The course of experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis, is affected by immunoregulatory T lymphocytes. When animals are immunized with encephalitogenic peptide of myelin basic protein and recover from the first episode of EAE, they become resistant to a second induction of this disease. Animals depleted of CD8+ T cells by antibody-mediated clearance were used to examine the role of CD8+ T cells in EAE. These cells were found to be major participants in the resistance to a second induction of EAE but were not essential for spontaneous recovery from the first episode of the disease.
Factors affecting the distribution and turnover of surface immunoglobulinsThe immunoglobulins which are present o n the membrane of B lymphocytes of different species are mobile in the plane of the membrane itself.This mobility results in the formation of spots of immunoglobulins when the cells are treated with divalent antibodies against immunoglobulins; the spots then combine into polar caps.The process of spot formation is not inhibited by different substances that inhibit cell metabolism, but is markedly inhibited in the cold.The formation of caps is followed by the disappearance of immunoglobulins from the cell membrane but, if the cells are not left in contact with the antiimmunoglobulin antiserum, there is a rapid resynthesis of new membrane immunoglobulins. It appears that the percentage of lymphocytes that resynthesize immunoglobulins is identical t o that of cells originally carrying immunoglobulins, but the amount of surface immunoglobulins of each cell is increased after antiserum treatment. Many other membrane antigens behave in a similar way after treatment with the corresponding antisera; the possible role of the mobility of membrane proteins for the immunological functions of lymphocytes is discussed.
The cotton rat Sigmodon hispidus has provided an animal model of adenovirus pneumonia that permits investigation of the viral gene products required to produce the disease and the molecular mechanisms effecting the damage. This study was One utility of the modern techniques of virology and molecular biology should be to reveal the basic molecular mechanisms by which viruses such as adenoviruses produce disease. The discovery that intranasal inoculation of type 5 adenovirus (AdS) into cotton rats results in development of a pneumonia that pathologically simulates that produced in humans (1) provided the opportunity to determine the viral gene functions required to produce the pneumonia and the molecular mechanisms by which the virus induced the disease. Extensive studies have been carried out on the replication of adenovirus in the lungs of the Sigmodon hispidus species of cotton rats and on the relationship of viral multiplication to the development of pneumonia (2, 3). Productive viral replication was only detected in the epithelial cells of the bronchi and bronchioles of the lung and the nasal mucosa. Onset of viral multiplication, which reached maximum titers 2-4 days after infection (depending upon the size of the inoculum), was soon followed by progressively increasing peribronchial, perivascular, and alveolar septal infiltration of lymphocytes and monocyte/macrophages and finally by lymphocytic infiltration of the basal bronchiolar wall into the epithelium; scattered polymorphonuclear leukocytes (PMN) were also present (2, 3). The maximum pathology was attained 5-7 days after infection, which was also dependent upon the viral inoculum. The use of conditionally lethal, temperature-sensitive mutants [e.g., H5ts125 (4)] unable to replicate their DNA at the cotton rat's normal body temperature, about 39.2°C, led to unexpected results: the cellular inflammatory response was the same as in wild-type (Wt) virus-infected lungs, although quantitatively not as extensive. These data indicate that only early gene products appear necessary to induce the inflammatory response to viral infection. It was further demonstrated that the E1B 58-kDa protein, which is required to shut off host protein synthesis during adenovirus productive infection (5, 6), is also essential for producing maximum viral pneumonia (3).Early region 3 (E3) has been termed a "nonessential" region since naturally occurring mutants or hybrid viruses in which almost the entire region is deleted still replicate like Wt virus in cultured cells (7). It seemed unlikely that almost 10% of the genome would have survived in evolution if its encoded genes did not play a significant role in the virus's life cycle. Therefore, extensive studies were done to determine whether the E3 region might play a critical role in pathogenesis. It is the objective of this communication to report the results of that investigation. Data will be presented to show that gene products of the E3 region do in fact play a strategic role in viral pathogenesis. However, their ...
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.
