Thyroid dysfunctions secondary to cancer immunotherapy.

BACKGROUND: Immunotherapy is a firmly established pillar in the treatment of cancer, alongside the traditional approaches of surgery, radiotherapy, and chemotherapy. Like every treatment, also cancer immunotherapy causes a diverse spectrum of side effects, collectively referred to as immune-related adverse events. OBJECTIVE: This review will examine the main forms of immunotherapy, the proposed mechanism(s) of action, and the incidence of thyroid dysfunctions. METHODS: A comprehensive MEDLINE search was performed for articles published up to March 30, 2017. RESULTS: Following the pioneering efforts with administration of cytokines such as IL-2 and IFN-g, which caused a broad spectrum of thyroid dysfunctions (ranging in incidence from 1 to 50%), current cancer immunotherapy strategies comprise immune checkpoint inhibitors, oncolytic viruses, adoptive T-cell transfer, and cancer vaccines. Oncolytic viruses, adoptive T-cell transfer, and cancer vaccines cause thyroid dysfunctions only rarely. In contrast, immune checkpoint blockers (such as anti-CTLA-4, anti-PD-1, anti-PD-L1) are associated with a high risk of thyroid autoimmunity. This risk is highest for anti-PD-1 and increases further when a combination of checkpoint inhibitors is used. CONCLUSIONS: Cancer patients treated with monoclonal antibodies that block immune checkpoint inhibitors are at risk of developing thyroid dysfunctions. Their thyroid status should be assessed at baseline and periodically after initiation of the immunotherapy.

Pituitary autoimmunity in patients with diabetes mellitus and other endocrine disorders.

OBJECTIVE: Pituitary autoimmunity is often found in association with other endocrine autoimmune or non-autoimmune diseases. Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) in patients with Type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In this casecontrol study 111 patients with T1DM, 110 patients with T2DM, and 214 healthy controls were enrolled in a tertiary referral center. Pituitary, thyroperoxidase, thyroglobulin, 21-hydroxylase, and parietal cell antibodies were assessed in all cases. Endocrine function was further assessed by basal hormone measurement and by dynamic tests, as well as a pituitary magnetic resonance imaging (MRI) was performed in those patients found positive for PitAb. RESULTS: PitAb prevalence was higher in T1DM (4 out of 111, 3.6%) than in T2DM (0 out of 110, p=0.045) and in healthy subjects (1 out of 214, 0.5% p=0.029). Prevalence of other autoimmune diseases was significantly higher in patients with T1DM (45 out of 111, 40.5%) when compared with patients with T2DM (18 out of 110 T2DM, 16.3%, p<0.001). Patients with T1DM and PitAb positivity were found with a pituitary lesion at MRI in 2 cases and pituitary dysfunction in one case. CONCLUSIONS: A significant association between pituitary autoimmunity and T1DM was found, in particular in subjects with one or more other endocrine autoimmune diseases.

Growth hormone and proopiomelanocortin are targeted by autoantibodies in a patient with biopsy-proven IgG4-related hypophysitis.

Hypophysitis is a chronic inflammation of the pituitary gland often caused by autoimmunity. Among the autoimmune diseases it is one of the few where the autoantigens remain to be identified. The goal of the paper was to characterize the antigenic profile in a previously reported patient with IgG4-related hypophysitis. Immunofluorescence and immunoblotting were performed to detect antibodies to human pituitary proteins. The proteins recognized by western blotting were then submitted to mass spectrometry for sequencing. The patient's autoantibodies recognized two unique bands around 40 and 30 kDa on immunoblotting. Sequencing revealed one peptide from proopiomelanocortin in the 40 kDa band and four peptides from growth hormone in the 30 kDa band. This work represents the first antigenic profile in IgG4-related hypophysitis, and the first recognition of proopiomelanocortin as a possible pituitary autoantigen. In addition, the work supports previous suggestions of growth hormone as a pituitary autoantigen. Further studies are needed to prove the pathogenicity and diagnostic utility of these two pituitary proteins.

Oncocytic mania: a review of oncocytic lesions throughout the body.

Oncocytic lesions are characterized pathologically by an abundance of oncocytes, that is by enlarged, eosinophilic, and finely granular cells enriched in mitochondria. They can arise in numerous organs and tissues, often in endocrine glands, and have been associated with hyperplasia, autoimmunity, and neoplasia. The causes and mechanisms that transform a normal cell into an oncocyte remain to be elucidated. Aim of this article is to review the most common oncocytic lesions, highlighting their key pathological features and clinical significance.

Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella.

OBJECTIVE: Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES. DESIGN: In this casecontrol study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center. METHODS: PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases. RESULTS: PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p<0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02). CONCLUSIONS: The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Diagnosis and treatment of autoimmune hypophysitis: a short review.

Medical therapy of autoimmune hypophysitis with immunosuppressive drugs can be effective to induce remission of the disease by treating both pituitary dysfunction and compression symptoms. We describe the case of a 41-yr-old man with autoimmune hypophysitis in whom prednisone therapy induced remission of the disease but was followed by a sudden relapse after withdrawal. A second trial of corticosteroid was started and succeeded in inducing remission of the disease. Eight months after the second withdrawal pituitary function was restored, pituitary mass had disappeared, only partial diabetes insipidus remained unchanged. Review of the literature identified 30 articles, among case reports and case series, reporting a total of 44 cases of autoimmune hypophysitis treated with glucocorticoids and/or azathioprine. Combining all the cases, medical therapy resulted to be effective in reducing the pituitary mass in 84%, in improving anterior pituitary function in 45%, and in restoring posterior pituitary function in 41%. Clinical aspects of autoimmune hypophysitis are discussed and a possible algorithm for the diagnosis and treatment of the disease is proposed.

Sjögren syndrome: advances in the pathogenesis from animal models.

Sjögren syndrome is an autoimmune disease characterized by hyposecretion of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. Individuals may experience primary Sjögren syndrome or a secondary form accompanying another rheumatic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The pathogenic mechanisms of Sjögren syndrome remain largely unknown, in part a consequence of the heterogeneity of the disease. Animal models have shed light on the connections between specific pathways and symptoms, but an ideal system is wanting. Improved disease models will enable a better understanding of Sjögren syndrome, including how immune tolerance is lost and potential therapeutic interventions. Most importantly, an optimal model will enable detection of disease biomarkers, since injury to the salivary glands may precede lymphocytic infiltration. This review aims to characterize available mice models of Sjögren syndrome, including advantages and disadvantages, from the researcher's perspective.

Transformation of rat thyroid follicular cells stably transfected with cholera toxin A1 fragment.

Activating mutations of the alpha subunit of the G protein G(s) (G(s)alpha) have been identified in thyroid adenomas and well-differentiated thyroid carcinomas. To examine the role of activating mutations of G(s)alpha in thyroid neoplasia, we transfected rat follicular thyroid (FRTL-5) cells with a transgene in which the cholera toxin A1 subunit (CTA1) is expressed under the control of the rat thyroglobulin gene promoter (TG). This transgene recapitulates effects of the activating mutation of G(s)alpha by its ability to ADP-ribosylate and thereby inhibit GTPase activity of endogenous G(s)alpha molecules. To assess the effect of G(s)alpha activation on cell growth, TGCTA1, or control, pM AM neotransfected FRTL-5 cells (10(4)-10(6)) were injected s.c. into nude mice. TGCTA1-transfected FRTL-5 cells grow in nude mice, whereas control cells do not. Tumor histology revealed increased mitotic activity, infiltration of skeletal muscle, perineural invasion, and plugging of lymphatic spaces. In addition, nude mice injected with TGCTA1 transfected cells or xenografted with the tumors developed metastases to lung. These results indicate that activation of G(s)alpha and constitutive production of cAMP in FRTL-5 cells can result in TSH-independent cellular proliferation and neoplastic transformation.

Increased cyclic adenosine 3',5'-monophosphate inhibits G protein-coupled activation of phospholipase C in rat FRTL-5 thyroid cells.

