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Biomedical subjects

C Griscelli

Publications and source records attributed to C Griscelli.

At least 145 records · Page 8Linked to original sources
PubMed1987

Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13.

The gene for X chromosome-linked severe combined immunodeficiency (SCID), a disease characterized by a block in early T-cell differentiation, has been mapped to the region Xq11-q13 by linkage analysis with restriction fragment length polymorphisms. High logarithm of odds (lod) scores were obtained with the marker 19.2 (DXS3) (z = 5.51 at a recombination fraction theta = 0.11) and with the marker cpX73 (DXS159) that showed complete cosegregation with the disease locus in the informative families analyzed (z = 5.27 at theta = 0.00). Other significant linkages were obtained with several markers from Xq11 to q22. With the help of a recently developed genetic map of the region, it was possible to perform multipoint linkage analysis, and the most likely genetic order is DXS1-(SCID, DXS159)-DXYS1-DXYS12-DXS3, with a maximum multipoint logarithm of odds score of 11.0. Our results demonstrate that the SCID locus (gene symbol IMD4) is not closely linked to the locus of Bruton's agammaglobulinemia (a defect in B-cell maturation). They also provide a way for a better estimation of risk for carrier and antenatal diagnosis.

Female↗
PubMed1987

Megaloblastic anemia and immune abnormalities in a patient with methionine synthase deficiency.

We report a case of methionine synthase deficiency associated with cellular immune deficiency discovered in a 14-year-old boy. Principal findings were: developmental delay, recurrent upper and lower respiratory tract infections, megaloblastic anemia, discovered at 3 months of age, unresponsive to cyanocobalamin and poorly responsive to folinic acid. Biochemical studies showed: an abnormal deoxyuridine suppression test despite normal serum folate, cobalamin and transcobalamin levels; a normal intracellular uptake of these two coenzymes; and an absolute requirement of methionine for fibroblast growth, suggestive of defective methionine synthesis. An absence of methionine synthase activity in the patient's bone marrow and a profound depression of this activity in lymphocytes and liver were found. Hypergammaglobulinemia with variable lymphopenia, depressed lymphocyte transformation after lectin or recall-antigen stimulation, defective delayed-type hypersensitivity and decreased natural killer activity were noted as well. The patient died at the age of 14.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1987

A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients.

We have studied the clinical presentation and course of a chronic inflammatory disease occurring in childhood and observed in 30 patients. The first symptoms were generally present at birth, except in a few patients where they were first noticed in early infancy. All the patients had the association of three main symptoms: neurological, cutaneous and articular. The skin rash was the first symptom observed in all the patients and looked like a chronic non pruritic urticaria varying during the day. The articular manifestations involved knees, ankles and feet, elbows, wrists and hands unaffecting the other joints. They could be mild giving arthritis during flare-ups or severe with major radiological modifications affecting the epiphysis, metaphysis and growth cartilage. The neurological manifestations were characterized by a chronic meningitis and symptoms indicating meningeal irritation: headaches, seizures, spasticity of legs. Most patients had a cerebral atrophy and a low IQ. Sensory organ involvement occurred progressively during the follow-up: ocular inflammation with optic atrophy, deafness and hoarseness. Common morphological features characterized these patients with short stature, head enlargement, saddle back nose and short and thick extremities with clubbing of fingers. The course was that of a chronic inflammatory disease with numerous flare-ups associating fever, splenomegaly and adenomegaly. Except for a high level of eosinophils in blood, CSF and tissues, the biology was non specific and only exhibited features of inflammation. Except for two families, the disease was sporadic. A high frequency of prematurity with features resembling a foetal infection was observed but no proof of a possible causal virus has so far been found so that etiology remains unknown.

Adolescent↗
PubMed1987

Dissociation between onset of natural killer E-rosette forming cells and of T3-positive cells following HLA-mismatched T cell depleted bone marrow transplantation.

