Ke-ita Tatsumi

Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders

There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders. Using a sensitive radioligand assay, we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1, 34.4%), mu-opioid receptor (OPRM1, 13.1%), 5-hydroxytryptamine receptor 1A (HTR1A, 7.4%), and dopamine receptor D2 (DRD2, 4.9%) in 122 psychiatric patients. Positive antibodies to CHRM1 were found in 34.1%, 34.9%, 33.3%, and 9.1% of patients with schizophrenic disorders (n=44), mood disorders (n=63), other psychiatric disorders (n=15) and autoimmune diseases (n=33), respectively. All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to CHRM1, OPRM1, and/or HTR1A. Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome.

Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3 −/− mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3 −/− mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3 −/− mice. Lipid metabolism disorders in Sik3 −/− mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice.

A novel PROP1 gene mutation (157delA) in Japanese siblings with combined anterior pituitary hormone deficiency

objective  The majority of cases of combined anterior pituitary hormone deficiency (CPHD) reported in Japanese patients have PIT1 abnormality. This study describes for the first time a homozygous mutation of the PROP1 gene in two Japanese siblings with CPHD born to consanguineous parents.

Frequent appearance of autoantibodies against prohormone convertase 1/3 and neuroendocrine protein 7B2 in patients with nonfunctioning pituitary macroadenoma

Among pituitary disorders having mass effect of the pituitary gland, nonfunctioning pituitary macroadenoma and lymphocytic hypophysitis are difficult to differentiate without histological examination. In order to efficiently distinguish lymphocytic hypophysitis and pituitary tumors, we studied the presence of autoantibodies against prohormone-processing enzymes, prohormone convertase (PC) 1/3, PC2, carboxypeptidase E (CPE), and PC2 regulatory protein, 7B2, by radioligand assay using recombinant human 35S-labeled protein in patients with clinically nonfunctioning pituitary macroadenoma, lymphocytic hypophysitis, and other pituitary diseases. The indexes for anti-PC1/3 antibodies (Ab) were significantly higher in patients with nonfunctioning pituitary macroadenoma than in patients with lymphocytic hypophysitis. Patients positive for either anti-PC1/3 or anti-7B2 Ab were significantly frequent among patients with nonfunctioning pituitary macroadenoma than in other pituitary diseases and healthy controls. None of the patients was positive for anti-PC2 Ab or anti-CPE Ab. These results suggest that autoantibodies against PC1/3 and 7B2 are novel tumor-associated autoantibodies and can be helpful in the diagnosis of clinically nonfunctioning pituitary macroadenoma.

Characteristics of experimental autoimmune hypophysitis in rats : Major antigens are growth hormone, thyrotropin, and luteinizing hormone in this model

We produced experim entalautoimmune hypophysitis (EAH) in rats and investi gated its characteristics. Female Lewis rats were immunized by two injections with homologous pituitary homogenate and complete Freund’s adjuvant. Blood was coll ected seri ally from the rats, and serum antibodies to pituitary antigens were examined . The rats were sacrificed 2 or 4 weeks after the final immunization, and hi stological examinations of the endocrineorgans were carried out. Hi stolog ical examination revealedslight , focal infiltration of mononuclearcells in the pituitary gland only in the rats immunized with the pituitary homogenate. Infiltration of mononuclearcells was not observed in the thyroidgland , pancreas, adrenal gland , or ovary. In the serological examination, antibodies to bothcytoso licantigens and cytoplas micparticle a nti gens from the pituitaryg land were detected by enzyme- linked immunosorbent assay (ELISA), and these antibody levels increased with time. We stern blottingusing the sennn antibodiesidentified an immunoreactive protein of -2 1.5 k.Daamo ng these antigens, and we confirmed that this protein was ratgrow thhormone (GH). Furth ermore, antibodies to GH, thyrotropin (TSH), and luteinizing hormone (LH) were detected by E LISA. Antibodies to folli cule stimulating horm one, prol actin , or adrenocorticotropin were not detected . These data suggest that several antigens from the pituitary gland are involved in EAH inrats, and that GH, TSH, and LH are major antigens among the pituitary antigens in this model.

