1、Patrizio Caturegli, MD MPH Associate Professor of Pathology, Endocrinology, & Immunology,Autoimmune Endocrinopathies,Lecture to Pathobiology students Sep 18, 2013,The endocrine glands,Glands characterized by:absence of a duct systemrich vascularizationLocated in different areas of the body,6 “Classi
2、c” Endocrine Glands,Hypophysis (or pituitary),Thyroid,Parathyroid,Adrenals,Pancreatic islets,Gonads,6 “Classic” Endocrine Glands,Autoimmune Endocrinopathies,Endocrine glands can be affected by numerous autoimmune diseases These autoimmune endocrinopathies often cluster in the same family (familial a
3、ggregation) or in the same patient (co-morbidity) Knowledge of these diseases and their associations lead to earlier diagnosis and management,Definition of Autoimmune Disease,Condition where a functional and/or structural damage to normal components of the body is caused by humoral and/or cellular i
4、mmune reactionsAutoimmunity is the actual cause of the human disease, not the consequence or the harmless accompaniment,Autoimmunity: the beginnings,1904: Donath & Landsteiner report that parossistic hemoglobinuria is caused by an antibody that binds to red cells at low temperatures, and then causes
5、 hemolysis at higher temperaturesThis observations is ignored because of the prevailing horror autotoxicus theory1933: Thomas Rivers publishes an experimental model (injection of rabbit brains into monkeys) of the second autoimmune disease: multiple sclerosis1951: William Harrington demonstrates (on
6、 himself) that thromobocytopenic purpura is caused by antibodies directed against platelets,Description of Autoimmune Endocrinopathies,Diseases that will be discussed,Type 1 diabetes mellitus Graves disease Hashimoto thyroiditis Addison disease Autoimmune hypoparathyroidism Autoimmune hypophysitis A
7、utoimmune Polyendocrine Syndromes,Diabetes Mellitus (DM),Group of metabolic disorders characterized by hyperglycemia resulting from: defective insulin secretion (beta-cell loss): type 1 resistance to insulin action: type 2 BothType 2 DM is the most common form (about 85% of all diabetic patients),Ty
8、pe 1 DM (beta cell loss),Type 1A: immune-mediate destruction of the pancreatic beta cells Type 1B: non-immune mediated forms of beta cell destruction, leading to absolute insulin deficiency There are about 1.5 million persons with type 1A in the US, 10% of which are children The incidence of type 1A
9、 DM is doubling approximately every 20 years, like that of asthma No cure available for type 1A DM. Treatment requires lifelong injections of recombinant insulin,Genetic Susceptibility,High concordance rate for monozygotic twins with type 1A DM: about 60%,disease,disease,no disease,no disease,Twin 1
10、,Twin 2,Concordance rate=,a,a + b + c,Concordance rate (pairwise concordance): proportion of affected pairs among the pairs in which at least one twin has the disease,Genetic Susceptibility,The major determinant of genetic susceptibility is the class II locus of the Major Histocompatiblity Complex (
11、MHC, called HLA in humans): mainly DR and DQ GWA studies have identified numerous genetic loci that can modify the risk of developing type 1A DM,Odds of developing type 1A DM,Odds ratio,Pathogenesis,In a genetically susceptible individual, the development of diabetes occurs in stages.,Pathogenesis,M
12、uch of what we know about the pathogenesis of type 1A DM comes from the study of the NOD mouse Type 1A DM is a T cell-mediated disease in which T cells infiltrate the pancreatic islets and ultimately kill the beta cells T cells, however, are not currently assessed in the clinical laboratory Thus, th
13、e diagnosis of autoimmunity in type 1A DM relies on serum autoantibodies,Laboratory Assessment of autoimmune endocrinopathies,Hormones to monitor the gland functions Autoantibodies to monitor the immunological pathogenesis Although T cells are fundamental for disease pathogenesis, T cell studies hav
14、e yet to become part of the clinical laboratory,Modern diabetes Ab tests,Four antibodies are currently used to predict and monitor the development of type 1A DM: GAD65 Abs (glutamic acid decarboxylase) IA-2 Abs (Islet-associated antigen 2) Insulin Abs ZnT8 Abs (zinc T8 transporter) More Abs = faster
15、 DM development,DM progression based on Abs,Autoimmune Thyroid Diseases,Big, smooth and soft,The thyroid in Graves disease,Graves disease,The hyperthyroidism is caused by caused by autoantibodies that bind to and stimulate the thyrotropin (TSH) receptor on the surface of thyroid follicular cellsThe
16、pathogenesis of ophthalmopathy and dermopathy is not knownHLA DR3 increases the risk of developing Graves disease. Also polymorphisms in the CTLA-4 geneConcordance rate in monozygotic twins is low: 25%Female sex remains the main risk factor,TSH-R antibodies: Clinical Utility,For diagnosis: littlecli
17、nical criteria and thyroid hormone measurements(TSH and free T3) are sufficient for making the diagnosisFor prognosis: importanthigh levels of TSH-R Ab at the time of diagnosis suggest persistent hyperthyroidismhigh levels of TSH-R Ab at the end of a cycle of anti-thyroid drug therapy predict relaps
18、e after drug withdrawalFor forecasting of neonatal hyperthyroidism: very importanta high maternal titer of TSH-R Ab in the third trimester of pregnancy accurately forecasts neonatal Graves disease,Hashimoto thyroiditis,Hashimotos thyroiditis (various forms),Classic Hashimotos thyroiditis Atrophic Ha
