinant IL-15 (rIL-15) or of human rIL-2, suggesting that IL-15 binding to PMN might involve the IL-2Rβ and IL-2Rγ chains, which have been shown to be constitutively expressed by PMN. In addition, we show by reverse transcription-PCR and by flow cytometry with a specific anti-IL-15Rα chain monoclonal antibody that PMN express the IL-15Rα chain at the mRNA and protein levels. Incubation with IL-15 activated PMN to secrete the chemotactic factor IL-8, and the amount secreted was increased by costimulation with heat-inactivated Candida albicans. In addition, IL-15 primed the metabolic burst of PMN in response to formyl-methionyl-leucyl-phenylalanine but was not sufficient to trigger the respiratory burst or to increase the production of superoxide in PMN exposed to C. albicans. IL-15 also increased the ability of PMN to phagocytose heat-killed C. albicansorganisms in a dose-dependent manner, without opsonization by antibodies or complement-derived products. In the same concentration range, IL-15 was as effective as gamma interferon (IFN-γ) and IL-2 in increasing the C. albicans growth-inhibitory activity of PMN. Taken together, these results suggest that IL-15 is a potent stimulant of both proinflammatory and antifungal activities of PMN, activating several antimicrobial functions of PMN involved in the cellular response against C. albicans.
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Ranganathan, Raghuveer. "Chimeric Antigen Receptor T Cells Redirected Towards Clonally Restricted Surface Immunoglobulin Efficiently Eradicate Mature B Lymphocyte-Derived Malignancies." Blood 132, Supplement 1 (November 29, 2018): 337. http://dx.doi.org/10.1182/blood-2018-99-110835.
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Abstract Background: Indolent B cell non-Hodgkin lymphomas (B-NHL) are typically described as having smoldering clinical courses. Chemotherapy plus CD20-targeting antibodies have made remissions in this type of disease possible, with fit patients sometimes consolidated with autologous stem cell transplant. However, these lymphomas commonly progress or relapse inexorably, requiring further interventions. Some B-NHL subtypes, such as mantle cell lymphoma (MCL) or advanced follicular lymphoma (FL) have unpredictable and sometimes clinically aggressive courses which are refractory to even frontline treatments, and remain principally incurable. Adoptive chimeric antigen receptor T cells targeting CD19 (CD19.CAR-T) has shown therapeutic promise for these B-NHL subtypes. Targeting this antigen, however, does not distinguish between normal and malignant B cells and may cause B-cell aplasia and agammaglobulinemia when CD19.CAR-T persist long-term. FL and MCL, along with many diffuse large B cell lymphoma (DLBCL), express surface immunoglobulin (Ig) that is clonally restricted to either the kappa (Ig-κ) or lambda (Ig-l) light chains. We explored targeting the Ig-κ or Ig-l individually with CAR-T, which would possibly spare B lymphocytes expressing the reciprocal light chain, and consequently reduce the impairment of humoral immunity. Methods/Results: Previous studies showed modifying the hinge and transmembrane (TM) regions could result in amplified tumor cytotoxicity. We explored refining our own CAR-T approach by first altering the hinge and TM regions of the CAR molecule itself, using the CD8a hinge and TM regions in lieu of the currently used CD28 hinge and TM sections. The costimulatory endodomains used were either CD28 or 41BB, each combined with the CD3ζ chain. When compared to the CD28 hinge and TM containing CAR molecules, we demonstrated the CD8a-containing hinge and TM CAR molecules targeting Ig-κ (CAR.κ) or Ig-l (CAR.λ) had augmented cytotoxicity, as well as increased IFNg and IL-2 cytokine production, in vitro against B-NHL derived tumor cell lines expressing Ig-κ or Ig-l, respectively. Furthermore, both CAR.κ and CAR.λ demonstrated selective cytotoxicity of the appropriately expressed tumor-associated immunoglobulin, while sparing the tumor cells expressing the reciprocal surface Ig. We conducted in vivo experiments using a NOD-scid gamma (NSG) xenograft murine models. NSG mice were treated with CAR-T targeting CD19 (positive control), non-transduced cells (negative control), and depending on the Ig light chain target, either CAR.κ.CD28ζ and CAR.κ.41BBζ, or CAR.λ.CD28ζ and CAR.λ.41BBζ. We also established a humanized murine model that reconstituted human B lymphocytes in NSG mice post-irradiation using CD34+ umbilical cord blood cells, replicating a humanized humoral immune system replete with a full complement of humanized B cells. We then measured the selective ability of CAR.