Mechanisms of Autoantibody-Induced Pathology

Frontiers in Immunology, Год журнала: 2017, Номер 8

Опубликована: Май 31, 2017

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% the population is affected by autoantibody-driven Pathways leading autoantibody-induced pathology greatly differ among different and autoantibodies directed against same antigen, depending on targeted epitope, can have diverse effects. To foster knowledge encourage development urgently needed novel therapeutic strategies we here categorized according their According our algorithm, be classified into following categories: (1) Mimic receptor stimulation, (2) blocking neural transmission, (3) induction altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation (7) inflammation. These mechanisms relation disease, well principles autoantibody generation detection reviewed herein.

Язык: Английский

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Graves’ disease

Nature Reviews Disease Primers, Год журнала: 2020, Номер 6(1)

Опубликована: Июль 2, 2020

Язык: Английский

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The Pathogenesis of Hashimoto’s Thyroiditis: Further Developments in our Understanding

Hormone and Metabolic Research, Год журнала: 2015, Номер 47(10), С. 702 - 710

Опубликована: Апрель 16, 2015

Abstract Hashimoto’s thyroiditis (HT) is part of a spectrum thyroid autoimmune conditions and this review provides an update on the latest developments in field. HT has genetic predisposition with number immune-related thyroid-specific genes conferring disease susceptibility. However, disentangling protective predisposing effect complex process that requires further work. The recent increase incidence implicates environmental factors pathogenesis including improved hygiene, increased dietary iodine intake, new treatment modalities chemical agents. Additional unmodifiable include stress, climate, age gender. Both cellular humoral immunity play role pathogenesis. Defects T regulatory cells activation follicular helper may have initiation/perpetuation. Infiltrating lymphocytes can be directly cytotoxic to (TFC) or affect cell viability/function indirectly through cytokine production, which alters TFC integrity modulates their metabolic immune function. Thyroid peroxidase thyroglobulin antibodies are present majority patients help management decisions. Antibodies against sodium iodide symporter pendrin minority little known about clinical relevance. In addition cells, work identified DNA fragments, generated following death, micro RNA as potential Despite large studies, mechanistic pathways still not fully understood required enhance our knowledge identify novel preventative therapeutic targets.

Язык: Английский

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Clinical Utility of TSH Receptor Antibodies

The Journal of Clinical Endocrinology & Metabolism, Год журнала: 2013, Номер 98(6), С. 2247 - 2255

Опубликована: Март 29, 2013

TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of in differential diagnosis hyperthyroidism, prediction remission GD fetal/neonatal thyrotoxicosis, and clinical assessment ophthalmopathy (GO) are controversial.We reviewed analyzed literature reporting primary data on use TRAb. We focused our analyses studies analyzing third-generation assays.The performance overt hyperthyroidism is excellent, with sensitivity specificity upper 90%. can accurately predict short-term relapses after a course antithyroid drugs but less effective predicting long-term or remissions. Pregnancies women negative highly unlikely to result fetal whereas high titers pregnancy require careful monitoring. patients GO frequently levels. there insufficient test response treatment.Third-generation assays suitable In GD, should be tested before deciding whether methimazole stopped. used pregnant assess risk thyrotoxicosis. The requires further studies.

Язык: Английский

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Autoimmune thyroid disease during pregnancy

The Lancet Diabetes & Endocrinology, Год журнала: 2017, Номер 6(7), С. 575 - 586

Опубликована: Дек. 13, 2017

Язык: Английский

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Alemtuzumab-Related Thyroid Dysfunction in a Phase 2 Trial of Patients With Relapsing-Remitting Multiple Sclerosis

The Journal of Clinical Endocrinology & Metabolism, Год журнала: 2013, Номер 99(1), С. 80 - 89

Опубликована: Окт. 29, 2013

Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial relapsing-remitting multiple sclerosis. The objective study was detailed description CAMMS223. Relapsing-remitting sclerosis patients (n = 334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses 12 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) assessed at screening, month 1, quarterly thereafter; antithyroid peroxidase antibodies screening every 6 months. episodes categorized post hoc by endocrinologist. During median follow-up 57.3 months, 34% alemtuzumab 6.5% SC IFNB-1a had (P < .0001). Ten percent 3% more than one episode dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred 22%, hypothyroidism 7%, subacute thyroiditis 4%. Of with overt hyperthyroidism, 23% spontaneously became euthyroid additional 15% developed hypothyroidism. hypothyroidism, 74% TBII positive. incidence first each year through 3 then decreased subsequent year. common IFNB-1a. There few serious episodes. Regular monitoring facilitated early detection. Unique features this population included high prevalence individual patients, spontaneous after TBII-positive

Язык: Английский

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Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Journal of Pharmacology and Experimental Therapeutics, Год журнала: 2015, Номер 353(2), С. 246 - 260

Опубликована: Фев. 3, 2015

G protein–coupled receptors (GPCRs) are the largest superfamily of encoded by human genome, and represent class current drug targets. Over last decade a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites can be targeted exogenous substances to modulate receptors' biologic state. Although many these likely serve other (e.g., structural) roles, they nonetheless appropriate properties serendipitously synthetic molecules. However, there also examples endogenous act as modulators GPCRs. These include only obvious example, i.e., protein, but variety ions, lipids, amino acids, peptides, accessory proteins display different degrees receptor-specific modulatory effects. This suggests some may true "orphan" for hitherto unappreciated modulators. Of note, increasing identification modulator inflammatory GPCR-targeted autoantibodies indicates disease context plays an important role in generation putative GPCR If substance shown play disease, this could impetus pursue neutral ligands novel therapeutic agents.