Thyroid cell growth and function are regulated by several hormones and growth factors that bind to cell surface receptors coupled via G proteins, Gs and Gq, to stimulation of adenylyl cyclase and phospholipase C (PLC), respectively. We created a permanently transfected FRTL-5 cell line (TG8) in which the thyroglobulin gene promoter directs expression of the cholera toxin (CT) A1 subunit (CTA1). CTA1 catalyzes ADP ribosylation of Gs alpha, which results in persistent activation of Gs alpha. Activated Gs alpha causes constitutive stimulation of adenylyl cyclase and increases levels of intracellular cAMP. Because G protein-coupled signaling pathways exhibit cross-talk, we compared TG8 cells to FRTL-5 cells transfected with the neomycin resistance gene (TG4) to determine whether constitutive stimulation of adenylyl cyclase influences the PLC pathway. PLC activity was assessed by measuring levels of total inositol phosphates (IPs) in TG4 and TG8 cells that had been preincubated with myo-[3H]inositol for 2 days. Baseline values of [3H]IP production were similar for the two cell lines. Incubation of TG4 control cells with 10(-8) M TSH, 300 microM ATP, and 100 microM norepinephrine for 60 min stimulated 2.5-, 8.1-, and 3.4-fold increases, respectively, in [3H]IP production over the control value. By contrast, there was no [3H]IP response to any of these ligands in TG8 cells. TG8 cells exhibit a decrease in [35S]adenosine 5'-(gamma-thio)triphosphate binding to their cell surface compared to TG4 control cells counterparts, but no decrease in [125I]TSH binding. Treatment of TG4 cells with 100 ng/ml CT, 50 microM forskolin, or 1 mM 8-bromo-cAMP for 2 days reproduced the loss of ligand-stimulated [3H]IP synthesis present in TG8 cells. Although levels of immunoreactive Gq alpha and Gq alpha 11 were normal in TG8 cells, sodium fluoride-induced [3H]IP production was also inhibited. Levels of immunoreactive PLC beta 3, the dominant subtype of PLC beta in FRTL-5 cells, were not altered in TG8 cells or by CT treatment of TG4 cells. These data indicate that elevated levels of cAMP can inhibit the activity of G protein-coupled PLC. Further study of this model will elucidate our understanding of the exact mechanism responsible for this interaction.

Antithyroid peroxidase autoantibodies in thyroid diseases.

Thyroid microsomal antibodies (anti-M Ab) have been recently proven to be directed to thyroid peroxidase (TPO). Methods to detect anti-TPO antibodies (anti-TPO Ab) employing purified antigen have been developed, but the available information on the clinical usefulness of this technique is still limited to small patient series. In the present investigation anti-TPO Ab were assayed by a newly developed monoclonal antibody-assisted RIA in a large number (n = 715) of subjects, including 119 normal controls and 596 patients with different autoimmune or nonautoimmune thyroid disease: Anti-TPO Ab were detected in 10 of 119 (8.4%; range, 11-210 U/mL) normal controls, 134 of 181 (74%; range, 11-74.000 U/mL) patients with Graves' disease, all but 1 of 144 (99.3%; range, 11-90.000 U/mL) with Hashimoto's thyroiditis (n - 98) or idiopathic myxedema (n = 46), 20 of 180 (11.1%; range, 11-6.700 U/mL) with miscellaneous nonautoimmune thyroid diseases, 16 of 83 (19.2%; range, 11-6.600 U/mL) patients with differentiated thyroid carcinoma, and in none of 8 patients with subacute thyroiditis. The highest anti-TPO Ab concentrations were found in untreated hypothyroid Hashimoto's thyroiditis, but no simple relationship between anti-TPO Ab levels and thyroid function was observed. Anti-TPO Ab significantly decreased in patients with Graves' disease after treatment with methimazole and in those with hypothyroid Hashimoto's thyroiditis or idiopathic myxedema during L-T4 administration. A highly significant positive correlation (r = 0.979; P less than 0.001) was found between anti-M Ab titers by passive hemagglutination (PH; available in 650 sera) and the corresponding average anti-TPO Ab by RIA; discrepant results were almost exclusively limited to sera with negative or low (1:100-1:400) anti-M Ab titers. Analysis of these discrepant data indicated higher autoimmune disease specificity and sensitivity of anti-TPO Ab RIA tests compared to anti-M Ab by PH. Absorption studies showed that interference of anti-Tg Ab was responsible for anti-M Ab-positive tests in occasional anti-TPO Ab-negative/anti-M Ab-positive sera from autoimmune thyroid disease patients. Anti-TPO Ab determination by RIA was unaffected by circulating thyroglobulin concentrations up to more than 10,000 ng/mL. In conclusion, anti-TPO Ab assay by monoclonal antibody-assisted RIA appears to be more sensitive and specific for thyroid autoimmune diseases than anti-M Ab determination by PH. Since the assay is easy to perform and employs only tracer amounts of purified antigen, these characteristics should allow its rapid diffusion to the clinical routine.

Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal?

