help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Spitzweg, C.
Right arrow Articles by Heufelder, A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Spitzweg, C.
Right arrow Articles by Heufelder, A. E.
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 4178-4184
Copyright © 1999 by The Endocrine Society

Original Studies

Analysis of Human Sodium Iodide Symporter Immunoreactivity in Human Exocrine Glands1

C. Spitzweg, W. Joba, K. Schriever, J. R. Goellner, J. C. Morris and A. E. Heufelder

Departments of Endocrinology (C.S., J.C.M.) and Pathology (J.R.G.), Mayo Clinic, Rochester, Minnesota 55905; and the Division of Gastroenterology, Endocrinology, and Metabolism, Zentrum für Innere Medizin, Philipps-University, D-35033 Marburg, Germany

Address all correspondence and requests for reprints to: Dr. Christine Spitzweg, Mayo Clinic, Endocrine Research Unit, Guggenheim 625, 200 First Street SW, Rochester, Minnesota 55905. E-mail: spitzweg.christine{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The human sodium iodide symporter (hNIS) is an intrinsic transmembrane protein that mediates the active transport of iodide across the basolateral membrane of thyroid follicular cells. In addition to normally functioning thyroid tissue, various extrathyroidal tissues, including salivary gland, lacrimal gland, gastric mucosa, choroid plexus, and lactating mammary gland, have been demonstrated to accumulate iodide. After cloning and molecular characterization of the sodium iodide symporter, expression of hNIS messenger ribonucleic acid has been detected in a broad range of extrathyroidal tissues using Northern blot analysis and RT-PCR. In this study we used both monoclonal and polyclonal antibodies directed against different portions of hNIS protein together with a highly sensitive immunostaining technique to assess hNIS protein expression in tissue sections derived from normal human salivary and lacrimal glands, pancreas, as well as gastric and colonic mucosa. Immunohistochemical analysis of normal human salivary and lacrimal glands revealed marked hNIS immunoreactivity in ductal cells and less intense staining of acinar cells. Further, immunostaining of gastric and colonic mucosa showed marked hNIS immunoreactivity confined to chief and parietal cells in gastric mucosa and to epithelial cells lining mucosal crypts in colonic mucosa. In normal human pancreas, hNIS immunoreactivity was located in ductal cells, exocrine parenchymal cells, and Langerhans islet cells. In conclusion, our study demonstrates the expression of hNIS protein by several human exocrine glands, suggesting that iodide transport in these glands is a specific property conferred by the expression of hNIS protein, which may serve important functions by concentrating iodine in glandular secretions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IODIDE UPTAKE across the basolateral membrane is a characteristic feature of normal thyroid follicular cells and is driven by the recently cloned and characterized human sodium iodide symporter (hNIS), an intrinsic membrane protein with 13 putative transmembrane domains (1, 2, 3, 4, 5, 6, 7, 8). In addition to the potent iodide-concentrating activity of the thyroid gland, weaker iodide uptake has been demonstrated in a variety of nonthyroidal tissues, including salivary and lacrimal glands, gastric mucosa, lactating mammary gland, choroid plexus, ciliary body of the eye, skin, placenta, and thymus (1, 9). Although not transported in a TSH-dependent manner, several data suggest that iodide is organified by certain extrathyroidal tissues (10, 11). In mammary gland, iodide has been shown to be organified by binding to caseins and other milk proteins in correlation with peroxidase activity (12, 13, 14). In addition, thyroidal and nonthyroidal iodide transport activities share several functional similarities, such as inhibition by thiocyanate and perchlorate as well as generation of iodide concentration gradients of similar magnitude (1). Using RT-PCR, Smanik et al. have demonstrated hNIS messenger ribonucleic acid (mRNA) expression in breast, colon, and ovary, suggesting that hNIS may mediate iodide uptake by these extrathyroidal tissues (6). Recently, using Northern blot analysis and RT-PCR followed by Southern hybridization, we demonstrated hNIS RNA expression in several extrathyroidal tissues, including parotid and submandibular gland, pancreas, testis, mammary gland, gastric mucosa, prostate and ovary, adrenal gland, heart, lung, and thymus (15). In addition, amplification and cloning of the hNIS gene coding region from parotid gland, mammary gland, and gastric mucosa revealed that the relatively low iodide transport and concentration by these extrathyroidal tissues does not result from an altered primary structure of the hNIS complementary DNA, suggesting differences in hNIS gene transcriptional activity (15).

