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PubMed1981

Enzymic diversification of the sodium pump in sheep red cells.

It is well-established that sheep are genetically dimorphic with respect to the K+ content of their mature red cells and that high-K+ (HK) and low-K+ (LK) red cells differ with respect to the activity and kinetic properties of the sodium pump and Na+-ATPase. In contrast, reticulocytes of both types have a high K+ content and are similar with respect to their pump and Na+-ATPase kinetic characteristics. Reticulocytes differ, however, from mature cells of either HK or LK sheep. The first part of this paper describes a comparative study of the side-specificity of Na+ and K+ interactions with Na--ATPase of inside-out membrane vesicles prepared from mature HK and LK red cells. The results indicate that the genetic difference between the two is expressed as differences in apparent affinities for both Na+ and K+ and that these differences are evident at the cytoplasmic as well as at the extracellular membrane surface. The second part of this paper describes a study of the nature of the maturation-associated changes in the sodium pump system of sheep reticulocytes. Maturation was followed both in vitro (long-term incubation at 37 degrees of reticulocytes) and in vivo (changes in density gradient fractionated HK cells followed at intervals during recovery from massive bleeding. The results support the conclusion that the dimorphism in the sodium pump of sheep red cells is a result of specific changes in Na+-ATPase and that these changes proceed differently during maturation of the two types of sheep red cells.

Anemia↗
PubMedDate not supplied

Evolution in microcosm: the rapid somatic diversification of lymphocytes.

The characteristic task of the immune system is learning to respond specificially to entirely novel antigens. How it may do this is discussed under 6 headings. 1. -- Vertebrate and invertebrate immune strategies are contrasted. Whereas among invertebrates whole individuals appear to be selected for their immunological fitness, vertebrates have developed an internal population of lymphocytes among which variants arise and are selectively stimulated by antigen to give a response which protects the "host". 2. -- The genetic mechanism underlying this variation of lymphocytes is of great interest, but its discovery will not, given present ignorance of eukarote DNA, answer those questions about variation at the phenotypic level which are vital to the rest of immunology: e.g. when, how fast, and under what conditions do variantes arise? 3. -- A great deal of indirect evidence suggests that the production of entirely new variant lymphocytes occurs throughout life, particularly after antigenic stimulation. 4. -- Experimental approaches are discussed which might provide direct evidence for or against the idea of rapid variation among stimulated lymphocytes. The method used was based on detecting the cross-reactive specificity of antibody produced by single cells. 5. -- Evidence obtained with this technique is briefly described. There were two main kinds of experiment. In the first, rapid variation (at the rate of about one variation event per 30 divisions) was demonstrated within single clones of proliferating antibody-forming cells. In the second group of experiments, it was shown that certain uncommon antibody-forming cell specificities present at the peak of a primary response were entirely absent at earlier stages. 6. -- A new immunological paradigm may emerge from work on the generation of diversity and on active control of response. There may be relatively few types of lymphocytes with germ-line-coded receptors. These are stimulated by environmental antigens and mitogens, and perhaps by self stimulated by environmental antigens and mitogens, and perhaps by self antigens. Extensive proliferation and variation occurs, which in turn elicits suppressor reactions directed against antigen or against idiotypes of responding clones. The immune repertoire of the adult vertebrate is a product of the evolution of its lymphocytes under the competing pressures of antigenic stimulation and active suppression.

Aging↗
PubMed1993

Structural analysis of the CD11b gene and phylogenetic analysis of the alpha-integrin gene family demonstrate remarkable conservation of genomic organization and suggest early diversification during evolution.

CD11b is a member of the beta 2 subfamily of the human leukocyte integrins. Its expression is limited to mature myeloid and NK cells and is up-regulated during the course of granulocytic and monocytic differentiation. The CD11b/CD18 (Mo1) heterodimer promotes adhesion of granulocytes and monocytes to C3bi-coated bacteria and endothelial cells. In an attempt to relate the exon structure to the known functional domains, as well as to identify and study cis-acting elements that are involved in its tissue-specific expression, we have isolated genomic clones encoding CD11b, deduced the exon/intron organization, and determined the transcriptional start site. The CD11b gene spans 55 kb and is encoded by 30 exons. Its structure closely resembles that of CD11c, another of the three leukocyte integrin alpha-chains, and suggests that these two genes arose by a gene duplication event. Furthermore, comparison of the CD11b gene structure with that of platelet glycoprotein IIb and Drosophila PS2 suggest how the human leukocyte integrins evolved and dispersed during the course of evolution.

Amino Acid Sequence↗
PubMed1996

Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification.

Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha-expressing cDNA were present in greater amounts that unrelated (non-CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.

Base Sequence↗
PubMed1995

[Studies on diversification and restriction of immune response against glycopeptide antigens].

The M and N human blood group antigens are complex glycopeptide determinants at the amino terminus of the red blood cell membrane glycoprotein, glycophorin A. The heavy and light chain variable region cDNA sequences were determined for eight murine monoclonal antibodies recognizing the M or N blood group determinants. Among anti-N, but not anti-M, hybridomas, apparent restriction was found: all four anti-N VH regions of the heavy chains were derived from the same family, VH2(Q52) and all used the same J4 gene segment. To determine whether the Fab fragments displayed on the bacteriophage surface retain the immunological characteristics of intact antibodies, Fab-phages were constructed from five murine monoclonal antibodies recognizing glycophorin A. In each case, the Fab-phage had similar immunological characteristics as the respective antibodies. These results suggest that Fab-phages may be useful in studying the immune response to human glycosylation-dependent peptidic epitopes.

Antigens↗
PubMed1996

Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.

The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.

Animals↗