We have studied immunological reconstitution following partially HLA-incompatible T cell depleted bone marrow transplantation, compared with reconstitution following HLA identical T cell depleted and HLA identical untreated bone marrow transplantation. We often observed an early emergence of E-rosette forming cells that were T3 negative and displayed strong natural killer activity in the first group of patients. This activity was shown with fresh leucocytes as well as interleukin 2 grown cells. The appearance of T3+ cells was delayed in this situation compared to that observed in HLA identical bone marrow transplantation. The delay in T3+ cell differentiation and in cellular immune function development probably explains why NK rosette forming cells are early detected within 3-4 months following HLA mismatched bone marrow transplantation. This NK subset is likely to be present at an early stage in all types of bone marrow transplantation, but is most commonly observed simultaneously with the T3+ cells in HLA identical untreated bone marrow transplantation. The respective role of T cell depletion and HLA incompatibility in this phenomenon are discussed while patients' conditioning, cyclosporine A and graft-versus-host disease have been shown to be irrelevant for the dissociation between NK E-rosette forming cells and T3+ subset onsets.

Bone Marrow Transplantation↗
PubMed1987

Serum IgG subclass deficiency in ataxia-telangiectasia.

Serum IgG subclass levels were determined using a competitive indirect immunoenzymatic assay with monoclonal antibodies in 16 patients with ataxia-telangiectasia. Eight children had IgA deficiency, two had IgG and IgA deficiency and six patients showed no immunoglobulin class abnormality. However, IgG4 and IgG2 levels were undetectable or low in almost every patient. An IgG3 deficiency was associated with the IgG2-IgG4 defect in three patients with undetectable IgA. IgG1 was very low in one patient with a total IgG deficiency. There was no clear correlation between subclass levels and the occurrence of infections.

Adolescent↗
PubMed1986

Prevention of graft failure by an anti-HLFA-1 monoclonal antibody in HLA-mismatched bone-marrow transplantation.

Seven patients with immunodeficiencies (Wiskott-Aldrich syndrome, combined immunodeficiency, and osteopetrosis) were given a mouse monoclonal antibody against the alpha subunit of human leucocyte functional antigen (HLFA-1; CD18) to facilitate the engraftment of mismatched haploidentical related-donor bone marrow. Other conditioning included busulphan, cyclophosphamide, and antilymphocyte globulin. To prevent graft-versus-host disease the bone-marrow T cells were depleted with sheep erythrocyte rosetting and cyclosporin therapy was given. HLFA-1 antibody injections were well tolerated without side-effects except slight, transient fever (38-40 degrees) after the first injection. Engraftment was rapid in all seven patients. The regenerating leucocytes were of donor origin in all cases, and two patients have a mixed chimera. Two patients died from infections. The others are alive and well 60-395 days after transplantation. In a historical control group given the same treatment without anti-HLFA-1 infusion, only one of seven transplants partially engrafted; only two patients remain alive with autologous reconstitution but with uncorrected immunodeficiency.

Antibodies, Monoclonal↗
PubMed1986

Bone-marrow transplantation for immunodeficiencies and osteopetrosis: European survey, 1968-1985.

In this retrospective analysis of allogeneic bone-marrow transplantation (BMT) carried out between 1969 and 1985 at fourteen European centres in 162 patients with sixteen different types of inherited immunodeficiencies and osteopetrosis, the overall survival with functional grafts was 51.7% (85 patients), with a minimum follow-up of 5 months. In patients with severe combined immunodeficiency HLA-matched (n = 41) and T-cell-depleted HLA-mismatched BMT (n = 46) resulted in 68% and 57% disease-free survival, respectively; after HLA-mismatched transplants, older age (greater than 6 months) and adenosine-deaminase deficiency resulted in poorer survival. Eight other lethal immunodeficiencies, including profound T-cell deficiencies, Wiskott-Aldrich syndrome, Kostmann syndrome, LFA-1/CR 3/p150,95 deficiency, and Chediak-Higashi syndrome as well as malignant osteopetrosis, have been successfully treated by BMT. In this group, survival with functional graft was 47% with HLA-matched and 29% with T-cell-depleted HLA-mismatched BMT. Engraftment failure was the major complication in this group. Poorer prognosis was associated with older patients, profound T-cell deficiencies, and the degree of HLA incompatibility.

Adolescent↗
PubMed1986

Role of the LFA-1 molecule in cellular interactions required for antibody production in humans.