The recent availability of high affinity anti-hNIS antibodies (4, 16, 17, 18) now offers the possibility to examine the expression of hNIS in extrathyroidal tissues on the protein level. Levy et al. have recently demonstrated extrathyroidal expression of NIS protein in the plasma membrane of rat mammary epithelial cells derived from lactating mammary gland (4). Further, using a polyclonal hNIS antibody, Jhiang et al. have shown hNIS immunoreactivity in ductal cells of salivary gland (17). We used both a monoclonal and a polyclonal antibody directed against different portions of the hNIS protein to assess hNIS immunoreactivity in several human exocrine glands.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Immunohistochemical staining

Immunohistochemical staining was performed using the Vectastain Elite ABC Kit (Vector Laboratories, Inc., Burlingame, CA). Paraffin-embedded tissue sections derived from human Graves’ thyroid tissue, normal human lacrimal gland, stomach, pancreas, colon, uterus, bladder, and tongue were subjected to a graded series of alcohols and pretreated by heating in citrate buffer (10 mmol/L citric acid) for 30 min. Frozen tissue sections derived from normal human salivary glands were fixed by incubation in cold acetone for 10 min. After inhibition of endogenous peroxidase activity and blocking of nonspecific binding with blocking serum for 30 min, slides were incubated with hNIS antibodies at predetermined optimal concentrations for 90 min at room temperature. Mouse monoclonal hNIS antibody (directed against amino acid residues 468–643 of hNIS) was applied at a dilution of 1:1600 (16). Rabbit polyclonal hNIS antibody (directed against amino acid residues 262–280 of hNIS) was applied at a dilution of 1:800. These antibodies have been characterized and demonstrated to specifically recognize hNIS by Western blotting and immunohistochemical staining (16).

Tissue sections were washed with phosphate-buffered saline (PBS) and incubated with biotin-conjugated antimouse and antirabbit Igs, respectively, for 1 h at room temperature, followed by incubation with preformed avidin and biotinylated horseradish peroxidase macromolecular complex. Diaminobenzidine was used as the chromogen and yielded a bluish-black precipitate indicative of hNIS-specific immunoreactivity. Tissue sections were counterstained with malachite green for 5 min before mounting. Parallel tissue sections with the primary and secondary antibody replaced, in turn, by PBS and isotype-matched nonimmune IgGs (Sigma Chemical Co., Deisenhofen, Germany) were routinely examined to ensure specificity and to exclude cross-reactivities between the antibodies and conjugates employed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Immunohistochemistry

Immunostaining of paraffin-embedded tissue sections derived from Graves’ thyroid tissue using rabbit polyclonal hNIS antibody revealed hNIS-specific immunoreactivity confined to the basolateral membrane of thyroid follicular cells (Fig. 1Go). Further, immunostaining of paraffin-embedded tissue sections derived from normal human lacrimal gland using each of the two hNIS antibodies revealed distinct hNIS immunoreactivity, which was concentrated at the basolateral membrane of interlobular ductal cells and less intense in acinar cells (Fig. 2Go). In frozen tissue sections derived from normal human salivary glands, marked distinct hNIS immunoreactivity was present in ductal cells and to a lesser extent in acinar cells (Fig. 3Go). In addition, paraffin-embedded tissue sections derived from normal human colon showed hNIS-specific immunoreactivity confined to epithelial cells lining mucosal crypts (Fig. 4Go). Immunostaining of paraffin-embedded tissue sections derived from normal human gastric mucosa showed hNIS-specific immunoreactivity confined to parietal cells and to chief cells at the base of gastric glands (Fig. 5Go). Paraffin-embedded tissue sections derived from normal human pancreas revealed strong hNIS immunoreactivity in pancreatic islet cells. Weaker staining was noted in ductal cells and exocrine parenchymal cells (Fig. 6Go). Parallel control sections of each tissue stained with primary and secondary antibodies replaced, in turn, by PBS and isotype-matched nonimmune IgGs were consistently negative ( Figs. 2–5GoGoGoGo). Immunostaining of paraffin-fixed sections of several human control tissues, including uterus, bladder, and tongue was negative (data not shown).



