Biomedical subjects
Yoh Hidaka
Publications and source records attributed to Yoh Hidaka.
[Immunologic tests: Anti-tropomyosin antibody].
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[Chronic thyroiditis (Hashimoto's disease)].
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Serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and their relation to cytokine production during and after normal pregnancy.
BACKGROUND: Since dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have been suggested to have immunoregulatory effects, changes in the levels of these substances during and after pregnancy might affect the maternal immune system. We examined serum concentrations of DHEA and DHEAS, and cytokine production during pregnancy and after delivery. METHODS: The subjects were 73 normal pregnant, 76 normal postpartum and 30 normal non-pregnant women. Whole-blood was stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin and the levels of cytokines in the supernatant were measured using enzyme-linked immunosorbent assay (ELISA). DHEA and DHEAS were measured using ELISA and gas chromatography-mass spectrometry (GC-MS), respectively. RESULTS: The serum DHEA levels increased in the first and in the second trimesters and decreased after delivery until 11 months postpartum. DHEAS levels were decreased in the second and in the third trimesters and returned to non-pregnant levels after pregnancy. All measured cytokines (IFN-gamma, IL-2, IL-4 and IL-10) were decreased during pregnancy and subsequently increased postpartum. We found significant negative correlations between DHEA and cytokine levels. CONCLUSIONS: Increase of serum DHEA in the first and the second trimesters may suppress immune reaction during pregnancy, while a decrease of DHEA after delivery may induce postpartum enhancement of the maternal immune system. DHEA may be involved in modifying the maternal immune responses during and after pregnancy.
Serum concentrations of androstenediol and androstenediol sulfate, and their relation to cytokine production during and after normal pregnancy.
Since it is known that androstenediol (ADIOL) has potent immunoregulatory effects, changes in ADIOL levels during and after pregnancy might affect the maternal immune system. We examined serum concentrations of ADIOL and androstenediol 3-sulfate (ADIOLS) together with IFN-gamma and IL-4 production levels during pregnancy and after delivery up to 10-11 months postpartum. The subjects were 73 normal pregnant, 76 normal postpartum, and 28 normal non-pregnant women. ADIOL and ADIOLS were measured using EIA and GC/MS, respectively. The cytokine levels in the supernatant of whole-blood cultures stimulated with phorbol 12-myristate 13-acetate and ionomycin were measured using ELISA. ADIOL levels significantly decreased compared to non-pregnant levels in the first trimester (P < 0.05) and were reversed in the third trimester (P < 0.05). After pregnancy, ADIOL levels gradually declined, and a significant decrease was observed at 10-11 months postpartum (P < 0.05). ADIOLS levels were significantly lower in the third trimester (P < 0.05) and significantly higher at the first month postpartum (P < 0.001) compared to non-pregnant women. IFN-gamma and IL-4 levels decreased during pregnancy and subsequently increased postpartum. On the other hand, we found significant negative correlations between ADIOL concentrations and production levels of IFN-gamma (P < 0.05) or IL-4 (P < 0.05). These findings suggest that ADIOL may be involved in modifying the maternal immune response during and after pregnancy.
[Differential diagnosis of hepatitis: development of new laboratory tests for autoimmune hepatitis and progress in pathophysiology].
Liver dysfunction has been found in 8.1% of postpartum women in the general population. This dysfunction was speculated to be developed by postpartum aggravation of subclinical autoimmune hepatitis. Therefore, we developed two methods for detection of autoantibodies to liver-specific antigens: an ELISA for anti-liver-specific arginase antibodies, and a highly sensitive radioligand assay for anti-CYP2D6 antibodies. Basic examinations of dilution curve, inhibition study and reproducibility were satisfactory for clinical application in both assays. Anti-arginase antibodies and anti-CYP2D6 antibodies were found in 28.6% and 42.6% of patients with autoimmune hepatitis, respectively. There was no correlation between the two autoantibodies and thus, combined use of these antibodies detects 55.3% of autoimmune hepatitis. Autoimmune hepatitis exists frequently when we include mild cases.
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.
Relation between post-partum liver dysfunction and anti-cytochrome 2D6 antibodies.