κ and CAR.λ cells to eliminate human B-lymphocytes expressing either the Ig-κ or Ig-l, respectively, while sparing the reciprocally expressed light chain-carrying B lymphocytes. We found that CAR.κ and CAR.λ showed respective high cytotoxic activity, similar to CD19.CAR, against the appropriate Ig-κ+ or Ig-l+ B-NHL tumor cell lines in vivo within the NSG xenograft murine model. We also demonstrated the selective elimination by the CAR.κ and CAR.λ of either the kappa or lambda light chain-expressing B lymphocytes, with sparing of the reciprocal light chain-expressing B lymphocytes, in the humanized murine model. Conclusion: Since κ/l expression is clonally restricted, and because mature B-lymphocyte derived malignancies are themselves clonally restricted, having a CAR-T that targets either light chain can potentially treat the full gamut of mature B-NHL subtypes. In addition, sparing the normal population of B lymphocytes would have negligible impact upon the patient's humoral immunity. Moreover, we showed equal efficacy of our CAR.κ.CD28 and CAR.λ.CD28 when compared with CD19.CAR. As such, adoptive transfer of CAR-T targeting the clonally restricted light chain can be a very feasible immunotherapy approach to treating advanced FL, MCL and DLBCL clinically, without entirely compromising humoral immunity. Disclosures No relevant conflicts of interest to declare.
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Mansilla-Soto, Jorge, Justin Eyquem, Sascha Haubner, Mohamad Hamieh, Judith Feucht, Noémie Paillon, Andres Zucchetti, et al. "132 HLA-independent T cell receptors effectively target low abundance antigens." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A142. http://dx.doi.org/10.1136/jitc-2021-sitc2021.132.
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BackgroundChimeric antigen receptors (CARs) engage antigen independently of HLA and enable sustained T cell proliferation when they are endowed with both activating and costimulatory functions. While remission rates have been noticeably elevated in numerous clinical trials targeting CD19, CD22 or BCMA, relapses are common. One of the several underlying relapse mechanisms is antigen escape, which refers to a relapsing tumor that is either negative for the targeted antigen or expresses the latter at a low level. Failure to eliminate antigen-low tumors raises questions about the sensitivity of CARs and the minimum antigen density that is required for effective tumor eradication. Unlike CARs, TCRs engage antigen in an HLA-dependent manner, and they do so with high sensitivity. We hypothesized that a TCR/CD3 complex containing the same heavy and light immunoglobulin chains as a CAR will display increased sensitivity to the target antigen.MethodsWe edited the TRAC locus in human primary T cells to establish a novel antigen receptor structure, termed HLA-independent TCR or HIT receptor, by incorporating into the TCR/CD3 complex the same heavy and light chains as those of a corresponding CAR. We assessed their antigen sensitivity against a panel of cell lines expressing different antigen levels, analyzing their cytotoxicity, cytokine secretion, signaling response and degranulation activity. HIT and CAR T cells were further evaluated for their anti-tumor response using established ALL and AML mouse models.ResultsCD19-TRAC-HIT and CD19-TRAC-CAR T cells lysed wild-type NALM6 (~27,000 CD19 molecules) and NALM6 variants with 100-fold less CD19. As CD19 levels decreased further, CAR T cells no longer killed their target, in contrast to HIT T cells. HIT T cells showed increased expression of IFN-gamma, IL-2 and TNF-alpha upon exposure to NALM6 cells expressing ~20 CD19 molecules per cell, compared to CAR T cells. This increased sensitivity of HIT receptors correlated to their greater signaling response, upon exposure to the low-antigen-density NALM6. Phospho-proteomic analyses further confirmed this increased response of HIT T cells to low antigen levels. Altogether, these results confirm that HIT receptors endow T cells with greater antigen sensitivity than canonical CARs. We further showed that HIT T cells have higher in vivo anti-tumor activity compared to CAR T cells in mice bearing low-antigen-density ALL or AML.ConclusionsHIT receptors consistently afford high antigen sensitivity and mediate tumor recognition beyond what current CARs can provide. HIT receptors open new prospects for targeting cell surface antigens of low abundance.Ethics ApprovalEight- to 12-week-old NOD/SCID/IL-2Rgamma-null (NSG) male mice (Jackson Laboratory) were used under a protocol approved by the MSKCC Institutional Animal Care and Use Committee.
