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PubMed1994

Failure in IgA secretion by surface IgA-positive B cells in common variable immunodeficiency (CVID).

CVID is an acquired disease with low serum immunoglobulins. Patients are classified into three groups on the ability of their B cells to secrete IgM and IgG in vitro in response to IL-2. We have now extended this patient classification to include IgA secretion and to assess whether the patients have IgA+ B cells in the circulation. B cells from almost all of the CVID patients studied were unable to secrete any IgA in vitro, with or without IL-2, although all B cells tested from normal donors showed some spontaneous IgA secretion. Thus, the defect with IgA secretion is more profound than with the secretion of IgM or IgG. Despite this failure to secrete IgA, using flow cytometry techniques all CVID patients tested were found to have IgA+ cells (expressed as a percentage of B cells) within the normal range. This suggests that CVID may involve a defect in the secretion of immunoglobulin isotypes rather than a defect in isotype switching.

B-Lymphocytes↗
PubMed1995

Defective insulin and glucagon secretion in isolated perfused pancreata of diabetic WBN/Kob rats.

To elucidate the pathophysiology of diabetes mellitus in male WBN/Kob rats, we performed pancreatic perfusion experiments and histopathological studies. Intraperitoneal glucose tolerance tests showed a diabetic pattern in 12-month-old WBN/Kob rats. In perfused pancreata of WBN/Kob rats, both the first and the second phases of insulin secretion in response to a 16.7 mM glucose challenge were markedly reduced compared with those in age-matched Wistar rats (p < 0.01, respectively). Furthermore, the insulin secretion rate in response to glucopenia (1.4 mM) was significantly higher (p < 0.05) and the decrement in insulin secretion was significantly lower (p < 0.05) in WBN/Kob rats. The decrement in glucagon secretion with 16.7 mM glucose was significantly blunted (p < 0.001), and the glucagon secretion rate in response to glucopenia was also significantly lower in WBN/Kob rats than in controls (p < 0.01). Although insulin secretion in response to 10 mM arginine was also moderately reduced in WBN/Kob rats (p < 0.05), the glucagon secretion rates in response to 10 mM arginine were similar in the two groups. Histopathological examination revealed widespread disappearance of acinar cells and islets, inflammatory changes, and marked fibrosis in the pancreata of WBN/Kob rats. Immunohistochemical studies showed decreased numbers of B cells in the islets of WBN/Kob rats. These findings suggest that this WBN/Kob rat strain is a useful model for studying not only pathogenesis, but also pathophysiology, i.e., defective hormonal secretion, in some types of human diabetes mellitus.

Animals↗
PubMed2006

Insulin secretion in health and disease: genomics, proteomics and single vesicle dynamics.

Defective insulin secretion from pancreatic islet beta-cells is a sine qua non of Type II (non-insulin-dependent) diabetes. Digital imaging analysis of the nanomechanics of individual exocytotic events, achieved using total internal reflection fluorescence microscopy, has allowed us to demonstrate that insulin is released via transient or 'cavicapture' events whereby the vesicle and plasma membranes fuse transiently and reversibly. Such studies reveal that an increase in the number of abortive fusion events contributes to defective insulin secretion in in vitro models of Type II diabetes. Complementary analyses of genome-wide changes in beta-cell gene expression, at both the mRNA and protein levels, are now facilitating the identification of key molecular players whose altered expression may contribute to the secretory defects in the diabetic beta-cell.

Animals↗
PubMed2001

Euglycemic clamp study in clozapine-induced diabetic ketoacidosis.

OBJECTIVE: To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. CASE SUMMARY: A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. DISCUSSION: Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale. CONCLUSIONS: The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.

Adult↗
PubMed1978

Secretion of cell wall polymers into the growth medium of lysis-defective pneumococci during treatment with penicillin and other inhibitors of cell wall synthesis.

