1. Autoimmunity and Diabetes Robert E. Jones, MD, FACP, FACE Professor of Medicine University of Utah School of Medicine

2. Objectives 1.Understand current concepts in the pathogenesis of autoimmunity 2.Learn the different types of the immunoendocrinopathy syndromes 3.Recognize the clinical presentations of the more common autoimmune conditions associated with type 1 diabetes

3. Immunity

4. The Players

5. Innate v Adaptive Immunity Innate immunity helps in the defense against a new unrecognized assault –Nonspecific –Tuberculosis, foreign body, etc Adaptive immunity is very specific –Repeated antigen exposure –Immunization

6. HLA Antigens HLA refers to Human Leukocyte Antigens MHC refers to major histocompatibility complex Class I MHC antigens Class II MHC antigens –Only found on professional antigen presenting cells –HLA DP; DQ; DR –Resemble a “hot dog and bun” Hot dog = processed antigenic peptide Bun = groove of histocompatibility molecule

7. T Cell Interactions Class II MHC

8. Dendritic Cell

10. HLA Involvement in Antigen Presentation

11. Theories of Autoimmunity

12. Inciting Events and Natural Prevention Triggers –Viral infection –Antigenic mimicry –Presentation error Tolerance –Recognition of ‘self’ –Very complicated and involves the development of thymic T-cells and linked recognition

13. Celiac Disease

14. Stages In The Genesis Of Type 1 Diabetes Beta cell mass Time (years) Immunologic abnormalities Blood glucose Decline in insulin 100% 0% Normal Precipitating event Intermittent hyperglycemia Overt diabetes

15. Model of Autoimmunity Thymus Periphery PAE cell T cell AIRE APS-I APCCD4 T cell Regulatory T cell FOXp3 FOXp3 IPEX Pathologic T cell Environment Innate Immunity HLA APS-II CD8 T cell B cell Cytokines Antibodies Eisenbarth GS, Gottlieb PA. NEJM 204;350:2068-2079.

16. Genetic Associations GeneProposed MechanismDiseaseInheritance HLAAntigen presentationAPS-IIMultigenic MIC-APriming of T-cellsType 1 diabetes; celiac; Addison Multigenic PTPN22T-cell receptor signalingType 1 diabetes; RA; SLE Multigenic CTLA-4Reduces T-cell activationType 1 diabetes; thyroid; celiac; Addison Multigenic AIREPeripheral antigen presentation to thymus APS-IAutosomal recessive FOXp3Transcription factor in T- cells IPEXX-linked

17. Autoimmune Polyendocrine Syndromes (APS)

18. Features of APS FeatureAPS-IAPS-II InheritanceAutosomal recessivePolygenic Generation AffectedSiblings onlyMultiple generations GeneAIRE mutationHLA-DR3 and DR-4 Gender AssociationEqual gender incidenceFemale preponderance Age at OnsetInfancyPeak onset 20-60 years Clinical FeaturesMucocutaneous candidiasis Hypoparathyroidism Addison disease Type 1 diabetes Autoimmune thyroid disease Addison disease

19. Autoimmune Conditions Associated with T1DM Associated DiseaseFrequencyRecommended Evaluation Addison Disease0.5%ACTH; 21-hydroxylase antibodies Hashimoto Thryoiditis15-30%TSH; TPO or Tg antibodies Celiac Disease5-10%Transglutaminase antibodies; biopsy Vitiligo1-9%Examination Pernicious Anemia0.5-5%CBC; B-12; anti-intrinsic factor antibody IgA Deficiency0.5%IgA levels Hypophysitis<0.5%Complex evaluation Gonadal Failure<0.5%History; sex steroid; LH/FSH

20. Genetic Associations GeneProposed MechanismDiseaseInheritance HLAAntigen presentationAPS-IIMultigenic MIC-APriming of T-cellsType 1 diabetes; celiac; Addison Multigenic PTPN22T-cell receptor signalingType 1 diabetes; RA; SLE Multigenic CTLA-4Reduces T-cell activationType 1 diabetes; thyroid; celiac; Addison Multigenic AIREPeripheral antigen presentation to thymus APS-IAutosomal recessive FOXp3Transcription factor in T- cells IPEXX-linked

21. Cases of Multiple Autoimmune Diseases and Type 1 Diabetes

22. Case 1 The patient is a 34 year old man who is referred for management of type 1 diabetes. He had enjoyed reasonable glycemic control (A1Cs 7.0-8.2%) and had been on an insulin pump for several years. Type 1 diabetes was diagnosed 7 years ago and he had no evidence of clinical complications. His profession involved travel, and he was recently admitted to a hospital because of severe hypoglycemia. In retrospect, he had noticed and increasing frequency of hypoglycemia over the preceding several months. He had also noted weight loss, nausea and fatigue. What causes increasing hypoglycemia in patients?