PROBLEM: Autoimmune thyroid disease frequently aggravates or develops after delivery through the immune rebound mechanism. However, little is known about the post-partum development of autoimmune hepatitis (AIH). METHOD OF STUDY: We examined 18 patients who developed liver dysfunction after delivery or abortion. Serial examinations were performed in 10 of these cases. Anti-cytochrome 2D6(CYP2D6) antibodies, which are liver-specific autoantibodies, were measured using a sensitive radioligand assay. RESULTS: Liver dysfunction developed between 1 and 5 months after delivery and was mild and transient except in one case. One patient developed liver dysfunction after abortion. Eight of 10 patients who underwent serial serologic examinations were positive for anti-nuclear antibodies, but anti-smooth muscle antibodies were positive in only three patients, and were present only at low titer. None of the patients had anti-mitochondrial antibodies. Nine of these 10 cases were diagnosed as definite or probable AIH according to the international scoring system of AIH. Nine of these 10 patients were positive for anti-CYP2D6 antibodies. The increase of anti-CYP2D6 antibodies was slightly delayed compared to increase of aminotransferase. Of the 18 patients who developed liver dysfunction, 15 cases (83.3%) were positive for anti-CYP2D6 antibodies. Of the 77 post-partum control subjects only three (3.9%) had positive antibodies. CONCLUSIONS: Autoimmune hepatitis developed after delivery, similarly to the development of post-partum autoimmune thyroid disease. Measurement of anti-CYP2D6 antibodies by a sensitive radioligand assay could provide information important for the detection of post-partum AIH.
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. PATIENTS: Twenty-eight untreated patients with Graves' disease were treated with thiamazole and followed for up to 13 years. MEASUREMENT: Antithyroid microsomal antibodies (MCHAs) and antithyroglobulin antibodies (TGHAs) were measured by the passive haemagglutination method. Anti-TSH-R antibodies were measured by a radioreceptor assay (TBII), and thyroid-stimulating antibodies (TSAbs) and TSH-stimulation blocking antibodies (TSBAbs) were measured by bioassays using FRTL-5 cells. Blocking antibodies were also measured by the conversion assay. In order to confirm the usefulness of the conversion assay, in vitro experiments using mixtures of TSAb serum and TSBAb serum were performed. RESULTS: In in vitro conversion experiments, the conversion assay sensitively detected coexisting blocking antibodies. TSBAb was found in seven patients and a positive conversion ratio was found in four patients, and, of these, three patients had both antibodies. Finally, eight patients (28.6%) had blocking antibodies and 25 of 28 patients (89.3%) had stimulating antibodies. These patients with blocking antibodies (Group A) responded well initially to antithyroid drugs and showed earlier normalization of the serum T4 level (3.0 +/- 1.2 weeks) than patients without blocking antibodies (Group B, 10.7 +/- 8.5, P < 0.001). Unexpectedly, remission of Graves' thyrotoxicosis was earlier in Group B (5.1 +/- 4.4 years) than in Group A (8.0 +/- 4.3 years, P < 0.05). Other parameters, including serum T4, goitre size, ophthalmopathy, TBII, TSAb, TGHA and MCHA, were not different between the two groups. CONCLUSIONS: Graves' patients with coexisting blocking antibodies initially respond well to thiamazole but are relatively slow to achieve remission. Measurement of blocking antibodies may be useful for selection of treatment options in Graves' disease.
Increased serum concentration of eosinophil-derived neurotoxin in patients with Graves' disease.
Eosinophil-derived neurotoxin (EDN) is released after activation and stimulation of eosinophils in allergic disease, which is a T(H)2-predominant condition. We previously reported that Graves' thyrotoxicosis develops or relapses after an attack of allergic rhinitis. In this study, to confirm the relation between Graves' disease and the allergic condition, we determined the serum level of EDN in 30 untreated patients with Graves' disease, 50 patients with Hashimoto's thyroiditis, and 39 normal controls. Compared to the serum level in normal subjects (30.1 +/- 15.6 ng/mL), EDN was increased in untreated patients with Graves' disease (52.4 +/- 27.6 ng/mL), but not in patients with Hashimoto's thyroiditis (thyrotoxic, 30.9 +/- 13.4 ng/mL; euthyroid, 30.0 +/- 11.9 ng/mL; hypothyroid, 23.4 +/- 10.2 ng/mL). A significant correlation was observed between the EDN level and the serum activity of thyrotropin (TSH) receptor antibody (r = 0.541, p < 0.0001). These data suggest that the allergic condition is closely related to Graves' disease and that a T(H)2-type immune response is crucial in the pathogenesis of Graves' disease.
