Thyroid as a target of adjuvant autoimmunity/inflammatory syndrome due to mRNA-based SARS-CoV2 vaccination: from Graves' disease to silent thyroiditis.

BACKGROUND: As COVID-19 became a pandemic, the urgent need to find an effective treatment vaccine has been a major objective. Vaccines contain adjuvants which are not exempt from adverse effects and can trigger the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is very little information about autoimmune endocrine disease and the ASIA after the use of mRNA-based SARS-CoV2 vaccination. CASE SERIES: We report three cases and also review the literature showing that the thyroid gland can be involved in the ASIA induced by the mRNA-based SARS-CoV2 vaccination. We present the first case to date of silent thyroiditis described in the context of SARS-CoV2 vaccination with Pfizer/BioNTech. Also, we discuss the first subacute thyroiditis in the context of SARS-CoV2 vaccination with the Moderna's vaccine. Finally, we provide another case to be added to existing evidence on Graves' disease occurring post-vaccination with the Pfizer/BioNTech vaccine. DISCUSSION: Adjuvants play an important role in vaccines. Their ability to increase the immunogenicity of the active ingredient is necessary to achieve the desired immune response. Both the Moderna and the Pfizer/BioNTech vaccines use mRNA coding for the SARS-CoV2 S protein enhanced by adjuvants. In addition, the cross-reactivity between SARS-CoV2 and thyroid antigens has been reported. This would explain, at least, some of the autoimmune/inflammatory reactions produced during and after SARS-CoV2 infection and vaccination. CONCLUSION: The autoimmune/inflammatory syndrome induced by adjuvants involving the thyroid could be an adverse effect of SARS-CoV2 vaccination and could be underdiagnosed.

Proposal of diagnostic criteria for IgG4-related thyroid disease.

Patients with IgG4-related disease (IgG4-RD) are diagnosed in Japan by comprehensive or organ-specific diagnostic criteria. To date, organ-specific criteria have been established for several organs, but not for the thyroid. We attempted to establish diagnostic criteria for IgG4-related thyroid disease (IgG4-RTD) based on IgG4-RD research by The Research Program on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan. These criteria have been publicly reported to members of both the Japan Endocrine Society and the Japan Thyroid Association. Thyroid diseases associated with IgG4 include Hashimoto's thyroiditis, Graves' disease and Riedel's thyroiditis. As a comprehensive definition that includes both systematic and organ-specific forms, we use the broad term 'IgG4-related thyroid disease'. Diagnostic criteria for IgG4-RTD comprise the following five items: I) enlargement of the thyroid, II) hypoechoic lesions in the thyroid by ultrasonography, III) elevated serum IgG4 levels, IV) histopathological findings in the thyroid lesion (IgG4+ plasma cells >20/HPF and IgG4+/IgG+ plasma cell ratio >30%) and V) involvement of other organs. "Definitive" diagnosis of IgG4-RTD is made when I, II, III and IV are all fulfilled, while "probable" diagnosis of IgG4-RTD is when I, II, and IV or V are fulfilled. Patients who fulfill I, II and III criteria are considered as "possible" IgG4-RTD. We believe that the proposed diagnostic criteria contribute to more accurate diagnosis of IgG4-RTD as well as exclusion of mimicry. Furthermore, they may lead to better understanding of the clinical implications and underlying pathogenesis of IgG4-RTD.

Comparison of the New, Rapid, and Fully Automated Kryptor TSH receptor Antibodies Assay (B.R.A.H.M.S.) with the Radioimmunological Assay (B.R.A.H.M.S.).

BACKGROUND: Radioimmunoassays, which are often not automated and time-consuming, are gradually being re-placed in medical laboratories by non-radioactive methods that need to be evaluated. The purpose was to compare the measurement of thyroid-stimulating hormone receptor antibodies (TRAb) by the new Brahms' kit using Kryptor TRACE technology and the Brahms' radioimmunoassay. METHODS: We prospectively collected all samples from patients who received thyroid-stimulating hormone receptor antibodies testing in July 2018 at the University Hospital of Brest. The radioimmunoassay used was the Dynotest TRAK human by BRAHMS Diagnostica (Berlin, Germany). The Kryptor method used the BRAHMS TRAK human Kryptor kit performed with the Kryptor Compact Plus system. RESULTS: The inter-assay coefficient variations for the radioimmunological and Kryptor methods were 11.07% and 8.36%, respectively, with the low level quality control and 8.36% and 4.38%, respectively, with the high level quality control. Forty-four patients were included in the study including thirty-two Graves' disease patients in follow-up. The sensitivity of the radioimmunological method for the detection of Graves' disease was 0.94 and the specificity was 0.73. The sensitivity of the Kryptor method was 0.91 and the specificity was 0.91. A non-proportional systematic bias in favor of higher values of TRAb concentrations with the radioimmunological method was observed: slope of 0.93 (0.74 - 1.07, 95% confidence interval) and an intercept of -0.69 IU/L (-1.58 to -0.30, 95% confidence interval). Compared to the Kryptor method, the radioimmunological method tends to overestimate TRAb concentrations by up to 120%. CONCLUSIONS: The fully automated Brahms Kryptor kit using TRACE technology to measure TRAb reduces sampling time and intra- as well as inter-assay variations. The Kryptor kit underestimates the results of TRAb leading to a lower sensitivity and higher specificity compared to the radioimmunoassay. Thus, the new Brahms Kryptor kit has good laboratory performances but the interpretation of the results must still be performed with caution.