Measurement of thyroglobulin (Tg) in serum with anti-Tg autoantibodies (TgAb) represents a difficult challenge. Immunoradiometric assays (IRMA) employing monoclonal anti-Tg antibodies not cross-reacting with endogenous TgAb have recently been developed and proposed for Tg assays in TgAb-positive sera. The aim of the present investigation was to assess the clinical reliability of this approach. Assays of serum Tg in patients with and without TgAb using one such monoclonal antibody IRMA (Thyroglobulin IRMA-Pasteur; IRMA-1) were compared with those obtained by a conventional IRMA employing polyclonal anti-Tg antibodies (HTGK-Sorin; IRMA-2). Preliminary studies for assessment of the interference of TgAb showed that the recovery of added Tg was significantly higher (P < 0.01) when determined by IRMA-1 (64.6 +/- 23%) than by IRMA-2 (49.5 +/- 20%). Study groups included 79 patients with differentiated thyroid carcinoma (DTC) treated by total thyroidectomy and radioiodine ablation; 24 had no metastases or residual thyroid tissue, 31 had a thyroid residue, and 24 had metastatic disease. Seventy-five patients with autoimmune thyroid disease (47 with Graves' and 28 with Hashimoto's disease) were also included. In TgAb-negative sera from DTC patients, similar Tg concentrations were found by both IRMA, i.e. undetectable in most patients with no residual thyroid or neoplastic tissue, low to moderately elevated in the majority of those with residual thyroid tissue, and markedly elevated in all patients with metastatic disease. Serum Tg was undetectable by both assays in several TgAb-positive sera from DTC patients with residual thyroid tissue or metastatic disease, respectively, in whom a detectable or even high serum Tg concentration was expected. Despite the lower in vitro interference of TgAb in IRMA-1, there was no difference between the two assays. In the group of patients with thyroid autoimmune disease, serum Tg concentrations were found to be high in TgAb-negative sera and much lower in TgAb-positive sera by both IRMAs. In conclusion, the present study demonstrates that the use of a monoclonal antibody IRMA for serum Tg, although less susceptible to in vitro TgAb interference, does not necessarily provide any substantial advantage with respect to a conventional polyclonal IRMA in detecting Tg in TgAb-positive sera. The finding of undetectable or lower than expected serum Tg by either method in TgAb-positive serum may well reflect a truly reduced serum Tg concentration. This might be due to an accelerated Tg metabolic clearance in the presence of TgAb.(ABSTRACT TRUNCATED AT 400 WORDS)

Complex alteration of thyroid function in healthy centenarians.

Several changes in thyroid function have been described in the elderly and largely attributed to concomitant nonthyroidal illness. The extent to which aging per se contributes to these changes remains to be elucidated, and scanty data are available in extremely old subjects. The present study was designed to focus on thyroid function during physiological aging, taking advantage of two groups of selected aged individuals: group A of healthy centenarians (n = 41; age range, 100-110 yr) and group B including healthy elderly subjects selected by the criteria of the EURAGE SENIEUR protocol (n = 33; age range, 65-80 yr). Control groups included 98 healthy normal adult subjects (group C; age range, 20-64 yr) and 52 patients with miscellaneous nonthyroidal illness (group D; age range, 28-82 yr). Our previous report of a low prevalence of thyroid autoantibodies in centenarians was confirmed and extended by the finding of a similar low autoantibody prevalence in the highly selected healthy elderly population of group B. Subclinical primary hypothyroidism was found in 3 (7.3%) centenarians, and their data were excluded from further statistical evaluation. No significant difference was found in the median serum free T4 levels of groups A-C. Median (and range) serum free T3 (FT3) was lower in centenarians [3.67 pmol/L (2.3-5.5)] than in group B [5.22 pmol/L (3.4-6.1)] and group C [5.38 pmol/L (2.9-8.4); P < 0.0001 vs. both groups]. Similarly, the median serum TSH level of centenarians [0.97 mU/L (< 0.09 to 2.28)] was lower than those in groups B [1.17 mU/L (0.53-2.74)] and C [1.7 mU/L (0.4-4.8); P < 0.0001 vs. both groups]; moreover, serum TSH was also significantly (P < 0.01) lower in group B than in group C. Both serum FT3 and TSH concentrations showed a significant inverse correlation (r = -0.634; P < 0.0001 and r = -0.377; P < 0.0001, respectively) with age. Median serum FT3 in centenarians was lower than that in group D patients [4.61 pmol/L (2.15-6.6); P < 0.0001]. In contrast, median serum rT3 in centenarians [0.40 nmol/L (0.20-0.77)], although higher than those in groups B [0.24 nmol/L (0.15-0.37); P < 0.0001] and C [0.22 nmol/L (0.05-0.46); P < 0.0001], was significantly lower than that in group D [0.60 nmol/L (0.13-2.08); P < 0.0001]. In conclusion, thyroid function appears to be well preserved until the eighth decade of life if healthy subjects are studied, whereas a reduction of serum FT3 is observed in extreme aging.(ABSTRACT TRUNCATED AT 400 WORDS)

