Autoimmunity and Diabetes

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

2. Objectives • Understand current concepts in the pathogenesis of autoimmunity • Learn the different types of the immunoendocrinopathy syndromes • 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

9. 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 Precipitating event Immunologic abnormalities Decline in insulin 100% Intermittent hyperglycemia Blood glucose Beta cell mass Normal 0% Overt diabetes Time (years)

15. Model of Autoimmunity B cell Thymus Antibodies Environment Innate Immunity Pathologic T cell FOXp3 IPEX AIREAPS-I HLA APS-II T cell PAE cell CD4 T cell APC CD8 T cell FOXp3 T cell Regulatory T cell Cytokines Periphery Eisenbarth GS, Gottlieb PA. NEJM 204;350:2068-2079.

16. Genetic Associations

17. Autoimmune Polyendocrine Syndromes (APS)

18. Features of APS

19. Autoimmune Conditions Associated with T1DM

20. Genetic Associations

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 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 What is going on?

29. Case 3 Radiology Normal Patient

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/m2. 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

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

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?