[ON THE ISSUE OF AUTOIMMUNE OVARY DAMAGE DURING PUBERTY].

The aim of the study was to ascertain the influence of AІТ on the formation of autoimmune damage to ovaries by determining the connections between the levels of AOAB, ATPO, gonadotropic and sex hormone levels, and the functional state of the ovaries and thyroid gland. 198 girls age 10-18 were studied: 166 with AIT (AIT+ Group), и 32- without AIT (the AIT- Group). A defined difference between TTH. and ATPO, was revealed, which is explained by the presence of thyroid pathology in the AIT+ Group. Prolactin levels and ovarian volume were notably higher, while Progesterone levels were lower in the AIT+ Group. No discernable differences among levels of AOAB, sex hormones, Estrogen, Testosterone or antral follicules were observed. A direct correlation was revealed between AOAB levels and the girls' age both in the AIT+ and AIT- groups. AOAB data was divided into three tertials in order to study links with various hormonal homeostasis. Analysis of data obtained showed numerous correlative links between ATPO, AOAB, gonadotropins, sex hormones, TTH and ovarian volume in all tertials of both the AIT+ and AIT- groups; correlative links were found, too, between AOAB and ATPO in the III tertial groups AIT+ and AIT-. In adolescents with AIT disbalance occurs at all levels of hormonal homeostasis as well as in ovarian structure. Such changes and the presence of ATPO and AOAB may be associated with emerging autoimmune ovary damage.

Natural history of subclinical hypothyroidism with TSH ≤10 mIU/l: a prospective study.

OBJECTIVE: The risk of progression of subclinical hypothyroidism (SCH) to clinical dysfunction is one of the factors considered in the decision to treat this condition. This study evaluated the natural history of SCH in women with TSH ≤10 mIU/l. DESIGN: This is a prospective study. PATIENTS: Two hundred and fifty-two women with SCH and TSH levels ranging from 4·5 to 10 mIU/l were followed up for a period of 5 years. RESULTS: Among the 241 patients followed up until the completion of the study, 46 (19%) required levothyroxine (L-T4) therapy, 55 (22·8%) had spontaneous normalization of serum TSH, and 140 (58·1%) continued to meet the criteria for mild SCH. In multivariate analysis, only initial TSH >8 mIU/l was a predictor of the need for L-T4. In contrast, initial TSH ≤8 mIU/l and the absence of thyroiditis [negative antithyroid peroxidase antibodies (TPOAb) and ultrasonography (US)] were predictors of TSH normalization. Of note, the natural history was similar in TPOAb-positive patients and patients with negative TPOAb but with positive US. CONCLUSIONS: Most women with mild elevation of serum TSH, ranging from 4·5 to 10 mIU/l, do not progress to overt hypothyroidism and even normalize their TSH. However, initial TSH seems to be a more important predictor of progression than the presence of antibodies or ultrasonographic appearance.

Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice.

NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO.

Evaluation of thyroid dysfunction and autoimmunity in gestational diabetes mellitus and its relationship with postpartum thyroiditis.

AIMS: To evaluate thyroid dysfunction and autoimmunity in women with gestational diabetes and to investigate the frequency of postpartum thyroiditis in women with gestational diabetes. MATERIALS AND METHODS: A total of 350 women with gestational diabetes and 350 healthy pregnant women were enrolled in the study. We studied the thyroid hormone profiles of the women in each group during pregnancy (at 24-28 weeks' gestation) and after delivery (at 6 weeks, 3, 6 and 9 months, and 1 year postpartum). RESULTS: A total of 342 women with gestational diabetes and 313 healthy pregnant women completed the follow-up during pregnancy and 1 year after delivery. Of the women with gestational diabetes, 16.6% had thyroid dysfunction, while of the healthy pregnant women, 6.1% had thyroid dysfunction. The prevalence of postpartum thyroiditis was higher in the women with a history of gestational diabetes (19.6%) than in the healthy pregnant women (10.2%), and this difference was statistically significant. CONCLUSION: According to the results of the present study, the prevalence of postpartum thyroiditis was higher in women with a history of gestational diabetes than in healthy women. We recommend that all women with gestational diabetes and women who have previous thyroid dysfunction should be screened for thyroid hormonal abnormalities during pregnancy and for 1 year after pregnancy.