False negative results observed in anti-thyroid peroxidase autoantibody determination by competitive radioimmunoassays using monoclonal antibodies.

OBJECTIVE: Anti-thyroid peroxidase autoantibody (anti-TPO) and anti-thyroid microsomal antibody (anti-M) are strictly related, but discrepancies are sometimes observed. The aim of this study was to assess the incidence and to identify the causes of these discrepancies. DESIGN AND ANTIBODY MEASUREMENTS: Anti-M by passive hemagglutination and anti-TPO by two competitive monoclonal antibody-assisted radioimmunoassays (RIA-1 and RIA-2) were measured in 10,103 sera from 4232 subjects (663 male, 3569 female) screened for thyroid disease. RESULTS: Anti-TPO and anti-M correlated quite well (r = 0.7 and p < 0.0001 by RIA-1: r = 0.74 and p < 0.0001 by RIA-2), with discrepancies mostly limited to sera with low antibody titers. After exclusion of the latter samples, anti-TPO were detected in only 79 (1.4%) out of 5317 anti-M negative sera, but were undetectable in a more consistent proportion (130/2880 = 4.5%) of sera from patients with autoimmune thyroid disease and positive anti-M. In 61 sera of the latter group, anti-TPO was measured by a non-competitive RIA (RIA-3). Forty-one (67.7%) were positive by RIA-3, suggesting the presence of anti-TPO not competing with the monoclonal antibodies of RIA-1 and RIA-2. The remaining 20 sera had undetectable anti-TPO also by RIA-3. Nineteen (95%) of these sera had positive anti-thyroglobulin (anti-Tg) autoantibody and preincubation with thyroglobulin inhibited the agglutination reaction of anti-M tests. CONCLUSION: Anti-TPO by competitive monoclonal antibody-assisted RIA is negative in a minority of sera of patients with autoimmune thyroid disease and positive anti-M. This could be accounted for by anti-Tg producing false positives in the anti-M assay and by a subset of anti-TPO not competing with the monoclonal antibodies in the RIA. When autoimmune thyroid disease is suspected on clinical grounds, a negative anti-TPO test with a competitive RIA should be confirmed always by a non-competitive assay.

Epitopes on thyroglobulin: a study of patients with thyroid disease.

Thyroglobulin antibodies (TgAbs) are typically found in autoimmune thyroid diseases and, more rarely, in nonautoimmune thyroid diseases and healthy subjects. To determine whether TgAbs associated with different conditions recognize different epitopes on the thyroglobulin molecule, we studied 28 patients with Hashimoto's thyroiditis, 30 with Graves' disease, 21 with thyroid carcinoma, 18 with nontoxic goiter, and 25 healthy subjects. All patients were selected for the presence of TgAbs; 4/25 healthy subjects also had TgAbs. The sera were assayed for the their ability to inhibit the binding of monoclonal antibodies to thyroglobulin in an ELISA assay. We found that: 1) TgAbs in Hashimoto's patients preferentially recognized three clusters of epitopes (II, III and typically VI), with no difference between the goitrous and the atrophic variants; 2) TgAbs in Graves' patients were directed toward cluster II, with no difference between the presence or the absence of ophthalmopathy; 3) TgAbs in thyroid carcinoma patients recognized the same clusters as Hashimoto's patients; 4) TgAbs in nontoxic goiter patients and in the four healthy subjects showed no restriction in epitope recognition. We suggest that in individuals with no overt clinical or biochemical thyroid abnormalities but with TgAbs, the finding that these TgAbs recognize particular immunodominant clusters may be utilized to predict full-blown thyroid disorders. Longitudinal studies are needed to evaluate the possible clinical application of this methodology.

[Radiometabolic therapy of the autonomous thyroid nodule]. / Terapia radiometabolica del nodulo tiroideo autonomo.