View larger version (160K):
[in this window]
[in a new window]
  		Figure 1. Immunohistochemical staining using rabbit polyclonal hNIS antibody of paraffin-embedded Graves’ thyroid tissue (original magnification, x200). HNIS immunoreactivity is confined in thyroid follicular cells and concentrated at the basolateral membrane.

 


View larger version (107K):
[in this window]
[in a new window]
  		Figure 2. Immunostaining of paraffin-embedded tissue sections derived from normal human lacrimal gland using mouse monoclonal hNIS antibody (original magnification: A, x100; B, x200) and rabbit polyclonal hNIS antibody (original magnification: C, x200), respectively. Marked hNIS immunoreactivity is detected in ductal cells (large arrows), and weaker staining is present in acinar cells (small arrows). Parallel control sections using isotype-matched nonimmune IgGs were negative (original magnification: D, x100; E, x200).

 


View larger version (131K):
[in this window]
[in a new window]
  		Figure 3. Immunostaining of frozen tissue sections derived from normal human salivary gland using mouse monoclonal hNIS antibody (original magnification: A and B, x 100) and rabbit polyclonal hNIS antibody (original magnification: C, x100), respectively. Marked distinct hNIS immunoreactivity is detected in ductal cells, and weaker staining is present in acinar cells. Parallel control sections with isotype-matched nonimmune IgG were negative (original magnification: D, x200).

 


View larger version (108K):
[in this window]
[in a new window]
  		Figure 4. Immunostaining of paraffin-embedded tissue sections derived from normal human colon using mouse monoclonal (A) and rabbit polyclonal (B) hNIS antibodies, respectively. Strong hNIS immunoreactivity is detected in epithelial cells lining mucosal crypts. Parallel control sections with isotype-matched nonimmune IgG were negative (original magnification: C, x400).

 


View larger version (94K):
[in this window]
[in a new window]
  		Figure 5. Immunostaining of paraffin-embedded tissue sections derived from normal human gastric mucosa using mouse monoclonal hNIS antibody (original magnification: A, x100) and rabbit polyclonal hNIS antibody (original magnification: B, x200), respectively. HNIS immunoreactivity is confined to parietal and chief cells at the base of gastric glands. Parallel control sections with isotype-matched nonimmune IgG were negative (original magnification: C, x400).

 


View larger version (77K):
[in this window]
[in a new window]
  		Figure 6. Immunostaining of paraffin-embedded tissue sections derived from normal human pancreas using mouse monoclonal hNIS antibody (original magnification: A, x200) and rabbit polyclonal hNIS antibody (original magnification: B, x400), respectively. Strong hNIS immunoreactivity is detected in pancreatic islet cells (A), and weaker staining is noted in ductal cells and exocrine parenchymal cells (B). Parallel control sections with isotype-matched nonimmune IgG were negative.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The sodium iodide symporter (hNIS) is an intrinsic membrane protein that catalyzes iodide uptake by thyroid follicular cells, thereby providing iodide as a substrate for thyroid hormone synthesis (1). The recent cloning and characterization of hNIS followed by generation of high affinity antibodies directed against the hNIS protein has facilitated analysis of hNIS protein expression, distribution, and cellular localization in thyroidal and nonthyroidal tissues (1, 2, 3, 4, 5, 6, 7, 8, 16, 17, 18, 19). Iodide transport in nonthyroidal tissues such as choroid plexus, ciliary body of the eye, salivary glands, and gastric mucosa is known to be mediated by an active iodide translocating system that maintains an iodide gradient between secreted fluid and serum (1). Several previous reports have suggested that extrathyroidal iodide transport may be driven by a transport protein similar to hNIS (1). We have recently demonstrated that hNIS mRNA is present in a variety of extrathyroidal tissues such as salivary glands (parotid and submandibular gland), gastric mucosa, and pancreas (15). Using a polyclonal hNIS antibody, Jhiang and colleagues have also demonstrated hNIS protein expression in ductal cells of salivary glands (17).