Clinicopathological features of Riedel's thyroiditis associated with IgG4-related disease in Japan.

Riedel's thyroiditis (RT) is a rare chronic fibrosing disorder characterized by a hard, infiltrative lesion in the thyroid gland, which is often associated with multifocal fibrosclerosis. Immunoglobulin G4-related disease (IgG4-RD) is typified by infiltration of IgG4-positive plasma cells into multiple organs, resulting in tissue fibrosis and organ dysfunction. In order to evaluate the clinicopathological features of RT and its relationship with IgG4-RD, we performed a Japanese literature search using the keywords "Riedel" and "Riedel's thyroiditis." We used the electronic databases Medline and Igaku Chuo Zasshi, the latter of which is the largest medical literature database in Japan. The diagnosis of RT was based on the presence of a fibroinflammatory process with extension into surrounding tissues. Only 10 patients in Japan fulfilled RT diagnostic criteria during the 25-year period between 1988 and 2012. Two patients with confirmed IgG4/IgG immunohistochemical findings demonstrated 43 and 13 IgG4-positive plasma cells per high-power field, respectively, and the IgG4-positive/IgG-positive plasma cell ratios of 20% and less than 5%. Of the 10 patients with RT, two received glucocorticoids, one of whom experienced marked shrinkage of the thyroid lesion. One patient had extra-thyroid involvement in the form of retroperitoneal fibrosis. Although the clinicopathological features of RT suggest that IgG4-RD may be the underlying condition in some cases, further investigation is needed to clarify the etiology of RT in relation to IgG4-RD.

Associations of autoantibodies, autoimmune risk alleles, and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and non-rheumatoid arthritis controls.

OBJECTIVE: The significance of non-rheumatoid arthritis (RA) autoantibodies in patients with RA is unclear. The aim of this study was to assess associations of autoantibodies with autoimmune risk alleles and with clinical diagnoses from the electronic medical records (EMRs) among RA cases and non-RA controls. METHODS: Data on 1,290 RA cases and 1,236 non-RA controls of European genetic ancestry were obtained from the EMRs of 2 large academic centers. The levels of anti-citrullinated protein antibodies (ACPAs), antinuclear antibodies (ANAs), anti-tissue transglutaminase antibodies (AGTAs), and anti-thyroid peroxidase (anti-TPO) antibodies were measured. All subjects were genotyped for autoimmune risk alleles, and the association between number of autoimmune risk alleles present and number of types of autoantibodies present was studied. A phenome-wide association study (PheWAS) was conducted to study potential associations between autoantibodies and clinical diagnoses among RA cases and non-RA controls. RESULTS: The mean ages were 60.7 years in RA cases and 64.6 years in non-RA controls. The proportion of female subjects was 79% in each group. The prevalence of ACPAs and ANAs was higher in RA cases compared to controls (each P < 0.0001); there were no differences in the prevalence of anti-TPO antibodies and AGTAs. Carriage of higher numbers of autoimmune risk alleles was associated with increasing numbers of autoantibody types in RA cases (P = 2.1 × 10(-5)) and non-RA controls (P = 5.0 × 10(-3)). From the PheWAS, the presence of ANAs was significantly associated with a diagnosis of Sjögren's/sicca syndrome in RA cases. CONCLUSION: The increased frequency of autoantibodies in RA cases and non-RA controls was associated with the number of autoimmune risk alleles carried by an individual. PheWAS of EMR data, with linkage to laboratory data obtained from blood samples, provide a novel method to test for the clinical significance of biomarkers in disease.

Genetic analysis of interferon induced thyroiditis (IIT): evidence for a key role for MHC and apoptosis related genes and pathways.

Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon-induced thyroiditis during high-dose interferon-α2b treatment.

CONTEXT: One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. OBJECTIVE: Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. DESIGN, PATIENTS AND METHODS: From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). RESULTS: Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P < 0·001). CONCLUSIONS: Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT.

Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

[Hashimoto's thyroiditis(chronic thyroiditis), IgG4-related thyroiditis].