The aim of this paper is to synthetically focus on current views on the use of radioiodine for the treatment of hyperthyroidism in single autonomously functioning thyroid nodules (AFN). Radioiodine administration represents a simple and effective alternative to surgical ablation of AFN, especially in elderly patients with small nodules (< 3 cm diameter). Radioiodine is very selectively accumulated in the thyroid, where it can deliver its energy without virtually affecting any other organ. Since its first use in 1942, 131I is (as Na131I) still the radioisotope of choice, due to easy availability and to its peculiar physical characteristics. These include a short half-life (8 days) and a spectrum of radiation (mainly of the beta type) with an optimal energy delivery in the nodule and with low penetration in the surrounding tissue. The effectiveness of radioiodine administration in permanently correcting hyperthyroidism in AFN has been demonstrated in many studies and may reach 80% with a single dose administration. The optimal dose has not been completely defined, but may be empirically calculated taking into account the weight of the nodule (evaluated by scintiscan or ultrasound) and the radioiodine uptake after 24 hours. In our and in many other institutions, indications to radioiodine treatment are currently the following: age > 35-40 years, diameter of the nodule < 3 cm and/or serious general diseases contraindicating surgical treatment. The only absolute contraindication to radioiodine treatment is pregnancy, due to the possible mutagenic effects on the foetus and to the extreme sensitivity of the foetal thyroid to radioiodine after the 10th week of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Methodological approach and diagnostic usefulness of a new assay for anti-thyroid peroxidase autoantibodies.

Although thyroid microsomal antibodies (anti-MAb) have been recently proven to be directly to thyroid peroxidase (TPO), current methods for MAb detection still employ unpurified microsomal fractions. The authors have therefore developed and evaluated a specific radioimmunoassay (RIA) for autoantibodies to TPO (anti-TPO Ab) based on competitive inhibition of 125I-TPO to an anti-TPO monoclonal antibody coated on plastic microtiter wells (RIA-1) or tubes (RIA-2). Preliminary experiments showed that both assays were able to specifically detect anti-TPO Ab, while negative results were obtained with normal sera and with sera containing other organ- and non-organ-specific autoantibodies including anti-thyroglobulin antibodies (anti-TgAb). No significant difference in sensitivity, specificity and reproducibility was found between RIA-1 and RIA-2, and the results obtained with the two techniques were therefore pooled together. Anti-TPO Ab were then assayed in 110 normal controls and in 441 patients with different autoimmune (AITD) or non-autoimmune (N-AITD) thyroid diseases and compared to anti-M Ab as assessed by passive hemagglutination (PH). Positive anti-TPO Ab were observed in 4/110 (3.6 p. cent) normal controls, 88/117 (80 p. cent) patients with Graves' disease, 122/123 with Hashimoto's thyroiditis or idiopathic myxedema and 21/201 (10.4 p. cent) with miscellaneous N-AITD. A highly significant positive correlation (r = 0.91, p less than 0.0001) was found between anti-MAb by PH and anti-TPO Ab by RIA ;discrepant results were limited to sera with negative or low (1/100-1/400) anti-M Ab titers.(ABSTRACT TRUNCATED AT 250 WORDS)

Hashimoto thyroiditis: clinical and diagnostic criteria.

Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment.

Application of innate immune molecules for a new class of drugs: infection, inflammation and beyond.

The innate immune system plays an important role systemically and locally in infectious and inflammatory diseases. Vaccines, vaccine adjuvants and anti-inflammatory drugs were developed by understanding mechanisms of the innate immune system and causative factors of infection and inflammatory diseases. Pattern-recognition receptors, such as Toll-like receptors, retinoic acid-inducible gene I (RIG-I)-like helicases and nucleotide-binding oligomerization domain(NOD)-like receptors, and their downstream signals have great potential as targets of therapeutics because they are involved in numerous diseases. Furthermore, proteolytic systems such as autophagy and immunoproteasomes play important roles in the innate immune system, making them potential therapeutic targets also. By taking advantage of the immune system, humankind has made a great effort to develop new therapeutic and preventive medicines. Accordingly, we have reported several studies on the development of vaccines and adjuvants based on novel mechanistic strategies. Additionally, we have elucidated the mechanism underlying an interaction between innate immunity and the endocrine system. This review introduces the possible use of innate immune molecules for the development of immunomodulatory drugs and the involvement of the immune system in endocrine metabolic diseases to discuss future applications of innate immune molecules to therapeutics of various inflammatory diseases.