Autolysin-defective pneumococci secrete into the growth medium choline-containing macromolecules during treatment with any one of a large number of inhibitors of cell wall biosynthesis, including beta-lactams, beta-halogeno-d-alanines, cephalosporins, and d-cycloserine. Secretion is closely related to the dose response of the bacteria to the various drugs: (i) secretion can already be detected at the minimum inhibitory concentration; (ii) the rate and extent of secretion is dependent upon the drug concentration; and (iii) secretion commences within minutes after the addition of the antibiotics to the cultures. Reversal of the growth-inhibitory effect of benzylpenicillin (by penicillinase addition) is accompanied by a halt in secretion just at the time when the bacteria resume normal growth. Secretion of the choline-containing macromolecules seems to be a specific consequence of the inhibition of peptidoglycan biosynthesis, since inhibition of growth by drugs affecting protein, ribonucleic acid, or deoxyribonucleic acid synthesis does not cause secretion. The choline-containing macromolecules include both the pneumococcal lipid-containing teichoic acid (Forssman antigen) and wall teichoic acids made after the addition of antibiotics. The appearance of these macromolecules in the growth medium is not due to the hydrolytic activity of an autolysin, since penicillin-induced secretion could be demonstrated in autolysin-defective mutants, in pneumococci grown on ethanolamine-containing medium (such cells are known to have defective autolytic systems), and in wildtype pneumococci grown under conditions nonpermissive for lysis.

Antimetabolites↗
PubMed1990

Influence of jejunal hypertonic glucose infusion on sham-feeding-stimulated gastric acid secretion: evidence of a defective mechanism in duodenal ulcer patients.

The aims of the present study were to determine in 14 healthy subjects and 14 duodenal ulcer patients the reproducibility of the acid secretory response to a modified sham-feeding test and the effect on this response of intrajejunal hypertonic glucose instillation, in order to evaluate the possibility of the existence of a defective inhibition of the cephalic phase of gastric acid secretion in duodenal ulcer disease. The reproducibility of the acid secretory response to a modified sham-feeding test was demonstrated in both groups in two consecutive tests. The hypertonic glucose instillation produced a significant inhibition of the acid secretory response to modified sham feeding only in the healthy subjects, suggesting that duodenal ulcer patients may have a defective mechanism of acid inhibition during vagal stimulation by modified sham feeding. Non-significant changes were observed in plasma gastrin and pancreatic glucagon levels.

Adult↗
PubMed2003

Selection of a secretion-incompetent mutant in the serum of a patient with severe hepatitis B.

BACKGROUND AND AIMS: A secretion-incompetent, highly replicating hepatitis B variant was previously found as the dominant viral population in the serum of a liver transplant recipient with severe hepatitis B reinfection. The secretion block resulted from mutations in the S protein, including the Gly145Arg substitution known to emerge under antibody to hepatitis B surface antigen immunoglobulin treatment. Here we investigated the mechanisms that allow selection of a secretion-incompetent virus as the predominant strain in the serum. METHODS: To reproduce the interaction of viral quasispecies occurring in vivo, cotransfection experiments were performed with full-length genomes containing wild-type or mutant sequences. In addition, the relevance of mutations in the common S part of the surface proteins for the competence of L and S protein to support viral secretion was studied. RESULTS: A small amount of wild-type virus or of a wild-type S protein-expressing variant rescued secretion of the defective mutant. In the secreted virions, the high-replicating mutant genome was predominant. Selection of the defective mutant was further supported by a transdominant negative effect of mutant S protein on wild-type virion secretion. In contrast, mutant L protein with the same c-terminal mutations as mutant S protein efficiently supported virion formation and secretion. CONCLUSIONS: Interaction of the variant with a small amount of wild-type virus can reverse its secretion-defective phenotype. Mutations in the common region of S and L protein have different consequences for the ability of the envelope proteins to support virion assembly and secretion.

Bodily Secretions↗
PubMed1998

Congenital disorders of platelet function: disorders of signal transduction and secretion.

Congenital defects in platelet function are associated with bleeding manifestations of variable intensity and arise by diverse mechanisms. Defects in platelet-vessel wall interaction (disorders of adhesion) may arise because of qualitative or quantitative abnormalities in plasma von Willebrand factor (von Willebrand disease) or in platelet glycoprotein Ib, the binding site on platelets for von Willebrand factor (Bernard-Soulier syndrome). Disorders characterized by abnormal platelet-platelet interaction (disorders of aggregation) arise because of absence of plasma fibrinogen (congenital afibrinogenemia) or because of qualitative or quantitative abnormalities in platelet glycoprotein IIb-IIIa complex (Glanzmann's thrombasthenia). Patients with abnormalities in platelet secretion and signal transduction are a heterogeneous group characterized by impaired aggregation responses and secretion of granule contents. A small proportion of these patients have deficiency of granule stores (storage pool deficiency [SPD]) or impaired production of thromboxane A2; in most, the mechanisms underlying the platelet dysfunction are unknown. Evidence is accumulating that at least some patients have abnormalities in early signal transduction events. Abnormalities in phospholipase C activation, G-protein activation, and other events (eg, protein phosphorylation) have been documented. Platelets play a major role in blood coagulation, and in Scott syndrome, there is an abnormality in platelet contribution to the mechanisms leading to thrombin generation. In most patients with inherited platelet dysfunction, the underlying mechanisms remain to be delineated. Future studies of these patients should yield valuable new information on normal platelet mechanisms.

