1/127. A normal level of adenosine deaminase activity in the red cell lysates of carriers and patients with severe combined immunodeficiency disease.The red cell lysates of two children with severe combined immunodeficiency disease (SCID) exhibited a virtually total absence of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) when standard volumes were assayed. Under these conditions the parents exhibited depressed specific activity except for one mother, whose lysate showed a normal value for activity. Upon storage of the lysate at 4 degrees, a significant amount of activity appeared in one of the SCID children, and the activity of the heterozygous carriers was stimulated. With the use of a sensitive spectrophotometric assay based on conversion of inosine to uric acid, it was shown that the specific enzymatic activity in each of the SCID patients increased progressively as the volume of lysate assayed was lowered. With the smallest amount of lysate this specific activity was in the normal range. Similarly, the specific activity of each of the parents' lysates increased to the level of normal (or, in one case, about twice normal) as smaller volumes were assayed. The activity in the SCID patient was inhibitable by 2-fluoroadenosine and N6-methyladenosine, known competitive inhibitors of human red cell adenosine deaminase. The lysate from the SCID patient was also shown to inhibit adenosine deaminase partially purified from a normal individual. The results are interpreted in terms of a genetically programmed production of an adenosine deaminase inhibitor in at least one variant of the severe combined immunodeficiency disease.- - - - - - - - - - ranking = 1keywords = activity (Clic here for more details about this article) |
2/127. C3 metabolism in a patient with deficiency of the second component of complement (C2) and discoid lupus erythematosus.A patient with a hereditary deficiency of the second component of complement and discoid lupus erythematosus with features of systemic lupus erythematosus was studied. The propositus had a 9-year history of rash and arthralgia. Transient renal disease had completely resolved; there was a history of seizures. Examination of his serum disclosed antinuclear antibodies but no total haemolytic complement activity. C2 was absent. serum concentrations of C1s, C3, C5 and C9 were elevated; other complement components were present in normal concentration, including C3 pro-activator. The patient's C3 pro-activator was electrophoretically converted by inulin and four of five lipopolysaccharides, but was poorly converted by aggregated human IgG. Two separate turnover studies with radiolabelled C3 showed fractional catabolic rates of 3-03 and 2-48% of the remaining plasma pool/hr (range of three normals: 1-62-2-18%/hr); and estimated C3 synthetic rates of 2-74 and 2-31 mg/kg/hr (range of three normals: 0-89-1-40 mg/kg/hr). serum complement profiles of the patient's family demonstrated that the C2 deficiency was inherited as an autosomal codominant. One sibling, homozygous for C2 deficiency, and three other siblings, both parents and one daughter, all heterozygous for C2 deficiency, are in good health. Immunofluorescent studies of the patient's diseased skin exhibited substantial deposits of IgG, IgM, C1q, and C4 but not of later acting complement components, properdin, or C3 proactivator. These studies do not support the notion that inflammation in C3-deficient individuals with lupus erythematosus is mediated by the alternative complement pathway.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
3/127. Heterogeneity of lymphocyte subpopulations in severe combined immunodeficiency. Evidence against a stem cell defect.Surface markers typical of T and B lymphocytes were present on varying proportions of peripheral blood lymphocytes from three infants with severe combined immunodeficiency disease. Despite this, functions mediated by T and B cells were either absent or very minimal in all three, including cell-mediated responses in vivo; the in vitro proliferative response to mitogens, allogeneic cells, or antigens; effector cell function in lymphocyte-antibody lymphocytolytic interaction assays; and in vitro synthesis of IgG, IgA, and IgM. In contrast, mononuclear cells from one of the infants were tested and found capable of lysing both human and chicken antibody-coated erythrocyte targets normally. Co-cultivation experiments with unrelated normal control lymphocytes failed to demonstrate suppressor cell activity for immunoglobulin synthesis in these infants. Augmentations of immunoglobulin production from 310 to 560% over that expected on the basis of individual culture data were noted in co-cultures of one of the infants' cells with two different unrelated normal control cells. These findings suggest that that infant may have had a T helper cell defect or that his T cells were unable to produce soluble factors necessary for B cell differentiation. The finding of cells with differentiation markers characteristic of T and B lymphocytes in each of these patients, though in variable quantities, is further evidence for heterogeneity among patients with the clinical syndrome of severe combined immunodeficiency and argues against the concept that their immunodeficiency was due to a stem cell defect.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
4/127. Suppressor cell activity in a male infant with T-and B-lymphocyte dysfunction treated with thymosin.A male infant with bilateral iris coloboma who had had repeated infections and malabsorption was studied. The levels of total lymphocytes and of T and B cells were normal or high, but IgA became undectable and IgG low, whereas IgM was normal. His lymphocytes did not respond to phytohemagglutinin (PHA), concanavalin a, pokeweed mitogen (PWM) or in mixed lymphocyte reactions (MLR), nor did they respond in vitro when thymosin was included in the test systems. He was skin-test-negative, even to dinitrochlorobenzene. His crudely isolated T lymphocytes and the supernatant of his PHA-stimulated lymphocytes inhibit the response of normal lymphocytes to PHA, PWM, and in MLR. During thymosin treatment skin test and lymphocyte reactivity to mitogen remained negative. He became faintly positive in MLR, and the suppressor activity in the supernatant of his PHA-stimulated lymphocytes no longer inhibited the response of normal lymphocytes to PHA, PWM, or in MLR. In parallel with thymosin treatment he showed quite marked clinical improvement.- - - - - - - - - - ranking = 0.5keywords = activity (Clic here for more details about this article) |
