Molecular and structural changes underlying long-term memory storage in Aplysia.
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Animals↗
Biomedical subjects
C Alberini
Publications and source records attributed to C Alberini.
Modulating secretion of antibodies.
Cells have means to ensure that only properly folded and assembled molecules are transported to their final destination, a phenomenon referred to as "quality control" of protein synthesis. Thus, plasma cells secrete only the polymeric form of IgM, retaining and degrading intracellularly assembly intermediates. Due to the failure to polymerize secretory IgM, B lymphocytes do not secrete IgM, while they express the membrane form of IgM on their surface. The selective retention of IgM assembly intermediates is due to disulphide interchange reactions which involve the C terminal cysteine of secretory microseconds chains and unknown protein(s) of the endoplasmic reticulum (ER). Assembly inhibits these reactions, as does addition of reducing agents. In the latter condition, assembly intermediates, otherwise retained and degraded in the ER, are transported to the Golgi, glycosylated and secreted. The developmental control of immunoglobulin secretion is discussed in the more general context of "quality control" of newly synthesized protein within the exocytic compartment.
Adjuvants, Immunologic↗
Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine.
B lymphocytes do not secrete IgM, and plasma cells only secrete IgM polymers. Here we show that both events are attributable to the tailpiece found at the carboxyl terminus of mus chains, and we specifically implicate Cys-575. Thus, if Cys-575 was mutated, IgM was secreted by B cells. Similarly, a mutant IgG containing a mus tailpiece became largely retained within the cell; secretion was restored upon mutation of the tailpiece cysteine. Removal of Cys-575 also allowed hypersecretion of monomeric IgM by plasmacytoma cells. Following further removal of Cmu1, heavy chains were secreted in the absence of light chains. Thus, in B and plasma cells, Cys-575 is involved both in the polymerization of IgM and in intracellular retention of unpolymerized intermediates.
Amino Acid Sequence↗
Interdependence of CD3-Ti and CD2 activation pathways in human T lymphocytes.
Human T lymphocytes can be activated through either the antigen/MHC receptor complex T3-Ti (CD3-Ti) or the T11 (CD2) molecule to proliferate via an IL-2 dependent mechanism. To investigate the relationship of these pathways to one another, we generated and characterized Jurkat mutants which selectively express either surface CD3-Ti or CD2. Here we show that CD3-Ti- mutants fail to be stimulated by either pathway to increase phosphoinositide turnover, mobilize calcium or induce the IL-2 gene. The activation capacity of these mutants via CD2 as well as CD3-Ti can be restored following reconstitution of surface CD3-Ti expression upon appropriate DNA transfer (e.g. Ti beta subunit cDNA into Ti beta- Jurkat variants). Collectively, these results demonstrate that CD3-Ti and CD2 pathways are interdependent and that phosphoinositide turnover is linked to the CD3-Ti complex.
Antigens, Differentiation↗
The control of membrane and secreted heavy chain biosynthesis varies in different immunoglobulin isotypes produced by a monoclonal B cell lymphoma.
The control of production of the membrane (m) vs secreted (s) forms of immunoglobulin heavy chains was investigated in a panel of cell lines expressing different heavy chain classes but identical light chains (lambda) and variable regions. These cell lines could be induced towards Ig secretion by mitogen treatment. During this process a shift from m to s heavy chain production takes place. Here we show that, similarly to IgA- and IgE-producing B cells, in IgG2a-producing I.29 cells the gamma m-gamma s shift was accompanied by a shift in the corresponding mRNAs, with a decrease of gamma m mRNA and an increase of the gamma s mRNA in LPS-stimulated cells. By contrast, the micron mRNA was increased in LPS-stimulated IgM-producing cells, albeit these cells synthesized reduced amounts of micron polypeptides. The utilization of the translational level in the early steps of B lymphocyte maturation thus distinguishes the mode of regulation of mu chains from those of the other isotypes. In addition, in B cells a post-translational event blocks the secretion of IgM but not of IgG or IgE.
