Complement-fixing Islet cell antibodies from some diabetic patients alter insulin release in vitro.

To explore humoral immunity in insulin-dependent diabetic (IDDM) patients, we studied insulin release from isolated mouse islets stimulated by glucose + theophylline after incubation with the sera of these patients and complement. Eleven of 21 IDDM sera suppressed the stimulated insulin release while the arginine-stimulated glucagon release remained unchanged. Morphologic evidence and the trypan-blue exclusion test suggested that the suppression of insulin release was due to a cytotoxic effect of the sera. No beta-cell inhibition of morphologic damage was detectable in the presence of sera from 30 healthy subjects, 8 non-insulin-dependent diabetic patients, and 5 nondiabetic patients with autoimmune diseases. Beta-cell inhibition by IDDM sera was not observed when complement was omitted. After serum fractionation, the cytotoxic potency of IDDM sera was located in the immunoglobulin G fraction. Using human islets, insulin release was suppressed by 3 of 6 IDDM sera. Complement-dependent cytotoxicity was found in 1 of 5 recent-onset IDDM patients and 11 of 16 IDDM patients with autoimmune phenomena. It was associated in all cases with the presence of islet cell antibodies as detected by immunofluorescence, and with the presence of circulating lymphocytes which suppressed insulin release in vitro. Complement-fixing antibodies may contribute to the selective beta-cell damage in IDDM.

Glucose counterregulation in pre-school-age diabetic children with recurrent hypoglycemia during conventional treatment.

To determine whether immature or defective glucose counterregulation was responsible for the severe recurrent hypoglycemic episodes (3.6 per patient per year) observed during conventional therapy (CT) in six pre-school-age diabetic children, we investigated their metabolic and hormonal responses to insulin infusion (40 mU/kg i.v. for 60 min). Counterregulation was considered adequate because no patient experienced symptoms requiring discontinuation of the test, and blood glucose (BG) nadirs averaged 42 +/- 5 mg/dl. Glucose production rate decreased from 4.2 +/- 0.2 to 2.6 +/- 0.6 mg X kg-1 X min-1. Blood 3-hydroxybutyrate levels were elevated (approximately 3 mM) and did not change during insulin infusion. The responses of epinephrine (from 137 +/- 37 to 393 +/- 143 pg/ml), norepinephrine (from 145 +/- 33 to 347 +/- 152 pg/ml), and growth hormone (from 6.0 +/- 1.5 to 20.3 +/- 5.1 ng/ml) were normal for this age group. As previously observed in diabetic adults, glucagon response was deficient (from 117 +/- 30 to 114 +/- 18 pg/ml). The six children were subsequently treated with continuous subcutaneous insulin infusion (CSII), which resulted in a 20-fold decrease in the number of severe hypoglycemic reactions. Predisposition to severe hypoglycemia in this subset of diabetic children, which remains a refractory problem even after considerable efforts have been made to decrease them, may thus be sharply decreased with CSII therapy. During this therapy, a significant inverse correlation appeared between the individual frequency of BG values less than 40 mg/dl and BG nadir during the insulin infusion test (r = .94, P less than .001).

Transient hypoparathyroidism induced by synthetic human parathyroid hormone-(1-34) treatment.

Daily injections of low doses of a synthetic fragment of human PTH [hPTH-(1-34) have increased iliac trabecular bone volume when used in the treatment of osteoporosis. In approximately 50 patients no major side-effects had occurred. However, during daily sc 100-micrograms injections of the peptide, one patient repeatedly developed parathyroid hypofunction which resolved each time treatment was stopped. Specific immunoglobulin G (IgG) antibodies binding [125I]hPTH-(1-34) were identified in the patient's serum, and positive immunohistochemical reactions were obtained when bovine parathyroid sections were exposed to the patient's IgG. After adsorption with PTH, the patient's IgG, free of anti-PTH antibodies, reacted with renal cell membranes, as demonstrated by indirect immunofluorescence and blocked renal PTH-dependent adenylate-cyclase activation in vitro. These results support the hypothesis that anti-PTH receptor as well as anti-PTH antibodies were generated during hPTH-(1-34) treatment, which led to the development of hypoparathyroidism when their titers were high.

An ELISA technique for the measurement of C1q in cerebrospinal fluid.