Hashimoto's thyroiditis emerges in patients who have genetic preponderance such as SNPs of CTLA-4 and risk factors such as excess intake of iodine, pregnancy or postpartum period, and smoking. Such risk factors also affect the entire clinical course. One of the major outcomes in Hashimoto's thyroiditis appears to be increased in cardio-vascular risks through subclinical hypothyroidism and concomitant metabolic syndrome, but in most cases, treatment with L-T4 has little effects on cardio-vascular benefit or quality of life. The pregnant women also have risks for obstetric complications and postpartum thyroid dysfunction. The women who have anti-TPO antibodies, type 1 diabetes, or previous history of post-partum thyroid dysfunction are recommended to be measured their TSH. It is noteworthy that Hashimoto's thyroiditis is sometimes complicated with encephalopathy, papillary carcinoma, or IgG4-related thyroiditis. IgG4-related thyroiditis is partly similar but partly discerned from a variant of Hashimoto's thyroiditis. The pathogenetic roles of this variant on autoimmune-based thyroiditis remain unclear.

A prospective study of lymphocyte subpopulations and regulatory T cells in patients with chronic hepatitis C virus infection developing interferon-induced thyroiditis.

OBJECTIVE: One of the side effects of interferon-alpha (IFN-α) therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT remains to be defined. The aim of this study was to assess different peripheral blood lymphocyte subpopulations, mainly CD4(+) CD25(+) CD127low/-FoxP3(+) regulatory T cells (Tregs), in patients with chronic hepatitis C virus (HCV) infection who developed IIT. DESIGN, PATIENTS AND METHODS: From 120 patients with chronic HCV who started antiviral treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-HCV). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment (PT) and at appearance of IIT (TT). RESULTS: Eleven patients developed IIT: three Hashimoto's thyroiditis, one Graves'disease, one positive antithyroidal antibodies, one nonautoimmune hypothyroidism and five destructive thyroiditis. During antiviral treatment, an increase in CD8(+) and in Tregs was observed in both groups. A decrease in CD3(+) , CD19(+) and NKT lymphocyte subpopulations was also observed (all P < 0·05). However, no changes were observed in the percentage of CD4(+) , CD3(+) γδ(+) and iNKT lymphocytes, Th1/Th2 balance and Bcl2 expression on B cells when BT was compared with ET. At the appearance of IIT (TT), IIT patients had a higher Th1 response (CCR5(+) CCR7(-) ) (P < 0·01) and a higher Tregs percentage (P < 0·05) than Co-HCV. CONCLUSIONS: Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Th1 response and Tregs in patients with HCV who developed IIT.

Catalytic antibodies: balancing between Dr. Jekyll and Mr. Hyde.

The immunoglobulin molecule is a perfect template for the de novo generation of biocatalytic functions. Catalytic antibodies, or abzymes, obtained by the structural mimicking of enzyme active sites have been shown to catalyze numerous chemical reactions. Natural enzyme analogs for some of these reactions have not yet been found or possibly do not exist at all. Nowadays, the dramatic breakthrough in antibody engineering and expression technologies has promoted a considerable expansion of immunoglobulin's medical applications and is offering abzymes a unique chance to become a promising source of high-precision "catalytic vaccines." At the same time, the discovery of natural abzymes on the background of autoimmune disease revealed their beneficial and pathogenic roles in the disease progression. Thus, the conflicting Dr. Jekyll and Mr. Hyde protective and destructive essences of catalytic antibodies should be carefully considered in the development of therapeutic abzyme applications.

Safety of current immune checkpoint inhibitors in non-small cell lung cancer.

Introduction: Immune checkpoint inhibitors (ICIs) achieved response rates around 20% in advanced non-small cell lung cancer (NSCLC) with 8% of patients becoming long-term survivors. Outcomes have improved with the addition of chemotherapy to immunotherapy or the combination of anti-PD(L)1 with anti-CTLA-4 agents.Areas covered: The incidence of immune-related adverse events (irAEs) in patients with NSCLC treated with ICIs varied across clinical trials and real-life studies. The onset of irAEs was 10 weeks. Toxic deaths from irAEs following anti-PD(L)1 administration resulted mainly from pneumonitis. Some irAEs such as rash and thyroiditis were probably associated with better clinical outcomes, though confounding biases exist. Investigations are on-going to determine ideal biomarkers to predict the occurrence, to screen for and to diagnose irAEs.Expert opinion: Prevention, anticipation, detection, treatment and careful monitoring are the five principles that characterize our management of irAEs. Distinguishing immune-induced pneumonitis from progression, pseudo progression, hyper progression, or other etiologies (COVID-19) can be particularly challenging in lung cancer due to the baseline vulnerable pulmonary function and thus requires caution and teamwork. We treat patients according to institutional and international guidelines and we only rechallenge them with ICIs after resolution of the AE and corticosteroid tapering.

