Biomedical subjects
Publications and source records attributed to W Strober.
The association between antigens of the HLA system and dermatitis herpetiformis (DH) using in vivo-bound IgA as an added criteria for diagnosis is reexamined. Twenty-eight of 33 (85%) immunologically proven patients with DH were HLA-B8 positive, whereas only 17 of 92 (18%) controls were HLA-B8 positive.
We have investigated the pathogenesis of the polyclonal hypogammaglobulinemia associated with BALB/c plasmacytomas TEPC-183 and SPQC-11 to gain insight into the hypogammaglobulinemia observed in human myeloma. With pokeweed mitogen-driven IgM biosynthesis by mouse splenocytes as the indicator system for suppression, we found that a protein extract of asscites cells obtained from these tumor-bearing animals could suppress immunoglobulin production, whereas like extracts from a non-suppressing plasmacytoma, modified RPC-5, caused no suppression in vitro. Extracts of tumor ascites depleted of mononuclear phagocytes by iron carbonyl treatment showed little suppressor activity. The active extract was not cytotoxic and contained no mycoplasma or common murine viruses. Furthermore, the active suppressor factor appears to be a low m.w. protein that is not affected by treatment with ribonuclease. These results and others are consistent with the idea that the hypogammaglobulinemia of myeloma is due to the formation of immunoregulatory macrophage-like cells which synthesize a suppressor substance.
With isolated subpopulations of human peripheral blood mononuclear cells, spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cellular cytotoxicity (ADCC) were demonstrated to be functions of a population of surface immunoglobulin (sIg)-negative, Fc receptor-positive lymphocytes. Organ distribution studies revealed that SCMC and ADCC effector cell activity occurred in parallel, being present in spleen and absent in tonsils. Treatment of effector cells with trypsin significantly inhibited SCMC but not ADCC and this inhibition was not reversed by short-term incubation in autologous plasma. These results demonstrate that SCMC and ADCC involve different cytotoxicity mechanisms and are consistent with two subsets of effector cells with separate functional capabilities or a single effector cell mediating both forms of cytotoxicity through separate mechanisms.
We have investigated suppressor T-cell activity in female NZB/NZW F1 mice using PWM-driven IgM biosynthesis in vitro as an indicator system. In initial we studied we observed that spleen cells from normal mice (BALB/c, C57BL/6), as well as from young (4 wk) and adult (18 wk) NZB/NZW mice, cultured in the presence of PWM synthesize 860 +/- 120 ng IgM/10(6) cells/7 days. However, when Con A (at 2 mug/ml) was added directly to the cultures (along with PWM), cells obtained from adult normal mice and young NZB/NZW mice showed a 94% suppression of IgM synthesis, whereas cells obtained from adult NZB/NZW mice were suppressed significantly less. To analyze these findings we studied the effect of Con A-induced suppressor cells (cells cultured with Con A for 24 h and washed free of Con A) on PWM-driven IgM biosynthesis. Spleen cells obtained from normal mice cultured in the presence of Con A-pulsed cells obtained from normal mice and young NZB/NZW mice showed an 83-88% suppression of PWM-driven IgM synthesis. Similarly, supernates obtained from Con A-pulsed cells of normal mice or of young NZB/NZW mice suppressed PWM-driven IgM synthesis. This suppression by Con A-pulsed cells and their supernates required T cells since T-cell fractions but not B-cell fractions eluted from anti-Fab Sephadex columns mediated suppression of co-cultured normal cells; in addition, Con A-pulsed cells treated with anti-theta and complement do not mediate suppression. These studies of Con A-induced suppressor cell activity in normal mice and young NZB/NZW mice contrast with studies of Con A-induced suppressor cell activity in adult NZB/NZW mice. We found that adult NZB/NZW Con A-pulsed cells and supernates obtained from the Con A-pulse cells had vastly decreased suppressor potential; in this case the Con A-pulse cells and supernatant fluids derived from such cells did not suppress PWM-driven IgM synthesis by normal cells. Finally, whereas spleen cells from young and adult NZB/NZW mice differ in their suppressor cell potential, cells from both sources could respond equally to suppressor signals in that Con A-pulsed normal cells or supernates derived from such cells caused equivalent suppression of PWM-driven IgM synthesis by young and adult NZB/NZW cells. These observations allow us to conclude that NZB/NZW mice lose suppressor T-cell activity as they age.