Radioiodine uptake is frequently observed in salivary glands when performing radioiodine whole body scintigraphy as part of the management of patients with differentiated thyroid cancer (20). In addition, uptake of radioiodine has been reported in the lacrimal sac of a patient with dacrocystitis (21) and in the orbital cavity of a patient with an artificial eye (21), suggesting that radioiodine may be secreted into tear fluid. Recently, significant quantities of radioiodine have been detected in tear samples obtained from a thyroid-ablated patient after ingestion of radioiodine (22). Accumulation of radioiodine by salivary and lacrimal glands may cause substantial damage to these glands, as shown by reports of significant dose-related salivary and lacrimal gland dysfunction in a majority of thyroid cancer patients after treatment with radioiodine (23, 24). In support of these clinical observations and our previous hNIS mRNA data, we now demonstrate that hNIS protein is predominantly expressed by ductal cells of lacrimal and salivary glands. Exocrine glands consist of a secretory portion containing acinar cells responsible for the secretory process as well as ductal cells specialized in ion transport, which transport the secretions to the exterior of the gland. Predominant expression of hNIS protein by salivary and lacrimal gland ductal cells suggests that hNIS is involved in active iodine transport in the ducts of these exocrine glands and in the pathogenesis of salivary and lacrimal gland dysfunction following radioiodine therapy (23, 24).

Iodide has been reported to be actively transported from plasma to gastric secretions by an iodide-translocating system, thus providing a higher iodide concentration in gastric secretions than in serum (1). There is evidence that iodide is also secreted in the colon (25). As with salivary and lacrimal glands discussed above, radioiodine uptake by the gastrointestinal tract, including gastric mucosa and colon, is a common finding when performing whole body scintigraphy in patients with thyroid cancer after thyroidectomy (20) and may play a role in some of the gastrointestinal side-effects associated with radioiodine therapy (26). In view of these clinical features, detection of hNIS immunoreactivity in gastric and colonic mucosa in our current study suggests that NIS may mediate iodide transport in the gastrointestinal tract. Inorganic iodide secreted by exocrine glands such as salivary and lacrimal glands and gastric and colonic mucosa followed by oxidation to hypoiodite may act as an antimicrobial agent, offering mucosal protection against environmental microorganisms (27).

Early investigations of accumulation and distribution of 125I and 131I in various body tissues of the pig have revealed marked radioiodine concentration by pancreatic acini and islets of Langerhans, in particular, ß-cells (28). We detected marked hNIS immunoreactivity in islet cells of normal human pancreatic tissue and to a lesser extent in ductal cells and parenchymal cells. Collectively, these data suggest that radioiodine accumulation may be a specific property of pancreatic cells that is conferred by the expression of hNIS protein.

Iodide organification is essential for a possible functional activity of trapped iodide in nonthyroidal tissues. In fact, several reports have suggested that organification of iodide occurs outside of the thyroid gland (10, 11). In addition to thyroid peroxidase, peroxidases in extrathyroidal tissues such as lacto-, myelo-, and eosinophil peroxidase have been demonstrated to organify iodide (29). In addition, iodide organification has been correlated with peroxidase activity, and the possibility of pituitary-derived TSH controlling iodination in mammary tissue has been raised (11, 12, 13, 14). These data support the idea that organification of iodide is not restricted to thyroid tissue. Possible functions of trapped and organified iodide in nonthyroidal tissues may include antiproliferative and antioxidative effects, as demonstrated for certain iodolipids in the thyroid gland (30). Interestingly, early studies in animals have shown that breast dysplasia and neoplasia are associated with iodine deficiency and can be prevented by the addition of iodine (11). Further investigations will have to assess extrathyroidal peroxidase activity and iodide organification, its hormonal regulation, and possible physiological roles.