Association of seasonal allergic rhinitis is high in Graves' disease and low in painless thyroiditis.
Hashimoto's thyroiditis is thought to be a T-helper cell type 1 (TH1)-dependent disease, but it is not clear whether Graves' disease is T-helper cell type 2 (TH2)-predominant or not. TH1-predominant diseases are infrequently and TH2-predominant diseases are frequently associated with allergic diseases. We examined the prevalence of seasonal allergic rhinitis to Japanese cedar pollen, a typical TH2-associated disease, in patients with Graves' disease (n = 126), painless thyroiditis (n = 46) and Hashimoto's thyroiditis (n = 88), and compared them to healthy controls (n = 766). Gender and age distribution were not different among patient groups and healthy controls, except for the higher age of patients with Hashimoto's thyroiditis. The prevalence of seasonal allergic rhinitis was significantly high in patients with Graves' disease (42.9%, p < 0.05) and low in patients with painless thyroiditis (13.0%, p < 0.01) but was not different in patients with Hashimoto's thyroiditis (26.1%) compared to that of healthy controls (32.6%). When patients with painless thyroiditis were included in Hashimoto's thyroiditis group, the prevalence of seasonal allergic rhinitis was 21.6% and significantly different from that of healthy controls (p < 0.05). These data indicate that Graves' disease is TH2 predominant and painless thyroiditis is a TH1-predominant disease. Our findings suggest that the shift from TH2 toward TH1 immunogenesis may be important for achieving earlier remission of Graves' disease.
Possible induction of Graves' disease and painless thyroiditis by gonadotropin-releasing hormone analogues.
Prolonged administration of gonadotropin-releasing hormone (GnRH) analogues induce a decrease in serum estrogen level, which may aggravate subclinical or mild autoimmune thyroid disease. Two patients developed Graves' thyrotoxicosis in association with an increase in anti-thyrotropin (TSH) receptor antibody activities at 4 months after initiation of buserelin acetate. GnRH analogue therapy was discontinued at the time of diagnosis but it took more than 2 years of methimazole therapy to obtain remission of Graves' disease. Another patient developed painless thyroiditis in association with an increase in antithyroid microsomal antibodies at 4 months after initiation of leuprolide acetate. These results indicate that GnRH analogues possibly induce clinical onset of Graves' thyrotoxicosis or destruction-induced thyrotoxicosis. Clinicians should be aware of this phenomenon. All patients who are to receive GnRH analogue therapy should be examined for antithyroid antibodies and family history of autoimmune thyroid disease, and should be followed accordingly.
Increase in serum levels of autoantibodies after attack of seasonal allergic rhinitis in patients with Graves' disease.
BACKGROUND: The prevalence of allergic disease is increasing worldwide, but its influence on the clinical course of autoimmune diseases is unknown. OBJECTIVE: The purpose of this study was to assess the effect of seasonal allergic rhinitis on the clinical course of Graves' disease, which has been considered a Th2-dominant autoimmune disease. METHODS: Ten patients with Graves' disease, who were considered to be in a state of remission or near remission, were serially examined for 18 months starting from August. Five of them had seasonal allergic rhinitis due to Japanese cedar pollen, and the remaining patients had no such allergic disorders. Peripheral eosinophil counts, serum concentrations of cedar-pollen-specific IgE, anti-TSH-receptor antibody, anti-thyroid-peroxidase antibody and antithyroglobulin antibody were assessed at 2- to 4-month intervals. Serum thyroid hormones and TSH levels were also measured to evaluate disease activity. RESULTS: All patients with pollinosis had attacks of allergic rhinitis caused by cedar pollen in early March. Subsequently, peripheral eosinophil counts, pollen-specific IgE activity and serum levels of anti-thyroid-peroxidase and antithyroglobulin autoantibodies markedly increased. Serum levels of anti-TSH-receptor antibody increased in 3 patients in association with an increase in serum thyroid hormones but were always negative in 2 patients. The control patients without pollinosis showed no consistent change of these parameters. CONCLUSIONS: Seasonal allergic rhinitis aggravated the clinical course of Graves' disease and induced an increase in serum antithyroid autoantibody concentrations as well as an increase in pollen-specific IgE concentration. These data suggest that environmental antigens induce not only local allergic reactions, but also stimulate thyroid immune reactions toward Th2 proliferation, and finally aggravate Th2-dependent autoimmune thyroid disease.