Determination of the C1q content of cerebrospinal fluid (CSF) may be of value in understanding the immunological reactions occurring within the central nervous system (CNS). A double sandwich ELISA method has been developed for the detection of C1q in human serum and CSF. It uses polyclonal antibodies and is sensitive in the nanogram range. The mean concentrations of C1q were determined to be 127 micrograms/ml in serum and 0.4 microgram/ml in CSF. These results suggest that increased levels of C1q in the CSF play a role in some neurodegenerative disorders.

[Circulating human pituitary prolactin cell autoantibodies and Alzheimer's disease]. / Autoanticorps circulants anti cellules a prolactine de l'hypophyse humaine et maladie d'Alzheimer.

Prolactin cell autoantibodies (PRL cells Ab) were detected in 96 p. cent of 27 cases of Alzheimer's presenile dementia and senile dementia, as defined by clinical criteria and data from CT scans. The very high frequency of these autoantibodies appears to be even more significant of Alzheimer's disease in that they were found with a similar frequency in patients with Down's syndrome aged from 13 to 33 years. The frequency of PRL cells Ab is very low in the general population including patients with endocrine disorders. Current evidence indicates that higher levels exist only in cases of arteriopathic dementia, in subjects over 80 years and in subjects with isolated organic memory disturbances, though their frequency may be such that it suggests the probability of Alzheimer's disease. The etiopathogenic significance of these autoantibodies is not clear, but they support a role of autoimmune factors in Alzheimer's disease.

[Parkinson's disease, dysautonomy, and auto-antibodies directed against sympathetic neurones (author's transl)]. / Maladie de Parkinson, dysautonomie et auto-anticorps dirigés contre les neurones sympathiques.

A study was conducted to evaluate possible correlations between auto-antibodies directed against sympathetic structures (Ab. S), in Parkinson's disease and the dysautonomy that may be associated with it, in 85 Parkinsonian patients and 85 controls. In all the patients with Parkinson's disease, the immunological study was coupled with an evaluation of functional signs of anomalies of neurovegetative function, and tests for postural hypotension. The results confirm the remarkable frequency of these auto-antibodies in patients with Parkinson's disease (66%), whereas they were present in only 20% of control subjects. Positive results were more frequent in early onset, long-standing cases. The presence of Ab. S in 85% of the pateints in whom the disease had started before 50 years of age could mean that these antibodies might constitute a marker for Parkinson's disease among other parkinsonian conditions. No correlation between Ab. S and the existence of a dysautonomy was found, but their frequency is slightly higher in patients with Parkinson's disease and postural hypotension (75%). This finding, together with the frequency and plurality of the mechanism of postural hypotension in elderly subjects, suggests a correlation with some types of postural hypotension.

[Demonstration of anti-pancreatic cellular immunity in insulin-dependent diabetics]. / Mise en évidence d'une immunité cellulaire anti-pancréatique chez des diabétiques insulino-dépendants.

A significant inhibition of insulin response was found after incubation of islet cells with blood lymphocytes from 18 out 20 insulin-dependent diabetics. No inhibition was found in 22 control subjects.

[Paget's bone disease. Preliminary serological study]. / Maladie osseuse de Paget. Etude sérologique préliminaire.

A serological study has been carried out in Paget's bone disease where the etiology still remains uncertain. Previous work on patients with the disease revealed specific osteoclast inclusions that could be linked to the presence of a virus of the paramyxovirus group. Conventional methods for exploring humoral immunity reveal no great differences in the concentration of antibodies against the various viral strains tested on sera from 46 patients with Paget's bone disease and from 46 paired controls. The viral origin of Paget's bone disease is reconsidered in the light of the results obtained. The eventuality of sub-threshold viral infection and the possible action of incomplete or defective virus leading to the chronic nature of the disease are discussed.

Antigonadotropic cell antibodies in the serum of cryptorchid children and infants and of their mothers.

An indirect immunofluorescence test allowed us to study circulating antigonadotropin-cell antibodies in patients with cryptorchidism. Antigonadotropin-cell activity was found in the serum in 14 of 23 cryptorchid boys aged 1 to 11 years and in 12 of 23 infants aged 1 to 3 months; in most of them the antibodies persisted during short-term follow-up. Results of paired study of the mother and infant were concordant in 14 of 15 cases. No such antibodies were found in 24 control male children. These data support the possible role of pituitary autoimmunity in the child and the mother as a factor in testicular maldescent. We found no correlation between the presence or absence of antibodies and the partial luteinizing hormone-Leydig cell deficiency usually found in cryptorchidism.