Considerable attention has been devoted recently, to the genetically defined differences that may exist amongst the immunoglobulins of different individuals belonging to the same species. This phenomenon (allotypy), is not confined to the immuuoglobulins, but it is particularly in this field that the presence of genetical markers allows a deeper insight in different physiological or pathological processes that are related with the synthesis of these molecules. One of the more interesting questions that, on the basis of the genetic markers, have been raised with regards to the synthesis of the immunoglobulins is whether, in an individual heterozygous at a given locus, the products of two allelic genes are manufactured by different immunoglobulin-producing cells.Clear evidence for a differentiation of plasma cells with regards to the molecular classes (1, 2) or the antigenic type (3, 4) of the immunoglobulins that they produce has been obtained by immunofluorescence studies of human lymphoid tissues; when, however, this same method has been applied to the localization of gamma globulin allotypes in lymph node cells of heterozygous rabbits, then it was found (5) that the products (A4 and A5) 1 of two aUelic genes were almost regularly present in the same cell.As the results of Colberg and Dray (5) were complicated by the fact that the fluorochrome-conjugated antisera that had been used contained some of the antigenic determinants whose cellular localization was being studied, we decided to reinvestigate this problem with the use of antisera that did not react between themselves. In addition to the study of rabbits heterozygous at the b locus, we examined also animals heterozygous at the a locus and we have found
Vaccination of mice with activated autoantigen-reactive CD4 ؉ T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8 ؉ regulatory T cells that are specific for pathogenic CD4 ؉ T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8 ؉ T cells emerge that preferentially lyse and regulate activated autologous CD4؉ T cells in a T cell receptor (TCR) V-specific manner. This TCR V-specific regulation is not observed in  2 -microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar V8-specific Qa-1-restricted CD8 ؉ T cells are also induced by TCV with activated CD4 ؉ V8 ؉ T cells. These CD8 ؉ T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR V8. Further, CD8؉ T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4 ؉ V8 ؉ T cell clone specifically recognize other CD4 ؉ T cells and T cell tumors that express V8 and the syngeneic Qa-1 a but not the allogeneic Qa-1 b molecule. Thus, V-specific Qa-1-restricted CD8 ؉
Interactions mediated by TCRs expressed on different T cell subsets may play a role in immunoregulation. To investigate this idea, we studied the regulation of superantigen-induced TCR V beta-restricted responses. We asked whether the in vivo regulation of CD4+ V beta 8+ T cells following SEB injection is controlled by CD8+ T cells. We found that in mice deficient in CD8+ T cells, the down-regulation of CD4+ V beta 8+ T cells below baseline is not observed. Moreover, following SEB administration, CD8+ T cells emerge that preferentially kill subpopulations of activated CD4+ V beta 8+ but not CD4+ V beta 8- T cells in vitro. This TCR V beta-specific cytotoxicity is dependent on beta 2-microglobulin and is inhibited by antisera specific for Qa-1 but not by antibody to MHC class Ia. These data suggest the idea that the specificity of immune regulation may involve CD8+ T cell recognition of TCR V beta determinants and Qa-1 molecules expressed on CD4+ T cells.
The function of immunoglobulin D (IgD) in the immune response is not yet clear; antibody activity in this immunoglobulin class has not been found as easily as in other classes and, so far, efforts to show a biological activity in IgD such as complement activation or reactivity with skin, mast cells, or neutrophiles have given negative results (1, 2). By contrast IgD has been found to be present on the membrane of a variable proportion of peripheral blood lymphocytes in human adults (3) and, recently, on a much higher percentage of newborn (cord) blood lymphocytes (4).The investigations to be reported here were performed to study the possible association of IgD with other immunoglobulin classes on the membrane of human lymphocytes and investigate whether IgD might be passively acquired as a cytophilic molecule. Our results show that IgD is usually associated with immunoglobulin M (IgM) on lymphocyte membranes and virtually eliminate the possibility that IgD is acquired by a cytophilic process. These findings provide support for the concept that IgD is a lymphocyte receptor.
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