Язык: Английский

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Laboratory Testing in Thyroid Conditions - Pitfalls and Clinical Utility

Annals of Laboratory Medicine, Год журнала: 2018, Номер 39(1), С. 3 - 14

Опубликована: Сен. 14, 2018

Thyroid disorders are common, affecting more than 10% of people in the US, and laboratory tests integral management these conditions. The repertoire thyroid includes blood for thyroid-stimulating hormone (TSH), free thyroxine, triiodothyronine, thyroglobulin (Tg), antibodies (Tg-Ab), peroxidase (TPO-Ab), TSH receptor (TRAb), calcitonin. frequently used to assess functional status thyroid. TPO-Ab TRAb diagnose Hashimoto's thyroiditis Graves' disease, respectively. Tg calcitonin important tumor markers differentiated carcinoma medullary (MTC), Procalcitonin may replace as a biomarker MTC. Apart from understanding normal physiology, it is be familiar with possible pitfalls caveats use so that they can interpreted properly accurately. When results discordant, clinicians laboratorians should mindful assay interferences and/or effects concurrent medications. In addition, function appear abnormal absence actual dysfunction during pregnancy critical illness. Hence, consider clinical context when interpreting results. This review aims describe above-mentioned diagnosis disorders, well their interpretation. With due knowledge care, will able fully appreciate utility tests.

Язык: Английский

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Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves' Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation

Endocrinology, Год журнала: 2013, Номер 154(9), С. 3008 - 3015

Опубликована: Июль 30, 2013

Graves' orbitopathy (GO) is a complication in disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 (IGF-1R) are considered relevant antigens. We show that genetic immunization human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR or control plasmids vivo muscle electroporation were evaluated for histopathology magnetic resonance imaging (MRI). Antibodies IGF-1R present animals challenged plasmid, predominantly blocking antibodies profoundly hypothyroid. Orbital pathology was characterized interstitial inflammation extraocular muscles CD3+ T cells, F4/80+ macrophages, mast accompanied glycosaminoglycan deposition resultant separation individual fibers. Some showed heterogeneity 1) large infiltrate surrounding the optic nerve 2) adipogenesis expansion retrobulbar adipose tissue. A striking finding underpins new model MRI scans mouse region provided clear quantifiable evidence hypertrophy protrusion (proptosis) eye. Additionally, eyelid manifestations chemosis, including dilated congested blood vessels, visually apparent. Immunization failed any pathology. Overall, these findings support as pathogenic antigen Development preclinical will facilitate molecular investigations on GO evaluation therapeutic interventions.

Язык: Английский

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Thyroid Stimulating Antibodies Are Highly Prevalent in Hashimoto's Thyroiditis and Associated Orbitopathy

The Journal of Clinical Endocrinology & Metabolism, Год журнала: 2016, Номер 101(5), С. 1998 - 2004

Опубликована: Март 10, 2016

Thyroid-associated orbitopathy (TAO) rarely occurs in patients with Hashimoto's thyroiditis (HT).There is evidence that TSH receptor stimulating antibodies (TSAb) play a role the pathogenesis of TAO. In this report, prevalence TSAb HT and without TAO was studied.This longitudinal observational study.The study took place an academic joint thyroid-eye clinic.A total 1055 subjects were included.TSAb measured Food Drug Administration-cleared bioassay uses Chinese hamster ovary cells expressing chimeric cAMP response element-dependent luciferase. Results activity reported as percentage specimen-to-reference ratio (SRR%, cutoff >140%).We association risk HT.Of 700 consecutive unselected HT, 44 (6%) had overt Patients HT+TAO older (P < .001), heavier smokers = .032), clustered less autoimmune diseases .005). All healthy controls negative. contrast, serum positive 30/44 (68.2%) 36/656 (5.5%, P .001) respectively. Compared to only, levels higher (median SRR%, 25th 75th percentiles): 45, 35-65 vs 192.5, 115-455.3, .001. Highest values noted active severe those mild inactive TAO: 486, 392-592 142, 73-192.5; The odds positivity for adjusted gender age 55.9 (95% confidence interval [CI], 24.6-127, .0001), whereas per 10-fold change SRR% (quantitative TSAb) 133 CI, 45-390, .0001). area under receiver operating characteristic curve qualitative quantitative 87.2% 80.6-93.8) 89.4% 84.1-94.7), respectively.TSAb strongly associated may contribute pathophysiology

Язык: Английский

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