Autoimmunity and Diabetes

Robert E. Jones, MD, FACP, FACE

Professor of Medicine

University of Utah School of Medicine

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

Immunity

The Players

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

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

T Cell Interactions

Class II MHC

Dendritic Cell

Dendritic Cell

HLA Involvement in Antigen Presentation

Theories of Autoimmunity

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

Celiac Disease

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

Model of Autoimmunity

Thymus

Periphery

PAE cell

T cell

T cell

AIREAPS-I

APCCD4 T cell

Regulatory T cell

FOXp3

FOXp3 IPEX

Pathologic T cell

Environment Innate ImmunityHLA

APS-II

CD8 T cell

B cell

Cytokines

Antibodies

Eisenbarth GS, Gottlieb PA. NEJM 204;350:2068-2079.

Genetic Associations

Gene Proposed Mechanism Disease Inheritance

HLA Antigen presentation APS-II Multigenic

MIC-A Priming of T-cells Type 1 diabetes; celiac; Addison

Multigenic

PTPN22 T-cell receptor signaling Type 1 diabetes; RA; SLE

Multigenic

CTLA-4 Reduces T-cell activation Type 1 diabetes; thyroid; celiac;

Addison

Multigenic

AIRE Peripheral antigen presentation to thymus

APS-I Autosomal recessive

FOXp3 Transcription factor in T-cells

IPEX X-linked

Autoimmune Polyendocrine Syndromes (APS)

Features of APS

Feature APS-I APS-II

Inheritance Autosomal recessive Polygenic

Generation Affected Siblings only Multiple generations

Gene AIRE mutation HLA-DR3 and DR-4

Gender Association Equal gender incidence Female preponderance

Age at Onset Infancy Peak onset 20-60 years

Clinical Features Mucocutaneous candidiasis

HypoparathyroidismAddison disease

Type 1 diabetesAutoimmune thyroid

diseaseAddison disease

Autoimmune Conditions Associated with T1DM

Associated Disease Frequency Recommended Evaluation

Addison Disease 0.5% ACTH; 21-hydroxylase antibodies

Hashimoto Thryoiditis 15-30% TSH; TPO or Tg antibodies

Celiac Disease 5-10% Transglutaminase antibodies; biopsy

Vitiligo 1-9% Examination

Pernicious Anemia 0.5-5% CBC; B-12; anti-intrinsic factor antibody

IgA Deficiency 0.5% IgA levels

Hypophysitis <0.5% Complex evaluation

Gonadal Failure <0.5% History; sex steroid; LH/FSH

Genetic Associations

Gene Proposed Mechanism Disease Inheritance

HLA Antigen presentation APS-II Multigenic

MIC-A Priming of T-cells Type 1 diabetes; celiac; Addison

Multigenic

PTPN22 T-cell receptor signaling Type 1 diabetes; RA; SLE

Multigenic

CTLA-4 Reduces T-cell activation Type 1 diabetes; thyroid; celiac;

Addison

Multigenic

AIRE Peripheral antigen presentation to thymus

APS-I Autosomal recessive

FOXp3 Transcription factor in T-cells

IPEX X-linked

Cases of Multiple Autoimmune Diseases and Type 1 Diabetes

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?

Examination Case 1

• BP 88/60 mmHg

• Pulse 106 bpm

• Marked hyperpigmentation and vitiligo

• Thyroid slightly enlarged and firm. No nodules

• DTRs demonstrated pseudomyotonia

Laboratory Case 1

Test Result Normal Range

ACTH 2056 pg/ml 9-45 pg/ml

Cortisol 1.7 ug/dl > 5.0 ug/dl

TSH 45 uIU/ml 0.3-4.0 uIU/ml

Free T4 0.5 ng/ml 0.8-1.7 ng/ml

Sodium 129 mEq/l 136-146 mEq/l

Potassium 6.4 mEq/l 3.7-5.1 mEq/l

Hemoglobin 8 gm/l 11-14 gm/l

What is your diagnosis?

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?

Case 2 Evaluation

• Tests for celiac disease– Tissue transglutaminase antibodies

– Endomysial antibodies

– Antigliadin antibodies (IgA/IgG)

– Biopsy

– Response to a gluten free diet

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?

Case 3 Laboratory

Test Result Normal

ACTH 7 pg/ml 9-45 pg/ml

Cortisol 2.1 ug/dl > 5.0 ug/dl

FSH 1.2 uIU/ml >30 uIU/ml (menopausal)

TSH 1.2 uIU/ml 0.3-4.0 uIU/ml

Free T4 0.6 ng/dl 0.8-1.7 ng/ml

IGF-1 < 30 ng/ml >90 ng/ml

Prolactin 3.0 ng/ml <22.0 ng/ml

What is going on?

Case 3 Radiology

PatientNormal

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?

Family History Case 4

Antibodies in Type 1 Diabetes

• Autoantibodies– GAD65– ICA512 (IA-2)– Insulin autoantibodies

Diabetes Type Islet Autoantibodies Comments

Type 1A Positive 90% non-Hispanic white50% black children

Type 1B Negative Rare in whites

Type 2 Negative If antibody is positive, likely a LADA (T1DM)

Other/MODY Negative

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.

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

Case 5 Laboratory

Test Result Normal

TSH <0.01 uIU/ml 0.4-4.0 uIU/ml

Free T4 >7.0 ng/ml 0.8-1.7 ng/ml

Total T3 567 pg/ml 70-180 pg/ml

TRAB Positive Negative

24 Hour RAIU 78% 15-30%

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?

Case 6 Laboratory

• A GAD65 antibody is ordered and returns positive (7.8 U/ml; normal <5 U/ml)

• Will she develop diabetes?