The lymphocyte function-associated antigen 1 (LFA-1) has been shown to play a role in various T cell functions in mice and humans including cytotoxicity, and proliferation to allogeneic cells and foreign antigens. These functions have been defined with specific monoclonal antibodies and were additionally confirmed by the investigation of patients with inherited deficiency in membrane LFA-1 expression. In this paper, we report our studies on the potential role of the LFA-1 molecule in T lymphocyte-dependent antibody responses. In a patient with a complete lack of membrane expression of LFA-1, there was no in vivo antibody response to vaccinal antigens such as tetanus, diphtheria toxoids, and polio virus, and no in vivo or in vitro antibody production to influenza virus, whereas serum immunoglobulin levels and antibodies to polysaccharides (isohemagglutinins, antibody to mannan, and a polysaccharide from Candida albicans) were detected in correlation with in vitro production of anti-mannan antibody. The defective antibody response to polypeptides was not secondary to poor antigen-specific T proliferation, because the latter was found to be present. Similarly, in vitro antibody production to influenza virus of normal cells was blocked by several anti LFA-1 monoclonal antibodies specific for the alpha subunit of the molecule, if they were added from the beginning of the culture. The antibody production blockade could be achieved with monoclonal antibody concentrations that partially preserved T cell proliferation. The helper effect of an influenza virus-specific helper T cell clone was also blocked. The targets of the blockade were shown by incubation experiments to be T cells and monocytes. In contrast, anti-LFA-1 monoclonal antibodies had no effect on pokeweed mitogen-induced B cell maturation into immunoglobulin-containing cells and on the anti-mannan antibody production. These combined data demonstrate that the LFA-1 molecule plays a role in T cell dependent antibody production to polypeptidic antigens but not in the antibody response to polysaccharides, although the antibody response to mannan is T cell dependent. It is proposed that the LFA-1 molecule is required to some extent for a antigen-presenting cells-T lymphocyte interaction and for the maintenance of a close association between antigen-specific helper T cells and small resting B lymphocytes. Polysaccharidic antigens that exhibit repetitive antigenic determinants might cross-link membrane immunoglobulins on B lymphocytes, thus allowing B cells to pass through a first step of activation requiring cognate T-B cell interaction.

Antibodies, Monoclonal↗
PubMed1986

Self-tolerance to host and donor following HLA-mismatched bone marrow transplantation.

The transplantation of T cell-depleted HLA-haploidentical bone marrow can correct the severe combined immunodeficiency disease (SCID) caused by the inherited absence of T lymphocytes. Despite a different environment, no severe graft-vs.-host reaction occurred and engrafted T lymphocytes became functional. We have studied tolerance of engrafted T lymphocytes to donor and host HLA antigens in four SCID patients who have been transplanted with bone marrow from one of their HLA-haploidentical parents. Graft-vs.-host reaction was prevented by T cell depletion of infused bone marrow using E rosetting and by in vivo administration of cyclosporine A. Subsequent to bone marrow transplantation (BMT), the engrafted T lymphocytes were shown to be unresponsive in vitro towards host cells collected prior to BMT. Generally, this tolerance could not be explained by a suppressive mechanism. Nevertheless, in one patient suppressive cells were found transiently. In contrast to the early appearance of a tolerance towards host, a reactivity of engrafted donor cells towards donor was always observed within the first 300 days post-grafting. This autoreactivity was mediated by T cells of donor origin and its targets were HLA class II molecules (at least HLA-DR and DQ). The progressive disappearance of this autoreactivity was correlated with the engraftment of Ia-positive cells (monocytes plus B lymphocytes) of donor origin and the achievement of complete immunological reconstitution. In the patient showing the strongest autoreactivity, a donor-specific T cell line has been grown which was shown to specifically inhibit the proliferative response of donor lymphocytes. Concomittantly, the immunological reconstitution remains poor in this patient. These data suggest that tolerance to HLA class II molecules is dependent on the presence of the relevant HLA class II molecule-expressing cells allowing the elimination or the suppression of T lymphocytes specifically directed at these molecules.

Bone Marrow Transplantation↗
PubMed1986

New data on clonal anomalies of chromosome 14 in ataxia telangiectasia: tct(14;14) and inv(14).