Since the cloning of hNIS, several studies have suggested that, in addition to TSHR, thyroperoxidase, and thyroglobulin, hNIS may act as a potential autoantigen in autoimmune thyroid disease. Sera from patients with autoimmune thyroid disease, including Hashimoto’s thyroiditis and Graves’ disease, have been reported to contain antibodies directed against NIS (31, 32, 33, 34, 35). Autoimmune thyroid disease is often associated with extrathyroidal autoimmune diseases such as pernicious anemia and Sjoegren’s syndrome, which is characterized by progressive immune-mediated destruction and dysfunction of salivary and lacrimal glands (36, 37, 38). In addition, patients who suffer from Sjoegren’s syndrome frequently exhibit hypochlorhydria, atrophic gastritis, and chronic pancreatic insufficiency. Up to 50% of patients with Sjoegren’s syndrome have been reported to develop autoimmune thyroid disease, and, conversely, approximately one third of patients with autoimmune thyroid disease report xerophthalmia and xerostomia, symptoms characteristic of Sjoegren’s syndrome (36). The close clinical association of autoimmune thyroid disease, Sjoegren’s syndrome, and pernicious anemia; the identification of hNIS as a potential autoantigen in the pathogenesis of autoimmune thyroid disease; and the expression of hNIS protein by several target tissues (salivary glands, lacrimal gland, stomach, and pancreas) suggest that hNIS may act as a shared target antigen for cross-reacting T cells and autoantibodies. As hNIS protein expression is also detected in pancreatic islet cells, it may be hypothesized that a role for hNIS as a shared autoantigen may extend to polyglandular autoimmune syndromes, which commonly involve organs such as thyroid, stomach, and pancreas. Future studies will have to address these possibilities and to examine the functional and immunological relevance of hNIS expressed by extrathyroidal tissues.


   Footnotes
 
1 This work was supported in part by grants [to A.E.H. (HE1485/5–2 and HE1485/5–3) and to C.S. (Sp 581/1–1)] from Deutsche Forschungsgemeinschaft, Bonn, Germany. Back

Received February 9, 1999.

Revised July 13, 1999.

