Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Braley‐Mullen, Helen; Sharp, Gordon C.; Medling, Brad; Tang, Haïwen

doi:10.1006/jaut.1999.0272

Cited by 162 publications

(263 citation statements)

References 45 publications

Supporting

Mentioning

240

Contrasting

Unclassified

Order By: Relevance

“…5). There is abundant evidence that Tg plays an important role in the etiology of AITD, including: (i) anti-Tg antibodies are detected in almost all patients with AITD (5), and these Tg antibodies are restricted in their epitope specificity in contrast to the polyclonal nature of Tg antibodies found in healthy individuals (40); (ii) immunization with Tg induces autoimmune thyroiditis in experimental animals (37-39); and (iii) spontaneous models of autoimmune thyroiditis are also characterized by the development of anti-Tg antibodies (41). This article extended these observations and demonstrated that Tg was directly involved in the genetic etiology of AITD.…”

Section: Discussionmentioning

confidence: 99%

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Ban

Greenberg

Concepcion

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

173

131

View full text Add to dashboard Cite

The 8q24 locus, which contains the thyroglobulin (Tg) gene, was previously shown to be strongly linked with autoimmune thyroid disease (AITD). We sequenced all 48 exons of the Tg gene and identified 14 single-nucleotide polymorphisms (SNPs). Case control association studies demonstrated that an exon 10 -12 SNP cluster and an exon 33 SNP were significantly associated with AITD (P < 0.01). Haplotype analysis demonstrated that the combination of these two SNP groups was more significantly associated with AITD (P < 0.001). Gene-gene interaction studies provided evidence for an interaction between HLA-DR3 and the exon 33 SNP, giving an odds ratio of 6.1 for Graves' disease. We then sequenced exons 10,12, and 33 of the mouse Tg gene in 19 strains of mice. Fifty percent of the strains susceptible to thyroiditis had a unique SNP haplotype at exons 10 and 12, whereas none of the mouse strains that were resistant to thyroiditis had this SNP haplotype (P ‫؍‬ 0.01). We concluded that Tg is a susceptibility gene for AITD, both in humans in and in mice. A combination of at least two Tg SNPs conferred susceptibility to human AITD. Moreover, the exon 33 SNP showed evidence for interaction with HLA-DR3 in conferring susceptibility to Graves' disease.Graves' disease ͉ Hashimoto's disease ͉ thyroiditis T he autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are among the most common human autoimmune diseases with recent data showing a prevalence of clinical AITD of up to 1% in the U.S. population (1, 2). The hallmark of GD is the production of thyroid-stimulating hormone receptor (TSHR)-stimulating antibodies causing hyperthyroidism, whereas HT is characterized by the apoptosis of thyrocytes, leading to hypothyroidism (reviewed in refs. 3 and 4). However, despite their contrasting clinical presentations, GD and HT share many features in common, mainly, infiltration of the thyroid by T cells and production of antithyroid autoantibodies [antithyroglobulin and anti-thyroid peroxidase (TPO) antibodies] (3-5). AITDs are complex diseases, which are caused by an interaction between susceptibility genes (6-8) and nongenetic factors, such as infection (9-12). This paradigm is based on solid epidemiologic evidence demonstrating a genetic predisposition to AITDs, including: (i) familial clustering (13); (ii) a sibling risk ratio ( s ) of Ͼ10 (7, 14); (iii) a high concordance rate in monozygotic twins when compared with dizygotic twins (15-18); and (iv) the presence of thyroid autoantibodies, which are markers of subclinical AITD, in up to 50% of siblings of patients with AITD (19,20).We have previously performed a whole-genome scan in a dataset of 102 multiplex, multigenerational AITD families (540 individuals; refs. 21-23). Three loci on chromosomes 6p, 8q, and 10q showed evidence for linkage with the entire AITD dataset giving maximum multipoint heterogeneity logarithm of odds (lod) scores of 2.0, 3.5, and 4.1, respectively. The 8q24 locus was also reported to be linked with AITD in a dat...

show abstract

Section: Discussionmentioning

confidence: 99%

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Ban

Greenberg

Concepcion

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

173

131

View full text Add to dashboard Cite

show abstract

“…ϩ T cells, B cells, and CD8 ϩ T cells (1)(2)(3)(4). Our previous studies showed that IFN-␥ has a dual role in SAT, promoting L-SAT and inhibiting thyroid epithelial cell hyperplasia and proliferation (TEC H/P) (5).…”