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Chen, Shixue, Lingling Li, Fan Zhang, Yu Wang, Yi Hu, and Lei Zhao. "Immunoglobulin Gamma-Like Therapeutic Bispecific Antibody Formats for Tumor Therapy." Journal of Immunology Research 2019 (February 11, 2019): 1–13. http://dx.doi.org/10.1155/2019/4516041.
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Bispecific antibodies (BsAbs) are a sort of dual functional proteins with specific binding to two distinct targets, which have become a focus of interest in antibody engineering and drug development research and have a promising future for wide applications in cancer immunotherapy and autoimmune disease. The key of clinical application and commercial-scale manufacturing of BsAbs is the amenability to assembly and purification of desired heterodimers. Advances in genetic engineering technology had resulted in the development of diverse BsAbs. Multiple recombinant strategies have been used to solve the mispairing problem between light and heavy chains, as well as to enforce accurate dimerization of heterologous heavy chains. There are 23 platforms available to generate 62 BsAbs which can be further divided into IgG-like ones and fragment-based ones, and more than 50 molecules are undergoing clinical trials currently. BsAbs with IgG-like architecture exhibit superior advantages in structure (similar to natural antibodies), pharmacokinetics, half-life, FcR-mediated function, and biological activity. This review considers various IgG-like BsAb generation approaches, summarizes the clinical applications of promising new BsAbs, and describes the mechanism of BsAbs in tumor therapy.
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Čabarkapa, Velibor, Zoran Stošić, Mirjana Đerić, Ljiljana Vučurević-Ristić, and Mirjana Drljača. "The Importance of Free Light Chains of Immunoglobulins Determination in Serum." Journal of Medical Biochemistry 26, no. 4 (December 1, 2007): 269–73. http://dx.doi.org/10.2478/v10011-007-0032-6.
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The Importance of Free Light Chains of Immunoglobulins Determination in SerumFor many years, Bence Jones proteinuria has been an important diagnostic marker for multiple myeloma. Relatively new serum tests for free kappa and free lambda light chains of immunoglobulins reflect the production of free light chains more accurately than urine tests. In this study, we examined the value of serum free light chains measurement in the diagnosis of some neoplastic diseases and the discrepance between the findings of serum protein electrophoresis and serum free light chains. Thirty one patients (f=19, m=12) were included in the study, most of them with blood malignant diseases. The results show that in six patients with normal gamma and beta electrophoresis fractions there are abnormal levels of free light chains and/or an abnormal κ/LD ratio. In 20 patients we found an abnormal κ/LD ratio, and in 21 patients we found an abnormal κ or LD level, or both. The obtained results show the important role of serum free light chains determination in identifying patients with monoclonal gammopathies.
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Chui, S. H., C. W. Lam, and K. N. Lai. "Light-chain ratios of immunoglobulins G, A, and M determined by enzyme immunoassay." Clinical Chemistry 36, no. 3 (March 1, 1990): 501–2. http://dx.doi.org/10.1093/clinchem/36.3.501.
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Abstract We describe an enzyme-linked immunosorbent assay for determination of light-chain ratios for IgG, IgA, and IgM in serum. A commercial serum with known overall kappa and lambda concentrations was used as standard. To capture the respective immunoglobulins, we used antibodies to gamma, lambda and mu chains coated onto microtiter plates. Peroxidase-conjugated anti-kappa and anti-lambda chain antisera were reacted with light chains on the captured immunoglobulins, and the amount of enzyme bound was monitored with o-phenylenediamine and urea-hydrogen peroxide as substrates. Calculation of absorbance ratios allowed determination of kappa and lambda chain concentrations of individual immunoglobulins in the standard and samples. Within-run and between-run CVs (n = 25) ranged from 5.9% to 13.0% for "high," "normal," and "low" kappa/lambda ratios for IgG, IgA, and IgM. The thoroughness of light-chain detection, expressed as, e.g., (IgA kappa + IgA lambda)/(total IgA), for 150 sera was 91-110%. The detection limit was 1 microgram/L. Reference intervals (mean +/- SD) for kappa/lambda ratios in sera from 100 apparently healthy adults were 2.34 +/- 0.80 for IgG, 1.59 +/- 0.40 for IgA, and 1.86 +/- 0.76 for IgM.