The role of self-antigen in the development of autoimmunity in Obese strain chickens with spontaneous autoallergic thyroiditis.

Neonatal thyroidectomy of Obese strain (OS) chickens showed that the spontaneous development of thyroid autoimmunity in these animals was fully dependent upon the presence of autoantigen, and could not be ascribed essentially to antigen-independent mechanisms such as polyclonal lymphocyte activation or innate distortions within the idiotype network. Similarly, removal of the gland in animals with established thyroiditis demonstrated the need for antigen to maintain the autoimmune response. Thyroglobulin from normal chickens induced autoantibodies in neonatally thyroidectomized OS birds, suggesting that an abnormality in the structure of this protein is not a prerequisite for the development of autoimmunity. This contention is supported by the finding that OS and normal thyroglobulin were immunochemically indistinguishable, whether compared using OS autoantibodies or rabbit anti-chicken thyroglobulin sera.

H-2K mutation controls immune response phenotype of autoimmune thyroiditis. Critical expression of mutant gene product in both thymus and thyroid glands.

Autoimmune thyroiditis (EAT) can be induced by immunizing mice against mouse thyroglobulin. A gene critical to the phenotypical expression of EAT was mapped to the H-2K locus by studying B6 mice and its mutant strain B6.H-2ba. To identify organs in which expression of the gene was decisive for the EAT phenotype, we transplanted thyroid or irradiated thymus glands into various strains of normal mice or thymusless nude mice. We found that the pathophysiology of EAT was controlled by the expression of specific H-2 genes in both the target thyroid gland and the thymus gland.

Cellular events during the induction of experimental thyroiditis in the rabbit.

With a modification of the Jerne plaque technique to enumerate plaque-forming cells (PFC) to bovine and rabbit thyroglobulin, the cellular kinetics of the antibody response were followed during two 5-day series of injections of an aqueous preparation of bovine thyroglobulin. The results support the suggestion that thyroiditis in the rabbit is mediated by antibody. The peak PFC appear in the spleen at the end of the second series of injections and are considerably greater for bovine than for rabbit thyroglobulin. PFC also appear in the thyroid gland; however, the numbers of PFC for bovine and rabbit thyroglobulin were similar, and they did not reach a peak until 7 days after the peak PFC in the spleen. There was an excellent correlation between the appearance of PFC in the thyroid gland and the appearance of thyroid lesions. The disappearance of antibody to rabbit thyroglobulin from the serum also correlated with the appearance of lesions. Migration inhibition factor (MIF) activity was not produced at any time throughout the study when rabbit thyroglobulin was added to peritoneal exudates of immunized rabbits containing circulating antibody to rabbit thyroglobulin. MIF activity was observed when bovine thyroglobulin was added to similar cells in the later stages of the study after lesions were present.

Transfer of experimental autoimmune thyroiditis by serum from thyroidectomized donors.

When rabbits were injected with 10.0 mg rabbit thyroglobulin in complete Freund's adjuvant, the earliest thyroid lesions were seen on day 5 and uniformly severe thyroid lesions were seen by day 14; these observations were not significantly different from the thyroid lesions observed at 1 and 2 months post-immunization. Pooled sera were obtained from immunized, thyroidectomized, and nonthyroidectomized donors on various days and transferred to normal recipient rabbits in different experiments. Successful transfer of thyroid lesions was seen when serum containing early antithyroglobulin antibody obtained from thyroidectomized donor animals at various times after immunization was injected into normal recipients in a sequential manner. Immunofluorescent studies of recipient thyroid glands showed focal fixation of rabbit gamma-globulin and beta(1C) complement in thyroid follicles. When purified antibody to rabbit thyroglobulin obtained from thyroidectomized donor sera was transferred sequentially as above, significant thyroid lesions were seen in recipient rabbits. In contrast, no thyroid lesions were seen in recipient animals injected with rabbit sera containing late antithyroglobulin antibody from thyroidectomized donors or hyperimmune sera from guinea pigs. No thyroid lesions were seen in recipient animals injected either with sera from donors given complete adjuvant without thyroglobulin or with globulin fraction of pooled sera containing early antithyroglobulin antibody obtained on various days from nonthyroidectomized donors. Similarly, rabbits rendered unresponsive to guinea pig gammaG-globulin and periodically injected with guinea pig anti-rabbit thyroglobulin showed no thyroid lesions.