Cortisol partially prevents the harmful effect of gluten on the jejunal mucosa of patients with gluten-sensitive enteropathy. To investigate further the pathogenesis of this disorder, we analyzed the effect of cortisol in cultures of jejunal specimens obtained by biopsy. Cultures were done with and without gluten or cortisol. Morphology and alkaline phosphatase activity were assessed before and after 24 hours. Biopsies from untreated patients cultured with gluten showed low enzyme values and cuboidal epithelial cells before and after culture. Biopsies cultured in a gluten-free medium showed a threefold increase in enzyme values (P less than 0.01) and morphologic improvement with change to columnar epithelial cells. Cultures with gluten plus cortisol showed rises in alkaline phosphatase and morphologic improvement indistinguishable from cultures without gluten. Cortisol and gluten had no effect on cultures from appropriate controls. Cortisol thus prevents the harmful effects of gluten on biopsies from patients with gluten-sensitive enteropathy in vitro.
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We studied a 15-year-old boy with chronic intestinal candidiasis who had normal serum IgA levels without IgA in his secretions. There was an elevated number of peripheral blood lymphocytes bearing surface IgA. In addition, the lymphocytes cultured in vitro with pokeweed mitogen produced IgA as well as other immunoglubulins. Despite this evidence of normal IgA synthetic capacity, the patient had greatly diminished levels of IgA in the saliva and jejunal fluid, and, as estimated by 14C-L-leucine incorporation, could not synthesize IgA locally at intestinal-mucosal sites. Finally, the patient had no detectable free secretory component in saliva or jejunal fluid in contrast to normal persons and to patients with IgA deficiency. The basis of this disorder is probably a defect in the homing of IgA precursor cells to secretory sites or in the selective proliferation/differentiation of IgA cells at such sites.
Decreased serum albumin levels are commonly observed in patients with carcinoid tumor, who also show several characteristic clinical and biochemical abnormalities. A large comparative study on a group of 96 carcinoid patients was performed with the purpose of identifying some of the mechanisms leading to hypoalbuminemia in patients with this form of cancer, and thereby to shed light on the cause of hypoalbuminemia of cancer in general. Serum albumin values were compared with a number of clinical parameters (including extent of liver metastases, severity of diarrhea, degree of right heart failure, and extent of gastrointestinal surgery) and of laboratory data (prothrombin time, BSP retention, serum transferrin concentration, hematocrit value, and daily urine excretion of 5-hydroxy-indoleacetic acid). In several patients the gastrointestinal protein loss was assessed by the 51Cr-albumin technique, whereas albumin renewal and distribution were evaluated by the use of 125I-albumin. The data obtained showed that the main factors in determining decreased serum albumin levels in patients with carcinoids are both reduced synthesis and increased loss of the protein. The hepatic synthetic defect appears to be related to a progressive decrease in the number of functioning liver cells; the origin of the gastrointestinal protein loss may be related to the obvious tumor involvement of the gut wall, as well as to the pharmacologically-induced diarrhea. Right heart failure occurring as a result of the carcinoid heart disease may be an additional cause for gastrointestinal protein loss in patients with carcinoid tumor.