Section: In Nodh-2h4 Mice Is Characterized By Infiltration Of Thyroimentioning

confidence: 99%

“…At various intervals after receiving NaI in water, thyroids were removed, and one thyroid lobe from each mouse was fixed in formalin, sectioned, and stained with H&E as previously described (2,5). All slides were coded before being scored by two individuals, one of whom had no knowledge of the experimental groups.…”

Section: Evaluation Of Thyroiditismentioning

confidence: 99%

“…The other thyroid lobe was snap-frozen in liquid nitrogen and stored at Ϫ70°C for use in immunohistochemical staining or for isolation of RNA for RT-PCR. Thyroid histopathology was scored for the extent of thyroid follicle replacement or destruction using a scale of 0 to 5ϩ as previously described (2,5). Briefly, a score of 0 indicates a normal thyroid, whereas 0ϩ indicates mild follicular changes and/or a few inflammatory cells infiltrating the thyroids.…”

Section: Evaluation Of Thyroiditismentioning

confidence: 99%

See 1 more Smart Citation

Thyrocytes Responding to IFN-γ Are Essential for Development of Lymphocytic Spontaneous Autoimmune Thyroiditis and Inhibition of Thyrocyte Hyperplasia

Yu¹,

Sharp²,

Braley‐Mullen

2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

IFN-γ promotes the development of lymphocytic spontaneous autoimmune thyroiditis (L-SAT) in NOD.H-2h4 mice and inhibits the development of thyrocyte hyperplasia and proliferation (TEC H/P). The precise mechanisms by which IFN-γ promotes L-SAT and inhibits TEC H/P are unknown. To determine whether responsiveness of lymphocytes or thyrocytes to IFN-γ is important for the development of these lesions, IFN-γR−/− mice, which develop TEC H/P similar to IFN-γ−/− mice, were used as recipients for adoptive cell transfer. Wild-type (WT) splenocytes or bone marrow induced L-SAT and inhibited TEC H/P in IFN-γ−/−, but not IFN-γR−/− recipients. IFN-γR−/− recipients of WT cells developed severe TEC H/P, but did not develop L-SAT, suggesting that thyrocytes responding to IFN-γ are important for inhibition of TEC H/P. Unexpectedly, IFN-γR−/− splenocytes or bone marrow did not induce L-SAT in IFN-γ−/− or WT mice even though IFN-γR−/− lymphocyte donors produced as much IFN-γ as lymphocytes from WT donors, and thyrocytes could respond to IFN-γ. Real-time PCR indicated that recipients of IFN-γR−/− bone marrow expressed less mRNA for IFN-γ-inducible chemokines compared with recipients of WT bone marrow. This might limit the migration of IFN-γR−/− lymphocytes to thyroids. Few IFN-γR−/− lymphocytes infiltrated thyroids even in the presence of WT lymphocytes, suggesting that lymphocytes unable to respond to IFN-γ are not induced to migrate to thyroids. These results suggest that thyrocytes must be able to respond to IFN-γ for the development of L-SAT and inhibition of TEC H/P, and lymphocytes must be able to respond to IFN-γ to induce L-SAT.

show abstract

“…In contrast to the human counterpart (Hashimoto thyroiditis), in NOD-H2 h4 mice thyroperoxidase antibodies develop only later (6), thyroxine remains normal (7), and males are as equally affected as females (4,5). Interestingly, the original authors also noted that addition of sodium iodide to the drinking water accelerated the incidence and severity of thyroiditis in the NOD-H2 h4 but not the parental NOD strain (8), an observation later confirmed and expanded by others (9,10). More specifically, once iodine-rich water supplementation is started (typically done at two months of age), thyroiditis ensues within two weeks and becomes fully prevalent at about five months of age (5).…”

Section: Introductionmentioning

confidence: 80%

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Sharma

Dalmazi

Caturegli

2016

Thyroid

View full text Add to dashboard Cite

Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. Methods: NOD-H2 h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment. Conclusions: This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD-H2 h4 mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.

show abstract

Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Cited by 162 publications

References 45 publications

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Thyrocytes Responding to IFN-γ Are Essential for Development of Lymphocytic Spontaneous Autoimmune Thyroiditis and Inhibition of Thyrocyte Hyperplasia

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Contact Info

Product

Resources

About