5/127. Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections.IL-12 plays a pivotal role in the stimulation of immune responses against intracellular infections. This role is manifested in the increased susceptibility to atypical mycobacterial and salmonella infections among individuals whose lymphocytes lack expression of IL-12Rbeta1. Here, we report on a patient with mycobacterium avium infection, recurrent staphylococcus aureus sinusitis, and multiple adverse drug reactions whose T cells were unable to produce IFN-gamma or proliferate in response to IL-12 despite the expression of wild-type IL-12Rbeta1 and IL-12Rbeta2. The defect in these functional responses to IL-12 was selective, as cytolytic activity induced by IL-12 was intact, and lymphocytes were responsive to stimulation by IL-2. An examination of cytokine signaling revealed that STAT4 and extracellular regulated kinase 1 (ERK1) activation by IL-12 was intact, whereas the activation of STAT1, -3, and -5 by IL-12 was lost. This impairment of STAT activation was specific for IL-12, as STAT activation by IL-2, IL-15, and IFN-gamma was unaffected. These findings demonstrate that the activation of STAT4 alone is not sufficient for IL-12-induced IFN-gamma production and proliferation and suggest that other STATs play a role in these responses to IL-12. While the etiology of the impaired IL-12 signaling in this patient has not yet been elucidated, the absence of mutations in IL-12Rbeta1 or IL-12Rbeta2 and the preservation of STAT4 activation raise the possibility that there may be a mutation in an as yet undiscovered component of the IL-12 signaling complex that is normally required for the recruitment and activation of STAT1, -3, and -5.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
6/127. brain migration disorder and T-cell activation deficiency associated with abnormal signaling through TCR/CD3 complex and hyperactivity of Fyn tyrosine kinase.In this study we report on a patient affected by a brain migration disorder and a T-cell activation deficiency presumably inherited as an autosomal recessive trait. The immunological evaluation revealed that the mitogen stimulation failed to induce a proper up-regulation of membrane expression of T-cell activation markers, and cell proliferation. This functional impairment was associated with abnormalities of the signal transduction process that follows T-cell receptor stimulation. A constitutive hyperphosphorylation of the Fyn tyrosine kinase was documented. This is the first report on a T-cell signaling abnormality associated with a developmental brain disorder. Whether the alteration of Fyn, which plays a role in both neurological and immunological systems, is responsible for either disorder remains to be elucidated.- - - - - - - - - - ranking = 0.33333333333333keywords = activity (Clic here for more details about this article) |
7/127. mutation in the class II trans-activator leading to a mild immunodeficiency.The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
8/127. Macroglobulinemia Waldenstrom complicated by autoimmune hemolytic anemia, meningeal sign and femoral lysis.A necropsied case of macroglobulinemia Waldenstrom with unusual complications was presented; the patient was found to have autoimmune hemolytic anemia, first. During the course of its treatment, he developed monoclonal immunoglobulin m in serum together with lytic osseous lesion in both femurs, and died of meningeal involvement by tumor cells. Clinically, he had hepatosplenomegaly and generalized lymphadenopathy. The macroglobulin was kappa type of light chain, ultracentrifugation showed sharp spike of 21S in 18.6%, and myelogram revealed increased lymphocytoid series of 29.6%. It was proved that autoantibody causing autoimmune hemolytic anemia was composed of IgG and macroglobulin itself had no activity as an anti-red cell antibody. An emphasis was made that autoimmune hemolytic anemia followed by macroglobulinemia is based on the state of immunodeficiency of this patient.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
9/127. Hyper-IgM syndrome with systemic tuberculosis.A 33-y-old man with Hyper-IgM syndrome developed a severe tuberculous disease complicated by pleuritis and spondylitis. An abnormally decreased CD4/CD8 ratio, decreased CD4 T-cell count and depressed natural killer cell activity implicated a coexistent cell-mediated immunodeficiency. To our knowledge, this is the first detailed report of tuberculosis associated with Hyper-IgM syndrome.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
10/127. Purine nucleoside phosphorylase deficiency: a new case report and identification of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a) is deleterious.Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal recessive immunodeficiency disease characterized by initial involvement of cellular immunity and neurological manifestations with subsequent abnormalities of humoral immunity. The initial presentation and clinical course has varied widely in the relatively few published cases. The molecular basis has been reported in only 10 patients, precluding evaluation of phenotype-genotype relationships. We now report clinical, immunologic, and molecular findings in a new case of relatively early onset that emphasizes hypotonia and developmental delay as early manifestations. The patient carried two novel missense mutations (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation abolished enzyme activity while the Val217Ile mutation was without obvious effect and is therefore a normal variant. Such "normal" polymorphisms might be associated with a variable response to the immunosuppressive PNP inhibitors currently in clinical trials.- - - - - - - - - - ranking = 0.083333333333333keywords = activity (Clic here for more details about this article) |
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