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Goñi, F., J. Chuba, J. Buxbaum, and B. Frangione. "A double monoclonal IgG1 kappa and IgG2 kappa in a single myeloma patient. Variation in clonal products and therapeutic responses." Journal of Immunology 140, no. 2 (January 15, 1988): 551–57. http://dx.doi.org/10.4049/jimmunol.140.2.551.
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Abstract Two electrophoretically homogeneous immunoglobulins were detected in the serum of a patient with multiple myeloma. The heavy chains were of different classes (gamma 1 and gamma 2). The light chains of both were kappa, but had different electrophoretic mobilities on polyacrylamide gels. Amino acid sequence analysis, carbohydrate determinations, and biosynthetic experiments indicated that the difference seen in their electrophoretic mobility was due to the glycosylation of one but not the other kappa-chain. The primary structure of both chains demonstrated that they both used a V kappa 1 and a J kappa 2 gene segment and the same C kappa allele, Km(1,2), and that both contained the same junctional three amino acid deletion. However, they varied by 19 amino acids in the first 94 amino terminal residues encoded for by the V kappa gene, with some of the substitutions requiring two base changes in the appropriate codons. Moreover, the malignant "clones" producing the two proteins differed in their responses to chemotherapy. These data indicate that, although the two clones producing the serum proteins were different at the time of study, they may have arisen from the same precursor clone.
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Bisegna, Maria Laura, Maria Assunta Limongiello, Stefano Fiori, Maria Stefania De Propris, Irene Della Starza, and Stefania Trasarti. "Gamma heavy chain disease associated with T-cell large granular lymphocyte lymphoproliferative disorder: case report and literature review." Mediterranean Journal of Hematology and Infectious Diseases 15, no. 1 (January 1, 2023): e2023010. http://dx.doi.org/10.4084/mjhid.2023.010.
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Heavy chain diseases are rare B-cell neoplasms consisting of the production of a monoclonal immunoglobulin composed of the only heavy chain without corresponding light chains. It is a rare adult disease that may involve several sites with a variable clinical course. It manifests itself on a large spectrum from indolent to rapidly progressive. We present a case of heavy chain disease and concomitant T- cell large granular lymphoproliferative disorder, an association described in only six cases before.
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Rock, E. P., P. R. Sibbald, M. M. Davis, and Y. H. Chien. "CDR3 length in antigen-specific immune receptors." Journal of Experimental Medicine 179, no. 1 (January 1, 1994): 323–28. http://dx.doi.org/10.1084/jem.179.1.323.
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In both immunoglobulins (Ig) and T cell receptors (TCR), the rearrangement of V, D, and J region sequence elements during lymphocyte maturation creates an enormous degree of diversity in an area referred to as the complementarity determining region 3 (CDR3) loop. Variations in the particular V, D, and J elements used, precise points of recombination, and random nucleotide addition all lead to extensive length and sequence heterogeneity. CDR3 loops are often critical for antigen binding in Igs and appear to provide the principal peptide binding residues in TCRs. To better understand the physical and selective constraints on these sequences, we have compiled information on CDR3 size variation for Ig H, L (kappa and lambda) and TCR alpha, beta, gamma, and delta. Ig H and TCR delta CDR3s are the most variable in size and are significantly longer than L and gamma chains, respectively. In contrast, TCR alpha and beta chain distributions are highly constrained, with nearly identical average CDR3 lengths, and their length distributions are not altered by thymic selection. Perhaps most significantly, these CDR3 length profiles suggest that gamma/delta TCRs are more similar to Igs than to alpha/beta TCRs in their putative ligand binding region, and thus gamma/delta and alpha/beta T cells may have fundamentally different recognition properties.