Blood Coagulation↗
PubMed2003

Loss of SEC-23 in Caenorhabditis elegans causes defects in oogenesis, morphogenesis, and extracellular matrix secretion.

SEC-23 is a component of coat protein complex II (COPII)-coated vesicles involved in the endoplasmic reticulum-to-Golgi transport pathway of eukaryotes. During postembryonic life, Caenorhabditis elegans is surrounded by a collagenous exoskeleton termed the cuticle. From a screen for mutants defective in cuticle secretion, we identified and characterized a sec-23 mutant of C. elegans. By sequence homology, C. elegans has only the single sec-23 gene described herein. In addition to the cuticle secretion defect, mutants fail to complete embryonic morphogenesis. However, they progress through the earlier stages of embryogenesis, including gastrulation, and achieve substantial morphogenesis before death. We demonstrated a maternal component of SEC-23 function sufficient for progression through the earlier stages of embryogenesis and explaining the limited phenotype of the zygotic mutant. By RNA-mediated interference, we investigated the effects of perturbing COPII function during various postembryonic stages. During larval stages, major defects in cuticle synthesis and molting were observed. In the adult hermaphrodite, reduction of SEC-23 function by RNA-mediated interference caused a rapid onset of sterility, with defects in oogenesis including early maturation of the germline nuclei, probably a result of the observed loss of the GLP-1 receptor from the membrane surfaces adjacent to the developing germline nuclei.

Amino Acid Sequence↗
PubMed2006

Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis.

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control (fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected (Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca(2+) channel subunit alpha1D, CPT2, SUR2, rab9, syt13), or inhibited (syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1alpha (HNF1alpha), HNF3beta/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

Animals↗
PubMed1978

[Pathogenesis of diabetes in adulthood. II. The nature of the insulin secretory defect].

Insulin secretion was studied during three successive stimulations: with tolbutamid, with tolbutamid +0.25 g glucose/kg body weight and with tolbutamid +0.50 g glucose/kg body weight in 30 patients with diabetes mellitus at a mature age, subdivided into two groups (SUP-sensitive and SUP-resistant). The rate of insulin secretion was found, in the first 10 minutes (early insulin secretion) to depend only on tolbutamid, remaining constant with blood sugar level fluctuations from 90 to 254 mg%. Later, insulinemia was higher in the test with combined loading, being most manifested with the most massive glucose loading. Similar correlation was not observed in the group of SUP resistant patients with diabetes. The results provide grounds to conclude that in SUP-sensitive diabetes, the ability of B-cells to synthesize and secrete insulin is being preserved but the sensitivity of glucose receptor versus the signal glucose information was declined. At the same time, the signal sensitivity versus other stimulations of insulin secretion, tolbutamid in this case, was still preserved. In this way, one of the possible pathogenic mechanisms of diabetes development at a mature age is elucidated.

Adult↗
PubMedDate not supplied

Insulin secretion and insulin sensitivity defects are a common feature of mild, clinically homogeneous, recently diagnosed type II (non-insulin-dependent) diabetics.

Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivity in vivo (hyperglycemic clamp) and in vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8 +/- 1.0 vs 4.8 +/- 0.8 microU/ml in controls, p less than 0.0005), with a significant reduction in early and late insulin secretion (14.0 +/- 1.5 vs 20.8 +/- 2.0 microU/ml, p less than 0.01 and 24.8 +/- 3.3 vs 34.7 +/- 2.14 microU/ml, p less than 0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30 +/- 0.32 vs 4.14 +/- 0.40, p less than 0.005). Endogenous glucose production was significantly increased (107 +/- 10.2 vs 84 +/- 3.7 mg/m2 per min, p less than 0.025) and displayed a positive correlation with fasting glycemia (r = 0.51, p less than 0.05). Insulin binding to monocytes was significantly lower than in controls (2.36 +/- 0.22% vs 4.06 +/- 0.32%, p less than 0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1 +/- 2.8 microU/ml, p less than 0.0005 vs controls) but, typically, lacked the early secretory phase (20.6 +/- 3.6 microU/ml vs baseline, n.s.). A similar increase of hepatic glucose production (107 +/- 11.2 mg/m2 per min, p less than 0.025 vs controls, n.s. vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I = 1.78 +/- 0.31, p less than 0.0005 vs controls, n.s. vs non-obese diabetics) was found in moderately obese diabetics, as well as a significant reduction of insulin binding to insulated monocytes (2.62 +/- 0.4% p less than 0.01 vs controls, n.s. vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.