[Demonstration by immunofluorescence and immunoperoxidase of an antigen of the measles type in the osteoclasts of Paget's disease of bone]. / Mise en évidence par immunofluorescence et immunopéroxydase d'un antigène de type rougeole dans les osstéoclastes de la maladie osseuse de Paget.

The intra nuclear and intra cytoplasmic inclusions described in osteoclasts in PAGET's bone disease are morphologically similar to those observed in subacute sclerosing panencephalitis. Immunological techniques using different specific immune sera demonstrate the presence of an antigenic structure of viral origin in osteoclasts in PAGET's bone disease. A measles or a measles like virus is most likely to be involved and may play a role in the etiology of the disease.

[Demonstration of measles virus antigens in osteoclasts in Paget's disease of bone]. / Mise en évidence d'antigènes viraux de rougeole dans les ostéoclastes de la maladie osseuse de Paget.

The first results of histo-immunological studies on biopsies in Paget's bone disease strongly favour the presence of antigenic material of viral origin in osteoclasts. Measles virus may play a role in the etiology of Paget's bone disease.

Binding interactions of leukemia inhibitory factor and ciliary neurotrophic factor with the different subunits of their high affinity receptors.

Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) share common components in their multimeric receptors. Both cytokine receptors contain gp130/interleukin-6-receptor transducer as well as gp190/low affinity LIF receptor. For CNTF, addition of a third subunit, or alpha subunit, defines the high-affinity CNTF receptor. In the present study, we analyzed the binding interactions of LIF and CNTF in human cell lines and showed a mutual displacement for LIF and CNTF toward the trimeric high-affinity CNTF receptor. Similar results were obtained in the JEG cell line, which only expressed the gp130/gp190 high-affinity LIF receptor, by adding a soluble form of the alpha CNTF receptor to the system to reconstitute the high-affinity-type CNTF receptor. The different receptor subunits were then expressed separately in transfected cells and their binding capacities analyzed. The results showed that the heterocomplex CNTF/alpha CNTF receptor bound to gp130 with an affinity of 3-5 x 10(-10)M, whereas LIF interacted mainly with gp190. In summary, the observed competition between LIF and CNTF does not result from the binding to a common site or receptor subunit, but rather to the interaction of the three receptor components to create a conformational site common to both LIF and CNTF.

Autoantibodies to prolactin-secreting cells of human pituitary.

A new autoantibody which reacted with anterior-pituitary tissue was deteected by immunofluorescent staining. Of 287 patients having one or more autoimmune endocrine diseases, sera from 19 reacted with pituitary glands obtained at hypophysectomy for breast cancer. Using specific rabbit antibodies to each of the six pituitary hormones and rhodamine-labelled goat-anti-rabbit-immunoglobulin (Ig) followed on the same unfixed cryostat section by a patients's serum counterstained with fluorescein-conjugated sheep-anti-human-Ig, it was posssible to show that the autoantibodies reacted specifically with the hypertrophied prolactin cells in these glands. The antibodies, belonging to the 3 main Ig classes, were complement fixing, with titres varying from 1 to 80. Double staining of prolactin cells and analogy with other autoimmune systems suggested that the antigen is in cytoplasmic organelles involved in the synthesis or delivery of the hormone. No pituitary antibodies were found in panhypopituitary cases, but there are indications that antibodies to other pituitary cells exist in some sera and that an autoimmune process may account for some cases of isolated pituitary hormone defects occurring in adult life.

[Paget's bone disease. Preliminary serological study]. / Maladie osseuse de Paget. Etude sérologique préliminaire.

A serological study has been carried out in Paget's bone disease where the etiology still remains uncertain. Previous work on patients with the disease revealed specific osteoclast inclusions that could be linked to the presence of a virus of the paramyxovirus group. Conventional methods for exploring humoral immunity reveal no great differences in the concentration of antibodies against the various viral strains tested on sera from 46 patients with Paget's bone disease and from 46 paired controls. The viral origin of Paget's bone disease is reconsidered in the light of the results obtained. The eventuality of sub-threshold viral infection and the possible action of incomplete or defective virus leading to the chronic nature of the disease are discussed.

Bone tissue in Paget's disease of bone. Ultrastructure and Immunocytology.

Ultrastructural observation in Paget's disease of bone clarify aspects of bone cells in bone tissue and demonstrate the presence of specific intranuclear inclusions composed of microcylinders in the osteoclasts. The morphologic analysis of these structures suggests an analogy with virus material of the measles group. Results obtained using indirect immunofluorescence and immunoperoxidase techniques lend further support to the hypothesis of a viral etiology in Paget's disease of bone.