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Biomedical subjects

W Strober

Publications and source records attributed to W Strober.

At least 181 records · Page 10Linked to original sources
PubMed1985

The proliferative response of cloned Peyer's patch switch T cells to syngeneic and allogeneic stimuli.

We previously defined a concanavalin A (Con A)-induced cloned T cell population in Peyer's patches (PP) that causes sIgM-bearing B cells to switch to sIgA-bearing B cells. In the present study we show that such IgA-specific switch T cells proliferate when exposed to syngeneic stimulator cells, i.e., the switch T cells are autoreactive. Detailed study of this phenomenon disclosed that both B cells and macrophages were capable of causing switch T cell proliferation, and in both cases, stimulation was enhanced by preactivation of the stimulator cells with lipopolysaccharide (LPS). In addition, fresh T cells can act as stimulators, but only if preactivated with Con A. Finally, it was clearly shown in blocking studies with the use of various antibodies directed at class II MHC specificities that class II MHC antigens were the stimulatory determinants. These studies suggest that IgA-specific switch T cells arise in PP as a result of autologous cell-cell interactions with activated (antigen-stimulated) B cells, macrophages, or T cells.

Animals↗
PubMed1985

Human peripheral blood mononuclear cells produce IgA anti-influenza virus antibody in a secondary in vitro antibody response.

The function and immunoregulation of human IgA memory B cells producing anti-influenza virus antibody was analyzed in vitro in antigen-stimulated cultures. Peripheral blood mononuclear cells (PBMC) from seven of eight normal adult volunteers naturally immunized to influenza virus produced IgA anti-influenza virus antibody when stimulated in vitro with inactivated A/Aichi/68 [H3N2] influenza virus. This IgA antibody response was approximately one-eighth the IgG antibody response. PBMC from each of five patients with selective IgA deficiency failed to produce any measurable IgA antibody. When tonsillar mononuclear cells (TMC) were studied in a similar manner, a relatively higher IgA antibody response was obtained (one-third the IgG antibody) than with PBMC. Additional studies were undertaken to investigate the immunoregulation of this IgA antibody production and the relatively lower amount produced by PBMC than by TMC. Co-cultures of peripheral blood B cells with irradiated peripheral blood T cells (to possibly inactivate a radiosensitive IgA suppressor cell) did not result in a relative increase in IgA antibody production. Also, co-cultures of B cells with increasing numbers of T cells produced parallel increases of IgG and IgA antibody when plotted on a log scale with slopes of approximately 1, suggesting that a single helper T cell was limiting for both isotypes. Finally, pokeweed mitogen-stimulated co-cultures of peripheral blood and tonsillar B and T cells revealed that the B cell population, but not the T cell population, determined the amount of IgA anti-influenza virus antibody produced. Precursor frequency analyses of tonsillar and peripheral blood B cells in antigen-stimulated cultures confirmed that tonsils contained a higher precursor frequency of B cells for IgA anti-influenza virus antibody production (3.95/10(6) B cells) than did peripheral blood B cells (0.65/10(6) B cells). Thus, IgA memory cells are preferentially found in tonsillar tissue as compared with the peripheral blood, consistent with the role of the tonsils as a mucosal immune organ.

Adult↗
PubMed1984

Bronchial lavage proteins as correlates of histopathologic airway changes in healthy smokers and patients with pulmonary carcinoma.

Cigarette smoking is known to be an important etiologic factor in several lung diseases; however, the number of smokers who develop these diseases represents a small segment of the smoking population. It is possible that evidence of inhalation-induced injury to bronchial epithelial cells of smokers will be reflected in the proteinaceous products of these cells, thereby identifying a high-risk subgroup. We have tested this hypothesis by analysis of 2 proteins, free secretory component (FSC) and the keratins, in lavage fluids obtained from 4 groups of subjects: 30 normal nonsmokers, 15 asymptomatic smokers, 22 symptomatic smokers, and 40 carcinoma patients. Among symptomatic smokers, FSC relative to total protein (FSC/TP) was depressed compared with that in nonsmokers and asymptomatic smokers. The keratins were detected only in symptomatic smokers and correlated with pack/years of smoking history (p = 0.017). Carcinoma patients had depressed FSC/TP and detectable keratin (33 of 38 patients studied). Lung sections from carcinoma patients studied immunohistochemically revealed an apparent inverse relationship between tissue FSC and keratins. This inverse relationship was borne out by analysis of these proteins in the lavage fluid of cancer patients (r = -0.4, p = 0.04). Thus, in cancer patients, immunohistochemical evidence of airway injury correlates with bronchial lavage levels of mucosal epithelial cell proteins. It is possible that smokers with altered levels of these proteins may be the ones at increased risk of smoking-associated lung disease.