19、shimotos thyroiditis (primary myxedema) Post-partum thyroiditis Silent (painless thyroiditis) Focal thyroiditis,Classic Hashimotos thyroiditis,Middle-aged woman Goiter. At presentation euthyroid or hypothyroid (rarely hyperthyroid: Hashitoxicosis). Chronic course with almost universal development of
20、 hypothyroidism Dramatic improvement in quality of life since introduction of synthetic T4,Hashimotos thyroiditis: pathogenesis,Unknown Importance of establishing an animal model (Rose and Witebsky, 1956) Importance of MHC haplotype and CD4+ T cells Role of thyroglobulin and thyroperoxidase antibodi
21、es: unclear,TPO antibodies: Clinical Utility,TPO antibodies are mainly measured to confirm a diagnostic suspicion of autoimmune thyroid diseaseTPO antibodies are an excellent marker of underlying autoimmune process in the thyroid glandIn one exception, post-partum thyroiditis, the measurement of TPO
22、 antibodies is clinically crucial: the presence of TPOAb during pregnancy is a strong indicator of the development of post-partum thyroiditis,TG antibodies: Clinical Utility,Similarly to TPOAb, TG antibodies are measured mainly to They are only used to confirm a diagnosis of autoimmune thyroid disea
23、sesIn one exception, follow-up of differentiated thyroid cancer, the measurement of TG antibodies is clinically crucial.In patients with differentiated thyroid cancer, after thyroidectomy and radioiodine therapy, the measurement of serum TG is useful to assess persistence or recurrence. TG antibodie
24、s may interfere with assays for TG, and therefore their presence should be sought when TG is measured,Addison disease,A primary adrenocortical insufficiency resulting in decreased levels of glucocorticoids, mineralcorticoids, and androgens and secondary elevation in ACTH Adrenal cortex becomes infil
25、trated with lymphocytes and eventually atrophic Autoimmunity is nowadays the most common cause of Addison disease (80% of the cases), followed by tuberculosis Addison disease can occur in isolation or as part of the autoimmune polyglandular syndrome type 1 or 2,Addison disease,Genetic predisposition
26、: MHC class II: the DR3 haplotype MHC class I-related molecule A (allele 5.1)Antibodies to 21-hydroxylase are found in the majority of patients and predict the development of adrenal insufficiency,Addison disease,Autoimmune hypoparathyroidism,Rare but increasingly recognized Occurs in isolation or a
27、s common component of the autoimmune polyendocrine syndrome type 1 It results in parathyroid hormone deficiency and thus hypocalcemia Traditionally diagnosed by exclusion, when no other causes of hypoparathyroidism and hypocalcemia can be identified More recently, antibodies to NALP5 have been uniqu
28、ely identified,Alimohammadi, NEJM 2008,Autoimmune Hypophysitis,Reticulin staining,52,7,5,12,37,12,8,17,Striking temporal association with pregnancy,Caturegli et al, Endocrine Reviews, 26: 599, 2005,Clinical Presentation of Hypohysitis: similar to that of all non hormone secreting pituitary masses,Sy
29、mptoms from compression of the structures surrounding the pituitary,meningi,headache,optic chiasm,visual abnormalities,oculomotors,diplopia,various degrees of hypopituitarism,hyper-prolactinemia,Symptoms from compression of the unaffected anterior pituitary,Diabetes Insipidus,Symptoms from compressi
30、on of the pituitary stalk,1,2,3,4,the CTLA-4 connection,Oncologists have begun to see hypophysitis Cancer patients treated with “boosters” of the immune response become susceptible to hypophysitisExample: patients with advanced melanoma1: vaccinated with melanoma gp100 antigen injected with an antib
31、ody that blocks CTLA-4 5% develop hypophysitis,Blansfield, J Immunother, 26: 593, 2005,APS-1 (or, APECED),Single gene (monogenic) defect Most common in Finns, Iranian Jews, and Sardinians Characterized by various clinical features, mostly autoimmune in nature Present in children (2-3 years old), typ
32、ically with mucocutanoues candidiasis involving mouth and nails (a non autoimmune feature) Children then develop hypotension and fatigue, from Addison disaese, and hypocalcemia from hypoparathyroidism,APS-1 (or, APECED),Caused by mutations in the AutoImmune Regulator gene (AIRE) It encodes a transcr
33、iption factor expressed mainly in the thymus (medullary epithelial cells) that controls the presentation of self antigens to the developing T lymphocytes When the gene is mutated, tolerance to multiple self antigens is lost,APS-2 (Schmidt-Carpenter syndrome),More common than APS-1 Affects adults, ma
34、inly women Defined by the presence of Addison disease plus autoimmune thyroid diseases or type 1A DM. Other diseases like pernicious anemia, hypopohysitis, vitiligo can also be present Diseases can develop years to decade apart,IPEX syndrome,Cuased by mutations in the forkhead box protein 3 gene (FO
35、XP3) Manifests in infants (first few months of life) with dermatitis, growth retardation, multiple endocrinopathies, and recurrent infections FOXP3 is a molecule that defines a subset ot T lymphocytes called Treg. When mutated, Treg loose their ability to suppress other lymphocytes and the patient develops overwhelming autoimmunity Bone marrow transplantation is currently the only chance for survival,