Adult↗
PubMed1989

Defective regulation of epithelial Cl- permeability and protein secretion in cystic fibrosis: the putative basic defect.

The search for a basic functional defect in CF appears to be converging on a defect in the regulation of epithelial Cl- permeability and perhaps protein secretion. Fundamental issues that remain unresolved include (1) the identity of the CF gene, (2) the precise role played by the CF gene product in regulating Cl- permeability and protein secretion, and (3) the identities and properties of alternate pathways for regulating Cl- permeability and protein secretion that are not compromised in CF. The first issue should be resolved in the near future as molecular genetic approaches are used to pinpoint the location of the CF locus on chromosome 7. The second issue is more complex and will require the development of generally useful assays of Cl- permeability and protein secretion that can be used to assess the abilities of candidate CF gene products to complement, or correct, the functional defect in CF cells. Characterizing the precise function of the CF gene product may be difficult if the regulatory pathways that control these cellular processes are complex (ie, involve multiple regulatory steps and second messengers) or if the CF gene is a regulatory gene (rather than a structural gene) that represses or induces the synthesis of proteins involved in modulating Cl- permeability and protein synthesis. The third issue relates to the development of therapeutic strategies for treating CF patients that involve elevating epithelial Cl- permeability or modulating protein secretion by pharmacologically activating regulatory pathways that are unaffected in CF. In this regard, it is important to note that the stimulation of the Cl- permeabilities of airway epithelial cells by Ca2+-mediated secretagogues appears not to be compromised in CF. Pharmacological manipulation of this or other regulatory pathways may provide a means to activate the Cl- permeabilities of CF affected cells.

Chlorides↗
PubMed1993

Molecular characterization of an operon required for pertussis toxin secretion.

Mutants of Bordetella pertussis which are defective in secretion of pertussis toxin were isolated and characterized. The region of the B. pertussis chromosome identified by mutagenesis as playing a role in transport of pertussis toxin was sequenced. Analysis of this region revealed eight open reading frames, seven of which predict a protein exhibiting homology with one of the VirB proteins of Agrobacterium tumefaciens, which are involved in the transport of the T-DNA molecule across bacterial and plant membranes. Thus a set of accessory proteins are most likely involved in the secretion of pertussis toxin, and these proteins appear to be members of a family of proteins involved in the secretion of macromolecules from bacteria.

Agrobacterium tumefaciens↗
PubMed1997

Growth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease.

Impaired growth involving both height and weight accompanying sickle cell disease (SCD) poses diagnostic and therapeutic problems. We undertook this study to test the hypothesis that this impaired growth is associated with abnormalities of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3) axis in 21 children with SCD and that SCD is associated with GH resistance. Nine of 21 children with SCD had a defective GH response to both clonidine and glucagon provocation (peak < 10 micrograms/L); these children differed from the 12 others in having slower linear growth velocity (GV and GVSDS), lower circulating concentrations of IGF-I and IGFBP-3, and either partial or complete empty sellae in computed tomographic scans of the hypothalamic-pituitary area. In this group of patients with SCD, it appears that defective GH secretion and consequent low IGF-I production are the major etiological factors causing the slow growth. The two groups with SCD did not differ significantly in dietary intake, body mass index (BMI), midarm circumferences, skinfold thickness, serum albumin concentration, or intestinal absorption of D-xylose. A single injection of GH produced a smaller increase in circulating IGF-I in children with SCD with or without defective GH secretion versus 10 age-matched children with idiopathic short stature (ISS) and 11 children with isolated GH deficiency (GHD), suggesting partial GH resistance in the SCD group. The presence of defective GH secretion, decreased IGF-I synthesis, and partial resistance to GH in short children with SCD suggests that treatment with IGF-I may be superior to GH therapy for improving growth.