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The presence of antibodies to native DNA, single-stranded DNA, and double-stranded RNA was determined for 37 patients with selective IgA deficiency, 11 patients with Wiskott-Aldrich syndrome, seven patients with common variable agammaglobulinemia, 14 patients with ataxia telangiectasia, six patients with intestinal lymphangiectasia, and one patient with Nezelof syndrome. Of 37 patients with selective IgA deficiency, 11 had antibodies to at least one nucleic acid; six had antibodies to native DNA, seven had antibodies to single-stranded DNA, and four had antibodies to double-stranded RNA. The only other congenital immune deficiency disease studied in which antibodies to nucleic acids were found was the Wiskott-Aldrich syndrome; in this group three of 11 patients had antibodies to native DNA. Retrospective analysis of our patients with SLE disclosed a 2.6% prevalence of IgA deficiency, a prevalence clearly higher than in the general population. These studies provide further evidence of the association between autoimmunity and abnormalities of IgA production and suggest a relationship between thymic-derived immune regulation and IgA production.
Chronic lymphocytic leukemia developed in four of five siblings, whose father succumbed to the same disease. The pattern of immune deficiency in the leukemic siblings resembled that found in nonfamilial cases of chronic lymphocytic leukemia, and was correlated with the severity of clinical involvement. In three siblings the peripheral blood leukemic cells shared delta-heavy and kappa-light chains as the only detectable surface immunoglobulin, suggesting that on a cellular and molecular level the chronic lymphocytic leukemia in family members is identical. The fourth and youngest sibling had no peripheral blood lymphocytes with detectable surface immunoglobulin. An inherited defect in the class of cells destined to express delta-heavy and kappa-light chains appears to underlie susceptibility to leukemia in this family.
The identity of the effector cells in human peripheral blood capable of mediating mitogen-induced cellular cytotoxicity (MICC) and antibody-dependent cellular cytotoxicity (ADCC) was investigated utilizing effector cell populations consisting of purified polymorphonuclear leukocytes, macrophages, lymphocytes, and cell surface immunoglobulin (sIg)-negative and sIg-positive lymphocyte subpopulations obtained by Sephadex anti-Fab immunoabsorbent column fractionation techniques. Chicken erythrocytes (CRBC) and Chang liver cells were used as target cells in both cytotoxicity assays. With CRBC targets MICC was mediated by polymorphonuclear leukocytes, macrophages, sIg-positive lymphocytes (B cells), and sIg-negative lymphocytes. On the contrary, with Chang liver cells as targets, MICC was mediated only by lymphocytes, and effector cells occurred exclusively in sIg-negative lymphocyte subpopulations containing thymus-derived lymphocytes (T cells). Further purification of sIg-negative lymphocyte subpopulations on antigen-antibody coated plastic surfaces yielded a nonadherent T lymphocyte population depleted of Fc receptor-bearing lymphocytes that was capable of mediating MICC against both CRBC and Chang cell targets. With use of CRBC targets, ADCC was mediated by polymorphonuclear leukocytes, macrophages, and sIg-negative lymphocyte subpopulations. However, with Chang cell targets, ADCC was mediated only by lymphocytes, and effector cells were present only in sIg-negative lymphocyte subpopulations. SIg-positive lymphocytes (B cells) and T lymphocytes were not effective in mediating ADCC against either CRBC or Chang cell targets. These studies demonstrate that the nature of the target cell employed in MICC and ADCC reactions is of critical imporatnce in defining the effector cell(s) capable of mediating cytotoxicity.
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IgE metabolic turnover studies with purified radioiodinated IgE were performed in normal individuals and in a patient with IgE myeloma. The validity of the turnover studies was established in several ways, including comparisons of radioiodinated IgE turnover with the turnover of endogenously labeled 14C-IgE and with the turnover of infused unlabeled IgE in a patient with hypogammaglobulinemia. The geometric mean serum IgE concentration in 73 normal adults was 96 ng/ml with a 68% confidence interval of 24 to 386 ng/ml. Metabolic turnover studies in 10 control individuals disclosed a geometric mean total circulating IgE of 4.1 mug/kg, a mean percentage of the total exchangeable IgE in the intravascular space of 41%, a mean half-time of survival of IgE of 2.7 days, a mean fractional catabolic rate of 94% of intravascular pool per day, and a geometric mean synthetic rate of 3.8 mug/kg/day. IgE has the lowest synthetic rate and highest fractional catabolic rate of the five major classes of immunoglobulin molecules. In contrast to these normal values, a patient with IgE myeloma had a serum IgE comcentration of 42 mg/ml, a total circulating IgE of 1.7 g/kg, and a synthetic rate of 270 mg/kg/day. Furthermore, although the synthetic rate was vastly increased, the survival time was prolonged and the fractional catabolic rate was decreased to 5.1 days and 16 to 22% of the intravascular pool per day, respectively. These data are compatible with the concept that IgE is catabolized in part by a mechanism common to all immunoglobulin classes and in part by a unique mechanism not available to other immunoglobulins. At very high IgE serum concentrations, such as those encountered in patients with IgE myeloma, the unique mechanism would be saturated and only the catabolic pathways available to all immunoglobulins would be available to IgE.