Adolescent↗
PubMed1984

Hypogammaglobulinemia due to abnormal suppressor T-cell activity in Crohn's disease.

Two patients are described who initially developed Crohn's disease followed by hypogammaglobulinemia. The immunologic profile of both was typical of acquired common variable hypogammaglobulinemia. The peripheral blood lymphocytes of neither patient were able to synthesize immunoglobulin when cultured with pokeweed mitogen in vitro nor were cultures containing mixtures of purified B cells and T cells. A potent suppressor T cell was present in the peripheral blood of both patients that was able to completely suppress immunoglobulin synthesis in cultures of normal B cells and T cells. When the patients' B cells were highly purified and appropriately stimulated in vitro, they were able to synthesize immunoglobulin, providing strong evidence that the circulating suppressor T cell was mediating the hypogammaglobulinemia. We have previously shown that many patients with Crohn's disease have a circulating "covert" suppressor T cell that is not expressed in cultures of unfractionated peripheral blood lymphocytes, but which becomes apparent after isolation of their T cells on antiimmunoglobulin columns. We conclude that these 2 patients represent instances in which the "covert" suppressor T cell of Crohn's disease has become overtly active in the systemic circulation and has resulted in hypogammaglobulinemia.

Adult↗
PubMed1984

Suppression of immunoglobulin synthesis by lymphocyte subpopulations in patients with Crohn's disease.

In previous studies, patients with mild or inactive Crohn's disease were found to have increased suppressor T-cell activity. To further characterize suppressor T cells in Crohn's disease, studies were carried out with the use of monoclonal antibodies. Excessive suppressor activity was eliminated by removal of OKT 8+ lymphocytes by complement-mediated lysis. However, the percentage of OKT 8+ (or Leu 2a+) cells and the ratio of OKT 4+ to OKT 8+ (or Leu 3a+ to Leu 2a+) cells were not significantly different from normal. Although the subgroup of patients with increased suppression of immunoglobulin synthesis had a significantly lower mean Leu 3a to Leu 2a ratio than that of normal subjects, in the whole group of Crohn's patients studied, neither the percentage of Leu 2a+ cells nor the ratio of Leu 3a+ to Leu 2a+ cells correlated with excessive suppression of immunoglobulin synthesis. A subpopulation of Leu 2a+ lymphocytes reactive with the monoclonal antibody HNK-1 (Leu 2a+ HNK-1+) was increased in patients with Crohn's disease. Furthermore, elimination of HNK-1-reactive lymphocytes by complement-mediated lysis diminished the excessive suppressor cell function in patients with Crohn's disease. The percentage of Leu 2a+ HNK-1+ lymphocytes correlated significantly with the suppression of pokeweed mitogen-stimulated immunoglobulin synthesis in vitro. Thus, patients with mild Crohn's disease have an increased suppressor cell activity in vitro which correlates with the presence of a subset of lymphocytes that have an HNK-1+ Leu-2a+ phenotype.

Adolescent↗
PubMed1983

Mechanisms regulating IgA class-specific immunoglobulin production in murine gut-associated lymphoid tissues. II. Terminal differentiation of postswitch sIgA-bearing Peyer's patch B cells.

Our previous studies indicated that cloned T cells obtained from Peyer's patches (PP) (Lyt-1+, 2-, Ia+, and H-2K/D+) evoked immunoglobulin (Ig) class switching of PP B cells from sIgM to sIgA cells in vitro; however, these switch T cells could not in themselves provide optimal help for the differentiation of postswitch sIgA-bearing PP B cells to IgA-secreting cells. Thus, in the present report we described studies focused on mechanisms regulating terminal differentiation of the postswitch PP sIgA-bearing B cells. First, to explore the effect of T cell-derived B cell differentiation factor(s) (BCDF) and macrophage factor(s) (MF) on the terminal maturation of PP B cells, LPS-stimulated PP B cells were co-cultured for 7 d with cloned T cells in the presence or absence of the above factors. In the absence of PP cloned T cells the BCDF and MF had only a modest effect on IgA production, whereas in the presence of PP, but not spleen cloned T cells, IgA production was increased. Next, to investigate the effect of T cells derived from a gut-associated lymphoid tissue (GALT), mesenteric lymph nodes (MLN), as well as from spleen on terminal differentiation of postswitch sIgA PP B cells, LPS-driven PP B cells were precultured with the cloned T cells to induce a switch to sIgA, and subsequently cultured with MLN or spleen T cells or a Lyt-2+-depleted T cell subset in the presence of a T-dependent polyclonal mitogen, staphylococcal protein A. Alternatively, in the second culture period BCDF alone was added, instead of T cells and protein A. Here it was found that B cells pre-exposed to switch T cells from PP, but not spleen, were induced to produce greatly increased amounts of IgA in the presence of protein A and T cells or a Lyt-2+-depleted T cell subset as well as in the presence of BCDF alone. Furthermore, in the presence of BCDF alone many B cells expressed cytoplasmic IgA. These observations strongly support the view that the terminal differentiation of postswitch sIgA B cells is governed by helper T cells and macrophages, or factors derived from such cells. Such cells or factors do not affect preswitch B cells.