No increase of blocking type anti-thyrotropin receptor antibodies during pregnancy in patients with Graves' disease.
Serial changes in serum levels of anti-TSH receptor antibodies were examined during and after pregnancy in six patients with Graves' disease receiving no or minimal maintenance doses of antithyroid drugs. During pregnancy, serum levels of TSH-binding inhibitory Igs (P < 0.001) and thyroid-stimulating antibodies (TSAbs) (P < 0.01) decreased gradually but increased after delivery in all patients. Activities of thyroid-stimulation blocking antibodies (TSBAbs) were lower than the cut-off value in early pregnancy, and values significantly decreased in four patients during pregnancy. The other two patients showed no significant change during pregnancy. In contrast, TSBAb levels increased significantly (P < 0.01) after delivery in all patients. We found that activities of TSH-binding inhibitory Igs, TSAb, and TSBAb decrease during pregnancy and increase after delivery, suggesting that amelioration of Graves' disease during pregnancy is induced by decrease of TSAb but not by the appearance of TSBAb.
Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease.
Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves' disease during or after anti-thyroid drug therapy, there is no reliable one to assure the complete remission. We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Fifty-seven patients with Graves' disease were treated with anti-thyroid drugs at the initial dose of 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU). Then, doses were gradually decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI 5 mg every other day or PTU 50 mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBII) were measured every one to two months for the first 6 months and every 3-4 months for the next 18 months to confirm continuous remission. After 2 years of drug cessation, 46 (81%) of 57 patients were in remission and the other 11 patients had relapsed into thyrotoxicosis. At the time of drug discontinuation, the serum concentration of FT4, FT3 and TSH, titers of anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies, goiter size were not different between the remission and relapse groups. At the time of drug cessation, the activities of TBII and thyroid-stimulating antibodies (TSAb) overlapped between the two groups, although they were significantly lower in the remission group than in the relapse group (p<0.01). Forty percent (4/10) of TBII positive patients and 71% (23/32) of TSAb positive patients continued to be in remission. On the other hand, thyrotoxicosis relapsed in 5 (11%) of 47 TBII negative and 2 (8%) of 25 TSAb negative patients. These data indicate that minimum maintenance therapy to keep euthyroid (normal FT4 and TSH) for 6 months is a practical measure for 81% prediction of remission in Graves' disease. The measurement of TBII or TSAb gave little additional information for predicting remission.
Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome.
The disturbance of the central nervous system and immunological abnormalities have been suggested in patients with chronic fatigue syndrome (CFS). We focused on immunological abnormalities against neurotransmitter receptors in CFS. Using a sensitive radioligand assay, we examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1), mu-opioid receptor (OPRM1), 5-hydroxytryptamine receptor 1A (HTR1A), and dopamine receptor D2 (DRD2) in patients with CFS (n=60) and results were compared with those in patients with autoimmune disease (n=33) and in healthy controls (n=30). The mean anti-CHRM1 antibody index was significantly higher in patients with CFS (p<0.0001) and autoimmune disease (p<0.05) than that in healthy controls, and positive reaction was found in 53.3% of patients with CFS. Anti-OPRM1 antibodies, anti-HTR1A antibodies, and anti-DRD2 antibodies were found in 15.2, 1.7, and 5.0% of patients with CFS, respectively. Anti-nuclear antibodies were found in 56.7% (34/60) of patients with CFS, but anti-nuclear antibody titers did not correlate with the activities of the above four autoantibodies. The patients with positive autoantibodies to CHRM1 had a significantly higher mean score (1.81) of 'feeling of muscle weakness' than negative patients (1.18) among CFS patients (p<0.01). Higher scores on 'painful node', 'forgetfulness', and 'difficulty thinking' were also found in CFS patients with anti-CHRM1 antibodies but did not reach statistical significance. In conclusion, autoantibodies to CHRM1 were detected in a large number of CFS patients and were related to CFS symptoms. Our findings suggested that subgroups of CFS are associated with autoimmune abnormalities of CHRM1.
Community postnatal care and women's health.
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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.