Each antibody-producing B cell makes antibodies of unique specificity, reflecting a series of ordered gene rearrangements which must be successfully performed if the cell is to survive. A second selection process occurs during immune responses in which a new antibody repertoire is generated through somatic hypermutation. Here only mutants binding antigen with high affinity survive to become memory cells. Cells expressing autoreactive receptors are counter-selected at both stages. This stringent positive and negative selection allows the generation and diversification of cells while rigorously controlling their specificity.

Clonal selection and learning in the antibody system

Antibody reacting with lymphocyte surface immunoglobulin molecules induces these to gather over one pole of the cell. This suggests a possible mechanism for lymphocyte triggering by antigen and raises questions about cell membrane structure.

Redistribution and Pinocytosis of Lymphocyte Surface Immunoglobulin Molecules Induced by Anti-Immunoglobulin Antibody

Transmembrane control of the receptors on normal and tumor cells: I. Cytoplasmic influence over cell surface components☆

Malignant Lymphomas Other than Hodgkin’s Disease

The arrangement of lipids and some proteins in the erythrocyte membrane has been discussed. The conclusions from this are listed here as a set of general guidelines for the structure of membranes of higher organisms: some of these rules may be wrong. But at this stage it seems useful to sharpen our thoughts in this way and thereby focus attention on various specific points. 1) The basis of a membrane is a lipid bilayer with (i) choline phospholipids and glycolipids in the external half and (ii) amino (and possibly some choline) phospholipids in the cytoplasmic half. There is effectively no lipid exchange across the bilayer (unless enzymatically catalyzed) (68). 2) Some proteins extend across the bilayer. Where this is so, they will in general have carbohydrate on their surface remote from the cytoplasm. This carbohydrate may prevent the protein diffusing out of the membrane into the cytoplasm; it acts as a lock on the protein. 3) Just as lipids do not flip-flop, proteins do not rotate across the membrane. Lateral motion or rotation of lipids and proteins in the plane of the bilayer may be expected. 4) Most membrane protein is associated with the inner, cytoplasmic, urface of the membrane. Proteins are not usually associated exclusively with the outer half of the lipid bilayer. 5) Membrane proteins are a special class of cytoplasmic proteins, not of secreted proteins.

Membrane Structure: Some General Principles

Small and medium lymphocytes from the peripheral blood and lymphoid tissues of the rabbit react in suspension with antibodies directed against different immunoglobulin determinants. Through immunofluorescence, it was possible to show that numerous discrete spots on the surface of the positive lymphocytes carry immunoglobulin molecules.

The positive lymphocytes are about one-half of all lymphocytes in the different preparations; thymus lymphocytes are all negative.

With antisera specific for rabbit IgM as well as with antisera directed against allotypic determinants specific for IgM or IgG, it was possible to show that about nine-tenths of the immunoglobulin-positive lymphocytes carry IgM molecules on their surface.

With antisera directed against a - and b -locus determinants, it was also possible to demonstrate that both heavy and light chains were present in the surface immunoglobulins. Furthermore, in animals which were heterozygous at the a or the b locus, it was found that each lymphocyte had immunoglobulins synthesized under the influence of only one of two alleles.

A very small proportion of lymphocytes could be shown to have a specific surface reaction with one antigen (horse ferritin); the proportion of these cells increased very much after immunization.

/pdf/immunoglobulin-spots-on-the-surface-of-rabbit-lymphocytes-10x646413i.pdf

Immunoglobulin spots on the surface of rabbit lymphocytes.

It is conceivable that immunoglobulin molecules in a suitable position on the external membrane of immunocytes may play the role of cell receptors. Through an interaction of these antibody molecules with the corresponding antigens, the cells might be triggered to proliferation and/or differentiation. This might be a crucial role played by membrane-bound immunoglobulins in the immune response, and it is therefore of considerable interest to study the presence, distribution and specificity of immunoglobulin molecules on the membrane of lymphoid cells. The first demonstration of the presence of immunoglobulin determinants on the membrane of lymphocytes has been provided by the blast transformation of these cells after contact with antiimmunoglobulin or antiallotype antisera.' More direct demonstration has been provided by the immunocytoadherence with marker erythrocytes sensitized with immunoglobulins or with radiolabeled antiimmunoglobulin an t ib~dies .~ Recently, a direct visualization of surface immunoglobulins on lymphocyte membrane has been achieved by immunofluorescence.4-8 The purpose of this paper is to report briefly further experiments on the immunoglobulins on the membrane of human or rabbit lymphocytes, and also give a preliminary account of immunoglobulins which are demonstrable on the membrane of some cells of the plasma cell series. Particularly interesting in the latter case is the comparison of the membrane immunoglobulins with the immunoglobulins present in the cytoplasm. These studies have been performed by means of immunofluorescence, utilizing appropriate double-staining procedures in two steps to study the surface and intracytoplasmic immunoglobulins of the same cells, in conjunction with optimal instruments which allow selective visualization of fluorescein or rhodamine.7

Immunoglobulins as cell receptors.

Filamentous structures in the cytoplasm of normal mononuclear phagocytes.

The localization of antibody in the interior of plasma cells of lymph nodes of rabbits hyperimmunized with ferritin was studied by electron microscopy. The cells were incubated with the antigen (ferritin) which was allowed to penetrate into the cells by suitable methods. Antigen-antibody precipitates were localized in the cisternae of the endoplasmic reticulum and in the perinuclear space. No evident association was found between ferritin and ribosomes or ferritin and outer cell membrane. Cells from control animals immunized with an unrelated antigen, incubated with ferritin, exhibited no labeling. From direct counts of ferritin molecules in plasma cells, a lower limit was evaluated for the antibody concentration in the endoplasmic reticulum (12.2 mg/cm3) and for the total antibody content of a plasma cell (7.0 x 10–3 gm).

https://rupress.org/jem/article-pdf/117/5/849/1081073/849.pdf

Localization of antibodies in plasma cells by electron microscopy.

Publisher Summary This chapter discusses the presence of immunoglobulins on lymphocyte membranes. The presence of immunoglobulin molecules firmly attached to the membrane of lymphocytes from different species has been demonstrated with a variety of methods. The proportion of immunoglobulin-positive lymphocytes varies according to the species and the source of lymphocytes; among peripheral blood lymphocytes, it was found that the immunoglobulin-positive cells were 10–30% in man and mice, whereas higher values, up to 60–70%, were found in the rabbit. In lymphoid organs, the percentage of immunoglobulin-positive cells is correlated with the expected population of B (bone marrow derived) lymphocytes and the thymus lymphocytes have been found to be immunoglobulin negative when tested by immunofluorescence in different species and at different ages ranging from fetus to adult.

B. Pernis

Papers

Immunoglobulin spots on the surface of rabbit lymphocytes.

Immunoglobulins as cell receptors.

Filamentous structures in the cytoplasm of normal mononuclear phagocytes.

Localization of antibodies in plasma cells by electron microscopy.

Immunoglobulins on Lymphocyte Membranes