From a series of 53 patients with ataxia telangiectasia, two large clones with a t tan or tct(14;14) and two with an inv(14) were observed among phytohaemagglutinin (PHA)-stimulated lymphocytes. Smaller clones with the same inv(14) were observed in two other cases. Similar breakpoints may exist, both for t(14;14) and inv(14): q11.1/q11.2 and q32, and it is postulated that the rearrangements are related to a recombination of the alpha-chain of the T-cell receptor and IgH clusters of genes.

Adolescent↗
PubMed1986

Impaired T8 lymphocyte-mediated suppressive activity in patients with partial Di George syndrome.

We have studied the in vitro B-cell maturation induced by pokeweed mitogen of lymphocytes from seventeen patients with partial Di George syndrome. These patients were characterized by a low number of T8(+) lymphocytes. They had normal immune functions with an increased level of serum IgE for most of them. These patients were investigated before the age of 1 month. In contrast to age-matched subjects, their lymphocytes were able to produce in vitro immunoglobulins, although the level of immunoglobulin production was lower than in adults. These data were explained by a lack of T-cell mediated suppressor activity normally found in newborns. There was a strong correlation between the low number of T8(+) lymphocytes and the magnitude of the in vitro immunoglobulin production by patients' cells. This was further demonstrated by the ability of residual T8(+) lymphocytes isolated from patients to normally suppress the PWM driven B cell maturation on a per cell basis. The defective T-cell mediated suppression progressively disappears within 5 months. It is possible that this phenomenon is secondary to a delayed differentiation of suppressor T-cells in patients with partial Di George syndrome.

Antigens, Surface↗
PubMed1986

A study of 25 patients with chronic granulomatous disease: a new classification by correlating respiratory burst, cytochrome b, and flavoprotein.

Twenty-five patients suffering from chronic granulomatous disease (CGD) and their families were investigated. Defects in the superoxide generating system were characterized at the level of the heme-containing cytochrome b and of the FAD-containing flavoprotein, both localized in the plasma membrane of granulocytes. It was confirmed that in most of the typical cases (18 of 22), the complete inability of superoxide generation was associated with the absence of detectable cytochrome b. Mothers but not fathers of such male patients were characterized by a diminished content of cytochrome b, confirming that the affected gene is localized on the X chromosome. In contrast, the granulocytes of four other typical patients (two female and two male) contained normal amounts of cytochrome b, whereas oxidative activity was absent. Since no abnormality of oxidative activity as well as of cytochrome b was found in granulocytes of the mothers and fathers of these patients, an autosomal recessive mode of inheritance of the disease is probable. The flavoprotein deficiency found in the granulocytes of four male patients was always associated with an absence of detectable cytochrome b. This could indicate a structural relationship between flavoprotein and cytochrome b (e.g., a flavocytochrome). Three further patients with mild X-linked CGD contrasted with the patients with severe or classic X-linked disease; the oxidative activity of their phagocytes was diminished but not absent, and the cytochrome b present, albeit in small amounts.

Adolescent↗
PubMed1986

Restriction of the in vitro anti-mannan antibody response by HLA-DQ molecules.

In humans, the in vitro antibody response directed towards mannan, a polysaccharide extracted from the cell wall of Candida albicans, has been previously shown to be dependent on the presence of T lymphocytes and monocytes. Evidence is now given for the existence of a genetic restriction governing this response since antibody production is achieved provided that monocytes and T lymphocytes on one side and monocytes and B lymphocytes on the other side are of the same origin. In order to delineate the restriction element governing these interactions, blocking experiments have been designed using well-defined monoclonal antibody, anti-HLA class II molecules. The results clearly indicate that the restriction element belongs to the HLA-DQ molecular series, as shown in T-cell proliferation and antibody production assays in the presence of either T cells or T-cell supernatants. Incubation of isolated cell populations (T, B lymphocytes and monocytes) with the monoclonal antibody have indicated that DQ determinants are involved in the mannan presentation by monocytes to T and B cells. The HLA-DQ mediated restriction of the in vitro immune response to mannan has been observed in all the subjects tested, suggesting that mannan epitopes are preferentially, or even only, recognized in association with an unique group of HLA-class II molecules, namely HLA-DQ.

Antibodies, Monoclonal↗