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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
Precipitating event
Immunologic abnormalities
100%
Beta cell mass
Decline in
insulin
Intermittent
hyperglycemia
Blood
glucose
Normal
0%
Time (years)
Overt
diabetes
Model of Autoimmunity
B cell
Thymus
Antibodies
FOXp3
IPEX
AIRE
APS-I
Environment
Innate
Immunity
Pathologic
T cell
HLA
APS-II
T cell
PAE cell
CD4
T cell
T cell
APC
CD8
T cell
FOXp3
Regulatory
T cell
Cytokines
Periphery
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
Peripheral antigen
presentation to thymus
APS-I
Autosomal
recessive
Transcription factor in Tcells
IPEX
X-linked
AIRE
FOXp3
Autoimmune Polyendocrine
Syndromes (APS)
Features of APS
Feature
Inheritance
Generation Affected
Gene
Gender Association
Age at Onset
Clinical Features
APS-I
APS-II
Autosomal recessive
Polygenic
Siblings only
Multiple generations
AIRE mutation
HLA-DR3 and DR-4
Equal gender incidence
Female preponderance
Infancy
Peak onset 20-60 years
Mucocutaneous
candidiasis
Hypoparathyroidism
Addison disease
Type 1 diabetes
Autoimmune thyroid
disease
Addison 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
Peripheral antigen
presentation to thymus
APS-I
Autosomal
recessive
Transcription factor in Tcells
IPEX
X-linked
AIRE
FOXp3
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
8 gm/l
11-14 gm/l
Hemoglobin
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
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
Free T4
What is going on?
Case 3 Radiology
Normal
Patient
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 white
50% 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
Positive
Negative
78%
15-30%
TRAB
24 Hour RAIU
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?