Accepted July 25, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Carrasco N. 1993 Iodide transport in the thyroid gland. Biochim Biophys Acta. 1154:65–82.[Medline]
  2. Dai G, Levy O, Carrasco N. 1996 Cloning and characterization of the thyroid iodide transporter. Nature. 379:458–460.[CrossRef][Medline]
  3. Endo T, Kaneshige M, Nakazato M, Ohmori M, Harii N, Onaya T. 1997 Thyroid transcription factor-I activates the promoter activity of rat thyroid Na+/I- symporter gene. Mol Endocrinol. 11:1747–1755.[Abstract/Free Full Text]
  4. Levy O, Vieja A, Carrasco N. 1998 The Na+/I- symporter (NIS): recent advances. J Bioenerget Biomembr. 30:195–206.[CrossRef][Medline]
  5. Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM. 1996 Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun. 226:339–345.[CrossRef][Medline]
  6. Smanik PA, Ryu K-Y, Theil KS, Mazzaferri EL, Jhiang SM. 1997 Expression, exon-intron organization, and chromosome mapping of the human sodium iodide symporter. Endocrinology. 138:3555–3558.[Abstract/Free Full Text]
  7. Spitzweg C, Heufelder AE. 1997 Update on the thyroid sodium iodide symporter: a novel thyroid antigen emerging on the horizon. Eur J Endocrinol. 137:22–23.[CrossRef][Medline]
  8. Spitzweg C, Heufelder AE. 1998 The sodium iodide symporter: its emerging relevance to clinical thyroidology. Eur J Endocrinol. 138:374–375.[CrossRef][Medline]
  9. Brown-Grant K. 1961 Extrathyroidal iodide concentrating mechanisms. Physiol Rev. 41:189–213.[Free Full Text]
  10. Evans ES, Schooley RA, Evans AB, Jenkins CA, Taurog A. 1966 Biological evidence for extrathyroidal thyroxine formation. Endocrinology. 78:983–1001.[Abstract/Free Full Text]
  11. Eskin B. 1970 Iodine metabolism and breast cancer. Trans NY Acad Sci. 32:911–947.[Medline]
  12. Strum JM. 1978 Site of iodination in rat mammary gland. Anat Rec. 192:235–244.[CrossRef][Medline]
  13. Strum JM, Phelps PC, McAtee MM. 1983 Resting human female breast tissue produces iodinated proteins. J Ultrastruc Res. 84:130–139.[CrossRef][Medline]
  14. Shah NM, Eskin BA, Krouse TB, Sparks CE. 1986 Iodoprotein formation by rat mammary glands during pregnancy and early postpartum period. Proc Soc Exp Biol Med. 181:443–449.[CrossRef][Medline]
  15. Spitzweg C, Joba W, Eisenmenger W, Heufelder AE. 1998 Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa. J Clin Endocrinol Metab. 83:1746–1751.[Abstract/Free Full Text]
  16. Castro RM, Bergert ER, Beito TG, et al. 1999 Monoclonal antibodies against the human sodium iodide symporter: utility for immunocytochemistry of thyroid cancer. J Endocrinol. In press.
  17. Jhiang SM, Cho J-Y, Ryu K-Y, et al. 1998 An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology. 139:4416–4419.[Abstract/Free Full Text]
  18. Saito T, Endo T, Kawaguchi A, et al. 1998 Increased expression of the sodium/iodide symporter in papillary thyroid carcinomas. J Clin Invest. 101:1296–1300.[Medline]
  19. Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T. 1997 Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves’ thyroid tissue. J Clin Endocrinol Metab. 82:3331–3336.[Abstract/Free Full Text]
  20. McDougall R. 1995 Whole-body scintigraphy with radioiodine-131. A comprehensive list of false-positives with some examples. Clin Nucl Med. 20:869–875.[CrossRef][Medline]
  21. Bakheet SM, Hammami MM. 1994 False-positive radioiodine whole-body scan in thyroid cancer patients due to unrelated pathology. Clin Nucl Med. 19:325–329.[CrossRef][Medline]
  22. Bakheet SM, Hammami MM, Hemidan A, Powe JE, Bajaafar F. 1998 Radioiodine secretion in tears. J Nucl Med. 39:1452–1454.[Abstract/Free Full Text]
  23. Malpani BL, Samuel AM, Ray S. 1996 Quantification of salivary gland function in thyroid cancer patients treated with radioiodine. Int J Radiat Oncol Biol Phys. 35:535–540.[CrossRef][Medline]
  24. Markitziu A, Lustmann J, Uzieli B, Krausz Y, Chisin R. 1993 Salivary and lacrimal gland involvement in a patient who had undergone a thyroidectomy and was treated with radioiodine for thyroid cancer. Oral Surg Oral Med Oral Pathol. 75:318–322.[CrossRef][Medline]
  25. Hays MT. 1993 Colonic excretion of iodide in normal human subjects. Thyroid. 3:31–35.[Medline]
  26. Van Nostrand D, Neutze J, Atkins F. 1986 Side effects of "rationale dose" iodine-131 therapy for metastatic well-differentiated thyroid carcinoma. J Nucl Med. 27:1519–1527.[Abstract/Free Full Text]
  27. Majerus PM, Courtois PA. 1992 Susceptibility of Candida albicans to peroxidase-catalyzed oxidation products of thiocyanate, iodide and bromide. J Biol Buccale. 20:241–245.[Medline]
  28. Prakash P, St Clair LE, Romack FE. 1976 Localization of radioiodine in the tissues of swine: an autoradiographic study. Acta Histochem. 57:282–290.[Medline]
  29. Turk J, Henderson WR, Klebanoff SJ, Hubbard WC. 1983 Iodination of arachidonic acid mediated by eosinophil peroxidase, myeloperoxidase and lactoperoxidase. Biochim Biophys Acta. 751:189–200.[Medline]
  30. Dugrillon A. 1996 Iodolactones and iodoaldehydes-mediators of iodine in thyroid autoregulation. Exp Clin Endocrinol Diabetes. 104:41–45.
  31. Raspe E, Costagliola, Ruf J, Mariotti S, Dumont JE, Ludgate M. 1995 Identification of the thyroid Na+/I- cotransporter as a potential autoantigen in thyroid autoimmune disease. Eur J Endocrinol. 132:399–405.[Abstract/Free Full Text]
  32. Endo T, Kaneshige M, Nakazato M, Kogai T, Saito T, Onaya T. 1996 Autoantibody against thyroid iodide transporter in the sera from patients with Hashimoto’s thyroiditis possesses iodide transport inhibitory activity. Biochem Biophys Res Commun. 228:199–202.[CrossRef][Medline]
  33. Endo T, Kogai T, Nakazato M, Saito T, Kaneshige M, Onaya T. 1996 Autoantibody against Na+/I- symporter in the sera of patients with autoimmune thyroid disease. Biochem Biophys Res Commun. 224:92–95.[CrossRef][Medline]
  34. Morris JC, Bergert ER, Bryant WP. 1997 Binding of Immunoglobulin G from patients with autoimmune thyroid disease to rat sodium-iodine symporter peptides: evidence for the iodide transporter as an autoantigen. Thyroid. 7:527–534.[Medline]
  35. Ajjan RA, Findlay C, Metcalfe RA, Watson PF, Crisp M, Ludgate M, Weetman AP. 1998 The modulation of the human sodium iodide symporter activity by Graves’ disease sera. J Clin Endocrinol Metab. 83:1217–1221.[Abstract/Free Full Text]
  36. Coll J, Anglada J, Tomas S, et al. 1997 High prevalence of subclinical Sjoegren’s syndrome features in patients with autoimmune thyroid disease. J Rheumatol. 24:1719–1724.[Medline]
  37. Carmel R, Spencer CA. 1982 Clinical and subclinical thyroid disorders associated with pernicious anemia. Arch Intern Med. 142:1465–1469.[Abstract/Free Full Text]
  38. Whittingham S, Youngchaiyud U, Mackay IR, Buckley JD, Morris PJ. 1975 Thyrogastric autoimmune disease. Clin Exp Immunol. 19:289–299.[Medline]