Animals↗
PubMed1983

Mechanisms regulating IgA class-specific immunoglobulin production in murine gut-associated lymphoid tissues. I. T cells derived from Peyer's patches that switch sIgM B cells to sIgA B cells in vitro.

To explore mechanisms of T cell regulation governing mucosal IgA immune response, concanavalin A-induced cloned T cell lines from Peyer's patches (PP) as well as spleen were established. The cloned cell lines expressed Thy- 1.2(+), Lyt-l(+)2(-) and were radioresistant (1,500 rad). The capacity of the cloned T cells to regulate Ig synthesis was determined by measuring their effect on lipopolysaccharide (LPS)-induced polyclonal Ig synthesis by PP B cells. In initial studies Ig secreted by B cells was determined by double antibody radioimmunoassay. LPS in the absence of cloned T cells induced abundant amounts of IgM (average 8,860 ng/2 x 10(5) B cells) and IgG (average 1,190 ng/2 x 10(5) B cells), but little or no IgA. The addition of PP cloned T cells markedly suppressed production of IgM (88 percent at the highest T/B cell ratio, 4:1), but the addition of spleen cloned T cells suppressed only a little or not at all. IgG production was inhibited by both PP and spleen T clone cells (70 percent at the 4:1 T/B ratio), wheras IgA synthesis was enhanced by both clones, but only to a limited degree. In subsequent studies the expression of class-specific surface Ig (sIg) and cytoplasmic Ig (cIg) on/in unseparated PP B cells as well as Ig class- specific PP B cells and spleen B cells during culture with or without the cloned T cells was determined by immunofluorescence. The major findings were as follows: (a) Compared with unseparated B cell cultures and cultures of purified sIgM B cells derived from PP containing LPS alone, cultures containing LPS and PP cloned T cells showed a marked decrease in cIgM-, sIgG-, and cIgG-expressing cells that was accompanied by a striking increase in sIgA-bearing, but not cIgA-containing, cells. In contrast, unseparated B cell cultures and cultures of purified sIgM B cells derived from PP containing LPS and spleen cloned T cells did not show any increase in sIgA- bearing cells. (b) Compared with purified sIgG-bearing PP B cell cultures containing LPS alone, purified sIgG-bearing PP B cell cultures containing both LPS and PP cloned T cells showed no substantial change in sIgG- or cIgG- expressing cells, and no sIgA- or cIgA- expressing cells appeared. (c) Compared with sIgA-bearing PP B cell cultures containing LPS alone, purified sIgA-bearing PP B cell cultures containing both LPS and PP cloned T cells showed no increased proliferation, and cIgA cells did not occur. Cultures of purified sIgM B cells derived from spleen containing LPS and PP cloned T cells showed qualitatively similar changes. From these results we conclude that PP cloned T cells induced class-specific switching from sIgM- to sIgA- bearing B cells, whereas spleen cloned T cells lacked this property, although they may have induced an IgM {arrow} IgG or intersubclass IgG switch. These processes seem to be in part tissue dependent. Furthermore, the PP switch T cells appear to operate as true switch cells, which govern the pathway of DNA recombination events, rather than as classical helper cells, which act to expand already differentiated cells. Finally, these switch T cells probably account for the fact that PP are an important source of IgA B cells and also a major site of IgA heavy chain class switching during gut-associated mucosal B cell proliferation and differentation.

Animals↗
PubMed1983

T cell regulation of IgA immunoglobulin production in gut-associated lymphoid tissues.