23. Examination Case 1 BP 88/60 mmHg Pulse 106 bpm Marked hyperpigmentation and vitiligo Thyroid slightly enlarged and firm. No nodules DTRs demonstrated pseudomyotonia

24. Laboratory Case 1 TestResultNormal Range ACTH2056 pg/ml9-45 pg/ml Cortisol1.7 ug/dl> 5.0 ug/dl TSH45 uIU/ml0.3-4.0 uIU/ml Free T40.5 ng/ml0.8-1.7 ng/ml Sodium129 mEq/l136-146 mEq/l Potassium6.4 mEq/l3.7-5.1 mEq/l Hemoglobin8 gm/l11-14 gm/l What is your diagnosis?

25. Case 2 A 43 year old woman is seen in follow up of type 1 diabetes and hypothyroidism. She has always been under excellent control (A1C < 7.0%) and her TSH was always normal on levothyroxine. She had recently noted a progressive feeling of fatigue. She had at least 3 episodes of “food poisoning” due to bad mayonnaise and found it harder to recover after each event. Routine labs documented abnormal liver functions with a low albumin; anemia; and her TSH was 22 uIU/L. What organ systems are involved? What are your thoughts?

26. Case 2 Evaluation Tests for celiac disease –Tissue transglutaminase antibodies –Endomysial antibodies –Antigliadin antibodies (IgA/IgG) –Biopsy –Response to a gluten free diet

27. Case 3 A 57 year old woman comes to clinic for evaluation of type 1 diabetes. She feels terrible. Fatigue, hypoglycemia, headaches and dizziness are her complaints. Her A1C is 5.7 %. Physical examination reveals a chronically ill woman without focal findings. Initial laboratory tests document hyponatremia (128 mEq/l), hypokalemia (3.1 mEq/l) and anemia. TSH is normal (1.2 uIU/l) and free T4 is low (0.6 ug/ml). Any other tests? Any thoughts?

28. Case 3 Laboratory TestResultNormal ACTH7 pg/ml9-45 pg/ml Cortisol2.1 ug/dl> 5.0 ug/dl FSH1.2 uIU/ml>30 uIU/ml (menopausal) TSH1.2 uIU/ml0.3-4.0 uIU/ml Free T40.6 ng/dl0.8-1.7 ng/ml IGF-1< 30 ng/ml>90 ng/ml Prolactin3.0 ng/ml<22.0 ng/ml What is going on?

29. Case 3 Radiology PatientNormal

30. Case 4 A 57 year old woman is referred for management of poorly controlled type 2 diabetes. She has been effectively managed with oral agents but her most recent A1C was 9.2%. She also has rheumatoid arthritis, hypothyroidism and vitiligo. She has also noted a worsening of depressive symptoms. Her BMI is 38 kg/m 2. What is the issue with this patient?

31. Family History Case 4

32. Antibodies in Type 1 Diabetes Autoantibodies –GAD65 –ICA512 (IA-2) –Insulin autoantibodies Diabetes TypeIslet AutoantibodiesComments Type 1APositive90% non-Hispanic white 50% black children Type 1BNegativeRare in whites Type 2NegativeIf antibody is positive, likely a LADA (T1DM) Other/MODYNegative

33. Case 5 You are seeing an old patient in follow up. Her last visit was two years ago. She has type 1 diabetes that had been very well controlled, but recently, she has noted that her glucose control has deteriorated. She reports taking much more insulin with less effect. She also notes frequent “insulin shock” with symptoms of palpitations, sweating and tremor, but she is puzzled because her symptoms can occur with glucose values over 200 mg/dl. She has also lost 15 pounds.

34. Case 5 Examination –BP 136/50 mmHg –P 120 bpm –Pronounced stare with exopthalmus –Thyroid enlarged with distinct bruit –Fine tremor –Skin warm and moist

35. Case 5 Laboratory TestResultNormal TSH<0.01 uIU/ml0.4-4.0 uIU/ml Free T4>7.0 ng/ml0.8-1.7 ng/ml Total T3567 pg/ml70-180 pg/ml TRABPositiveNegative 24 Hour RAIU78%15-30%

36. Case 6 A 47 year old woman is seen with a very ‘simple’ question, “will I develop type 1 diabetes?” She has hypothyroidism due to chronic lymphocytic thyroiditis and is on levothyroxine. Her family history is filled with autoimmune thyroid disease and type 1 diabetes. She is unaware of any endocrinopathy in her family. She has been dying her hair for 20 years because of ‘silvering’ which is aa common family trait. Her A1C is 5.3% and her fasting glucose values are always <75 mg/dl. What is her risk for type 1 diabetes?

37. Case 6 Laboratory A GAD65 antibody is ordered and returns positive (7.8 U/ml; normal <5 U/ml) Will she develop diabetes?