Since patients with myeloma have serious abnormalities of humoral immunity, we applied an in vitro assay to determine the capacity of B lymphocytes to mature into immunoglobulin-secreting cells. In peripheral blood lymphocytes from 22 normal persons, geometric mean immunoglobulin synthesis was 4910 ng for IgM, 1270 ng for IgA and 1625 ng for IgG. The synthesis rates of peripheral blood lymphocytes of 22 patients with myeloma were 458 ng for IgM, 321 ng for IgA and 218 ng for IgG. Circulating mononuclear cells from three of six patients tested suppressed polyclonal immunoglobulin synthesis by cocultured normal lymphocytes. Suppressive activity was not mediated by purified T cells alone. Removal of phagocytic mononuclear cells from lymphocyte populations of one patient nullified suppressive activity. Removal of phagocytic mononuclear cells from lymphocyte populations of a second patient led to a nearly 10-fold increase in polyclonal immunoglobulin synthesis. Therefore, host suppressor cells may play a part in the decreased capacity of B lymphocytes to secret immunoglobulin in certain patients with myeloma.
A patient with constrictive pericarditis, secondary intestinal lymphangiectasia, and protein-losing enteropathy was demonstrated to have the characteristic immunologic deficiency associated with intestinal lymphangiectasia: hypogammaglobulinemia, lymphocytopenia, cutaneous anergy, impaired allograft rejection. and diminished in vitro lymphocyte proliferative responses. Following surgical correction of the cardiac abnormality, the intestinal lymphangiectasia and protein-losing gastroenteropathy resolved and was accompanied by a slow but progressive return of normal immune function. This documented reversal of the immunologic deficiency in intestinal lymphangiectasia supports the concept that the immune defect in this syndrome is due to the excessive loss of lymphocytes and immunoglobulins into the gastrointestinal tract.
Gluten-sensitive enteropathy is characterized by flattening of intestinal villi and malabsorption caused by the toxic effect of gluten, a wheat protein. Gluten activates an endogenous mechanism of toxicity that may be the local mucosal immune system: local mucosal immunoglobulin and antigluten antibody production occur soon after gluten ingestion. Approximately 80% of patients with this disease possess HL-A8, a second segregant series antigen. This association also occurs in dermatitis herpetiformis, a disease with vesicular skin lesions and gluten-sensitive flattening of intestinal villi. The association suggests that the fundamental abnormality in enteropathy is a binding reaction involving gluten protein and a binding site on a cell surface, determined in part by the histocompatibility gene; this reaction then results in a local mucosal immune response to gluten. Alternatively, the fundamental abnormality may be the presence of an abnormal immune-response gene linked to the HL-A8 gene or acting in concert with it; this immune-response gene results in local mucosal production of antigluten antibody.
Immunodeficiency and hypogammaglobulinemia are shown to occur by a variety of pathophysiologic mechanisms. Hypogammaglobulinemia may be caused by decreased synthesis of all classes of immunoglobulins, or may involve defective synthesis of selective classes of immunoglobulins. Alternatively, hypogammaglobulinemia may be due to a disorder of endogenous catabolic pathways of a single immunoglobulin class, or of all immunoglobulin classes. Finally, hypogammaglobulinemia may be caused by excessive loss of immunoglobulins into the urinary or gastrointestinal tracts.