To explore mechanisms of gut-mucosal IgA immune response, we have established Con A-induced cloned T cell lines originating from PP and spleen. These cloned cells expressed Thy-1.2+, Lyt-1+2-, Ia (I-A and I-E) and H-2 (K/D) surface antigens. Cloned T cells derived from PP were found to suppress LPS-induced IgM and IgG synthesis and secretion of co-cultured PP B cells; in addition, whereas the PP cloned T cells did not bring about IgA production, they did cause the appearance of large numbers of cells expressing sIgA. In contrast, cloned T cells derived from spleen had little or no effect on LPS-induced IgM synthesis and secretion by PP B cells; in addition, whereas they did suppress IgG production, they neither brought about IgA production nor the appearance of cells expressing sIgA. These studies provide evidence for the existence of a new type of T cell in PP, a switch T cell, which is able to induce B cells to undergo class-specific switches from IgM to IgA; the PP switch T cells appear to govern the pathway of DNA recombination (or RNA splicing) rather than cellular events resulting in terminal differentiation. Thus, these switch T cells are probably responsible for the fact that PP are a major source of mucosal IgA B cells. In additional studies, we show that post-switch IgA B cells, i.e. cells precultured with PP cloned T cells, have the capacity to undergo terminal differentiation into IgA producing plasma cells. provided they are exposed to helper T cells (uncloned) and an appropriate mitogenic stimulus (staphylococcal protein A). We can conclude, therefore, that the development of PP B cells into IgA-producing plasma cells in gut-associated lymphoid tissues (GALT) appears to require at least two steps: one which involves heavy chain switching to IgA and which is governed by IgA class-specific switch T cells in PP, and one which involves differentiation of post-switch B cells and which is governed by helper T cells in lymphoid tissues outside of PP (such as MLN and spleen).

Animals↗
PubMed1983

NIH conference: Primary biliary cirrhosis: a model autoimmune disease.

Primary biliary cirrhosis is characterized by chronic inflammation and necrosis of the intrahepatic bile ducts and by chronic cholestasis. The presence of autoantibodies in serum, the association of this disease with other autoimmune diseases, the histologic appearance of typical hepatic lesions, the presence of bile duct lesions that resemble those seen in chronic graft-versus-host disease, and the possible recurrence of a chronic cholestatic syndrome in patients having hepatic transplants indicate that immune mechanisms play a role in the syndrome's pathogenesis. Patients have diminished function of suppressor T cells that may be due to abnormal activation of suppressor T cells caused by interactions with autologous non-T cells. This nonspecific immunologic defect and other immune defects may cause the autoimmune manifestations of primary biliary cirrhosis. Treatments to arrest the disease's progress have included corticosteroids, azathioprine, cyclosporin, and D-penicillamine. These treatments, which affect immune functions, have not had a beneficial effect on the disease process. Better understanding of the pathogenesis of primary biliary cirrhosis is needed to develop specific immunotherapies.

Antibody Formation↗
PubMed1983

Studies on the autologous MLR in primary biliary cirrhosis: evidence that the autologous MLR is a negative feedblock response stimulated by activated B cells.

Patients with primary biliary cirrhosis (PBC) were found to have diminished suppression of pokeweed mitogen (PWM)-stimulated immunoglobulin synthesis by in vitro cultures containing autologous T and B cells. The possibility that this abnormality is due to a defect of autologous cell-cell interactions was suggested by the finding that patients with PBC have a significantly diminished proliferative response in the autologous mixed lymphocyte reaction (MLR). In studies of normal lymphocytes, it was found that T cells activated in the autologous MLR have the capacity to suppress PWM-stimulated immunoglobulin synthesis, but do not have augmented helper function. Furthermore, when T cells were activated with lymphoblastoid B cells, augmented suppressor activity was observed. These findings suggest that the autologous MLR represents a negative feedback loop in which activated B cells initiate a suppressor T cell pathway. The defect in the autologous MLR in patients with PBC may account for the diminished suppressor cell function observed in this disease.

Antigens↗
PubMed1981

Simultaneous induction of antigen-specific IgA helper T cells and IgG suppressor T cells in the murine Peyer's patch after protein feeding.

The effects of feeding the dietary protein antigen, ovalbumin (OVA), on OVA-specific IgG and IgA immune responses involving Peyer's patches (PP) and mesenteric lymph nodes (MLN) were examined. Mice were administered soluble OVA by gastric intubation. One to 3 days later, PP, MLN, or spleen cells from these donor mice were adoptively transferred into normal syngeneic recipients. After two subsequent immunizations, spleens from the recipient mice were assayed for IgA and IgG anti-OVA plaque-forming cell (PFC) responses. None of the tissues from normal (unfed) mice had the inherent ability to alter recipients' IgG or IgA PFC responses. Within 1 day of OVA feeding, however, cells were generated in the PP that could augment recipients' IgA anti-OVA PFC responses and suppress IgG PFC responses. Three days after OVA feeding, these cells were present in MLN as well, and whereas the IgG suppressor cell also appeared to migrate to spleen, the IgA helper cell did not. The cells mediating antigen-specific IgG suppression and IgA help were both T cells but could be distinguished by surface phenotype. We therefore conclude that protein feeding induces differential, isotype-specific immunoregulation in gut-associated lymphoid tissues, part of which is mediated by an antigen-specific IgA helper T cell.

Animals↗