Animals↗
Differentiation in the murine B cell lymphoma I.29: individual mu + clones may be induced by lipopolysaccharide to both IgM secretion and isotype switching.
Cells from the monoclonal B cell lymphoma I.29 expressing surface IgM (mu +) are capable of differentiating in vitro to IgM secretion and of switching to IgA or IgE production in response to lipopolysaccharide (LPS) stimulation. To determine whether a single mu + B cell is capable of undertaking both differentiative pathways (isotype switch and plasma cell differentiation) I.29 mu + cells were cloned by limiting dilution and a panel of clones were analyzed by immunofluorescence, endogenous labeling and Northern blotting. While 100% of the clones could differentiate toward IgM secretion, only a proportion of them (greater than 70%) also switched to IgA and/or IgE production. Certain clones switched preferentially to a specific isotype. Taken together with the observation that C gamma genes were never the target of switching in our experiments, these data suggest that individual mu + clones from the I.29 lymphoma are "precommitted" as for their switching potentials. The subclones that showed a high frequency of switching to IgA transcribed the germ line C alpha gene(s), suggesting a role for chromatin structure in determining the isotype switch specificity. Switch variant clones expressing either IgA or IgE on the cell surface were isolated and found capable of further differentiating toward Ig secretion in response to LPS. On the contrary, we could not induce switch to IgA in IgE-producing cells. Unlike mu + and alpha + cells, all the switch variant clones expressing IgE tested by endogenous labeling constitutively secreted large amounts of IgE in the supernatants even in the absence of LPS stimulation.
Animals↗
Lymphocyte subpopulations in the neonate: high percentage of circulating B73.1+, HNK-1- cells.
The reactivity of B73.1 monoclonal antibody was evaluated on unseparated and on T cell-depleted and T cell-enriched fractions of both cord blood lymphocytes (CBL) and adult peripheral blood lymphocytes (a-PBL). The reactivity of this monoclonal antibody with the E-, OKT3-, OKT8+, HNK-1- subset of CBL, previously demonstrated to have NK activity, was also studied. The data show that B73.1+ cells were present in similar percentages in CBL and a-PBL while HNK-1+ cells were very low in CBL. In addition the B73.1 monoclonal antibody reacted with about 50% of the E-, OKT3-, OKT8+, HNK-1- CBL and within this subset the majority of the B73.1+ cells were PNA-. These data support the hypothesis that part of this neonatal subpopulation, belongs to the NK cell lineage. Moreover the results obtained by double-labelling with B73.1 monoclonal antibody and PNA suggest that the E-, OKT3-, OKT8+, HNK-1- CBL include either different subsets or various differentiation stages of the same subset.
Adult↗
Lymphocyte subpopulations in Down's syndrome: high percentage of circulating HNK-1+, Leu 2a+ cells.
Peripheral blood lymphomononuclear cells (PBL) from 35 patients with Down's syndrome (DS, trisomy-21; 25 institutionalized and 10 non-institutionalized) were phenotypically characterized by means of various monoclonal antibodies. They included a high percentage of T lymphocytes with low avidity for sheep erythrocytes as well as an extremely high percentage of HNK-1+ cells and of lymphocytes reacting with the OKT8 and Leu 2a antibodies. The HNK-1+ cells of DS include four different subsets: (a) E+, OKT3+, OKT8-, Leu 2a-; (b) E+, OKT3+, OKT8+, Leu 2a+; (c) E-, OKT3-, OKT8-, Leu 2a- and (d) E-, OKT3-, OKT8+, Leu 2a+. Subsets (a) and (c) are also present in PBL from karyotypically normal controls while subsets (b) and (d) have a phenotype which has not been previously reported. These findings may be related to the triple expression by trisomic cells of the receptor for interferon, which is coded by a gene located on chromosome number 21. Alternatively, the high number of 'immature' NK cells of DS, possibly identical with pre-T lymphocytes, may originate from the congenital thymic derangement associated with trisomy 21.
Adolescent↗