Adrenergic alpha-Agonists↗
PubMed1993

Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism.

The integrity of the Tg structure as a protein is essential for adequate synthesis of thyroid hormone. Also a large supply of iodine and of thyroid hormone is stored into the Tg molecule and available for secretion on demand. Mutations in Tg gene or hyposialylated Tg due to a defective sialyltransferase activity would cause a structurally defective protein and severely impair the functional ability of Tg. In this review we attempt to cover the abnormalities in the synthesis of Tg described in both animals and man. Hereditary congenital goiter with or without hypothyroidism is the phenotypic major clinical finding in these species. Affected animals include sheep, bovine cattle, bongo antelope, goats, and mice. As in man the inheritance mode is autosomal recessive. In most animal studies structurally abnormal Tg is present. The molecular basis for the defective Tg synthesis was attributable to nonsense mutation in exon 9 (Afrikander cattle) and in exon 8 (Dutch goats). In man the Tg defective synthesis has been reported in 89 subjects and frequently more than one sibling is affected in a given generation. Characteristically these patients exhibit hereditary congenital goiter with relatively low Tg levels that do not increase after stimulation with bovine TSH. High PBI concentrations with low serum T4 values indicate the serum presence of iodinated proteins (mainly iodoalbumin). Also iodinated peptides are frequently excreted into the urine. Tissue studies confirm that there is an absent Tg peak at gel filtration, and virtually no immunoassayable Tg is present in the tissue extracts. The molecular basis of these defects have been recently reported in a patient and includes low tissue Tg mRNA probably due to premature degradation of a defective Tg mRNA. The responsible mutation is a cytosine to thymine transition creating a stop codon at position 1510. The point mutation is removed by the preferential accumulation of a 171 nt deleted Tg mRNA. In another subject molecular studies revealed that exon 4 was missing from the major Tg transcript due to a cytosine to guanine transversion at position minus 3 in the acceptor splice site of intron 3. It is anticipated that other mutations responsible for these defects will be identifiable in the near future.

Amino Acid Sequence↗
PubMed1978

Persistent Epstein-Barr virus infection in a child with hypergammaglobulinaemia and immunoblastic proliferation associated with a selective defect in immune interferon secretion.

A 5-year-old girl had a chronic disease characterised by fever, lymphoid hyperplasia, interstitial pneumonitis, thrombocytopenia, and polyclonal hypergammaglobulinaemia. Evidence for severe, persistent Epstein-Barr virus (E.B.V.) infection was found: titres of antibody to E.B.V. viral capsid antigen (IgM and IgG) and early antigen were extremely high, cells containing E.B.V.-associated nuclear antigen (E.B.N.A.) were found in lymph nodes and blood, and spontaneous permanent lymphoblastoid cell lines were established from both sources over a period of a year. After exacerbation of the polyclonal proliferation of immunoblasts the patient died 19 months after the onset of the disease. No defect in humoral or cellular immunity was detected, except for a selective defect in immune interferon secretion by peripheral mononuclear cells. Our results suggest an important role for immune interferon in host defence against E.B.V. infection and in the regulation of immune responses.

Antibodies, Viral↗
PubMed2000

CD8(+) T cells secreting type 2 lymphokines are defective in protection against viral infection.

Effector T cells secreting type 1 and/or type 2 lymphokines (Tc1, Tc0, Tc2) were generated in vitro from CD8(+) T cells of mice with a transgenic TCR recognizing lymphocytic choriomeningitis virus (LCMV) glycoprotein to compare their effector function in vitro and in vivo. Tc1, Tc2, and Tc0 showed similar Fas- and perforin-mediated cytotoxicity in vitro. Upon adoptive transfer, Tc2 and Tc0 effectors were less efficient than Tc1 at controlling LCMV or recombinant vaccinia virus expressing the LCMV glycoprotein in vivo. Tc2 and Tc0 had decreased surface VLA-4 density and deficient activation-induced LFA-1/ICAM-1-dependent homotypic adhesion in vitro. Therefore, the reduced antiviral activity in vivo of Tc2 and Tc0 compared with Tc1 is not due to reduced cytotoxic activity or IFN-gamma secretion but may be explained by defective homing to the target organ due to decreased expression and/or lower activity of adhesion molecules.

Adoptive Transfer↗