Blocking‐type anti‐TSH receptor antibodies and relation to responsiveness to antithyroid drug therapy and remission in Graves’ disease

objective Antithyroid drugs are effective in some patients with Graves’ disease but not in others. The factors responsible for this difference are still unknown. We examined the relationship between the nature of anti‐TSH receptor (TSH‐R) antibodies and responsiveness to drugs in Graves’ disease.

Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases

Autoimmune diseases, especially autoimmune thyroid disease, frequently develop after delivery due to the immune rebound mechanism. Most cases involve transient dysfunction of affected organs. Weexamined three patients who developed liver dysfunction after delivery. They were all diagnosed with definite or probable autoimmune hepatitis using the scoring system of the International Autoimmune Hepatitis Group. Moreover, all of them had anti‐CYP2D6 antibodies detected by a sensitive radioligand assay. Our findings strongly suggest that liver dysfunction is induced by postpartum autoimmune hepatitis, and clinicians should be aware of this disease.

Anti-CYP2D6 antibodies detected by quantitative radioligand assay and relation to antibodies to liver-specific arginase in patients with autoimmune hepatitis.

BACKGROUND Antibodies to cytochrome P4502D6 (CYP2D6) were measured and their prevalence compared with that of antibodies to liver-specific arginase in patients with autoimmune hepatitis (AIH). METHODS Anti-CYP2D6 antibodies were measured by sensitive radioligand assay and enzyme-linked immunosorbent assay (ELISA), and anti-arginase antibodies were measured by ELISA in 132 patients (definite AIH 11, probable AIH 36, hepatitis C 20, hepatitis B 23, other autoimmune diseases 42) and 50 healthy controls. RESULTS CYP2D6 index (radioligand assay) was significantly higher in all groups of patients than those in healthy controls. A higher index than the cut-off value (mean+3 S.D. in healthy controls) was found in 36.4%, 44.4%, 25.0%, 17.4% and 28.6% of patients with definite AIH, probable AIH, hepatitis C, hepatitis B and other autoimmune diseases, respectively. CYP2D6 index was not related to serum IgG, anti-nuclear antibody or AIH scores, and was weakly correlated with anti-arginase antibody activity. When CYP2D6 index and anti-arginase antibodies were combined, 55.3% of AIH patients were positive for either one or both antibodies. CONCLUSIONS Anti-CYP2D6 antibodies by radioligand assay were frequently present in patients with AIH. Combined tests for anti-CYP2D6 radioligand assay and anti-arginase antibodies resulted in detection of 55% of AIH patients.

Genetic basis of congenital hypothyroidism : Abnormalities in the TSHβ gene, the PIT1 gene, and the NIS gene

Abstract We have elucidated the molecular pathology of three types of congenital hypothyroidism. Thyrotropin (TSH) is the major regulator of thyroid function. In cases of isolated congenital TSH deficiency, we found that they are caused by a missense mutation in the conserved CAGYC region of the TSHβ gene. Pit-1/GHF-1 is a pituitary specific POU-domain DNA binding factor, which transactivates the growth hormone (GH), prolactin (PRL), TSHβ genes, and the PIT1 gene itself. In cases of combined deficiency of GH, PRL, and TSH, we found that they are caused by abnormalities in the PIT1 gene, either recessively or dominantly. Sodium dependent iodide symporter (NIS) actively transports iodide into the thyroid cells to produce thyroid hormones. In cases of iodide transport defect, we elucidated that a missense mutation in the transmembrane region of the NIS gene caused them.

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx is highly unusual, with only three reported cases in the world literature. We describe the clinical presentation and radiologic findings in one patient with such rare lesions. A 46-year-old male with typical symptoms of Graves disease was found to have a mass on magnetic resonance imaging. An otolaryngologic examination revealed a nasopharyngeal mass lesion, which was endoscopically resected. The results of immunohistochemical staining for thyroid-stimulating hormone were positive. After the resection, the patients TSH was within normal limits. The clinical significance of the case and a brief literature review are presented.