This article has been cited by other articles:


Home page
 INT J SURG PATHOLHome page
A. Farnedi, L. H. Eusebi, F. Poli, and M. P. Foschini
Immunohistochemical Expression of the Human Sodium/Iodide Symporter Distinguishes Malignant From Benign Gastric Lesions
International Journal of Surgical Pathology, August 1, 2009; 17(4): 327 - 334.
[Abstract] [PDF]

Home page
 Eur J EndocrinolHome page
G. Riesco-Eizaguirre and P. Santisteban
A perspective view of sodium iodide symporter research and its clinical implications.
Eur. J. Endocrinol., October 1, 2006; 155(4): 495 - 512.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
M. Josefsson, L. Evilevitch, B. Westrom, T. Grunditz, and E. Ekblad
Sodium-iodide symporter mediates iodide secretion in rat gastric mucosa in vitro.
Experimental Biology and Medicine, March 1, 2006; 231(3): 277 - 281.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Unterholzner, M. J. Willhauck, N. Cengic, M. Schutz, B. Goke, J. C. Morris, and C. Spitzweg
Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells
J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 69 - 78.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. A Fragoso, V. Fernandez, R. Forteza, S. H Randell, M. Salathe, and G. E Conner
Transcellular thiocyanate transport by human airway epithelia
J. Physiol., November 15, 2004; 561(1): 183 - 194.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
I. L. Wapnir, M. Goris, A. Yudd, O. Dohan, D. Adelman, K. Nowels, and N. Carrasco
The Na+/I- Symporter Mediates Iodide Uptake in Breast Cancer Metastases and Can Be Selectively Down-Regulated in the Thyroid
Clin. Cancer Res., July 1, 2004; 10(13): 4294 - 4302.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
I. L. Wapnir, M. van de Rijn, K. Nowels, P. S. Amenta, K. Walton, K. Montgomery, R. S. Greco, O. Dohan, and N. Carrasco
Immunohistochemical Profile of the Sodium/Iodide Symporter in Thyroid, Breast, and Other Carcinomas Using High Density Tissue Microarrays and Conventional Sections
J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1880 - 1888.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
O. Dohan, A. De la Vieja, V. Paroder, C. Riedel, M. Artani, M. Reed, C. S. Ginter, and N. Carrasco
The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance
Endocr. Rev., February 1, 2003; 24(1): 48 - 77.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. T. Kloos, V. Duvuuri, S. M. Jhiang, K. V. Cahill, J. A. Foster, and J. A. Burns
Nasolacrimal Drainage System Obstruction from Radioactive Iodine Therapy for Thyroid Carcinoma
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5817 - 5820.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. Spitzweg, K. J. Harrington, L. A. Pinke, R. G. Vile, and J. C. Morris
The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3327 - 3335.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
J.-M. Bidart, L. Lacroix, D. Evain-Brion, B. Caillou, V. Lazar, R. Frydman, D. Bellet, S. Filetti, and M. Schlumberger
Expression of Na+/I- Symporter and Pendred Syndrome Genes in Trophoblast Cells
J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4367 - 4372.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Spitzweg, C.
Right arrow Articles by Heufelder, A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Spitzweg, C.
Right arrow Articles by Heufelder, A. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals