1. Immunology of Endocrine Gland Diseases
بنام خدا
Immunology of Endocrine Gland Diseases
Dr. Mohammad Vojgani
Farimah Masoumi
Immunology Department
TUMS

2. The endocrine glands

3. absence of a duct system
The endocrine glands
rich vascularization

4. Autoimmune Endocrinopathy
Adrenal Glands
Autoimmune Response
Pituitary Gland
Thyroid
Autoimmune Endocrinopathy
Ovaries
Pancreas
Parathyroid
Testes

5. Graves disease
Hashimoto thyroiditis
diabetes mellitus
Autoimmune polyendocrinopathy syndrome
Addison disease

6. Diabetes

7. Glucose Intolerance
Hyperglycemia
FBS > 126 mg/dl HbA1c > OGTT >200 mg/dl

8. Signs & symptoms Hyperglycemia Polyuria Ketoacidosis Ketonuria
Ketunemia
Nausea
Hyperventilation
Weight Loss

9. Presence of autoantibodies
Immune-mediated (Juvenile onset/IDDM)
B. Idiopathic
Presence of autoantibodies
Type 1
(Fulminant)
Diabetes Mellitus (DM)
Type 2
(NIDDM)
Gestational diabetes

10. environmental factors
Stages in the development of type 1A diabetes.

11. Genetic susceptibility
environmental factors
Genetic susceptibility
Active autoimmunity

12. environmental factors
Stages in the development of type 1A diabetes.

13. Stages in the development of type 1A diabetes.

14. Stages in the development of type 1A diabetes.

15. Clinical manifestation
Immune destruction of β cells
months to years
overt hyperglycemia
Clinical manifestation

16. Clinical manifestation
Immune destruction of β cells
months to years
overt hyperglycemia
Clinical manifestation

17. Autoimmune Response β‑cell hormone insulin (or proinsulin)
glutamic acid decarboxylase (GAD65)
Islet cell autoantigen (ICA) 512
ZnT8 (zinc transporter)
ICA512 (IA2)
PDX1

18. Genetic susceptibility
IDDM
Environmental Factors

19. Genetic susceptibility
HLA genes
Genetic susceptibility
Non-HLA genes
Coxsackie B virus
Infections
Rubella virus
Milk proteins
Environmental Factors
vitamin D

20. Non-HLA genes CTLA-4 PTPN22 CD25 CD40 Insulin
Protein tyrosine phosphatase, non-receptor type 22 (lymphoid),
Several modulators of T-cell signaling have been defined as
important susceptibility determinants in autoimmunity.15 For
example, CTLA4 polymorphisms are associated with increased
risk of a variety of autoimmune diseases, including type I diabetes,
Graves disease, and RA. Similarly, a functional polymorphism
in PTPN22 has been identified as a major risk factor for
several human autoimmune diseases, including SLE, RA, and
type I diabetes. Although the exact mechanisms underlying
susceptibility to autoimmunity remain unclear, in both cases
the polymorphisms appear to regulate the balance of stimulatory
and inhibitory signaling in effector and regulatory T cells,
favoring effector T-cell activation.

21. ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB).

22. Role of HLA genes

23. Genetic susceptibility
HLA genes
Genetic susceptibility
Non-HLA genes
Coxsackie B viruse
Infections
Rubella virus
Environmental Factors
Milk proteins
vitamin D

24. coxsackie viral protein 2 C (P2-C)
coxsackievirus B
Molecular mimicry
GAD65

25. Coxsackie viral protein 2 C (P2-C)
Bind to
HLA-DR3
Molecular mimicry
GAD65

26. Genetic susceptibility
IDDM
Environmental Factors

29. Bystander activation

30. inhibit the suppressive activity of Treg
viral infections
TLRs
inhibit the suppressive activity of Treg
Auto-aggressive
T cells
T Reg cells

31. Abnormality in Treg suppressive function
viral infections
TLRs
inhibit the suppressive activity of Treg
Abnormality in Treg suppressive function
T Reg cells
Auto-aggressive
T cells

32. Milk Proteins (Cow's milk )
bovine serum albumin (BSA)
Molecular Mimicry
BSA
ICA-69

33. Molecular Mimicry
BSA
ICA-69
Oral tolerance

34. Role of immune cells in β-cell destruction?

36. β-cell proteins are phagocytosed by professional antigen-presenting cells (APCs), such as dendritic cells. APCs process these proteins to peptide fragments that are presented by MHC class II molecules to pro-inflammatory T helper 1 (TH1) cells, which in turn activate a cascade of immune responses, including activation of B cells (which produce islet antigen-specific autoantibodies) and islet antigen-specific cytotoxic T lymphocytes (CTLs) that can directly lyse β-cells presenting islet peptides by MHC class I molecules on their surface. Alternatively, APCs can present islet antigenic peptides to regulatory T (TReg) cells that suppress the pro-inflammatory cascade, preventing β-cells from being destroyed. Several immunological features (boxes) distinguish patients with type 1 diabetes from healthy individuals, collectively predisposing them to disease.

38. Selective destruction of pancreatic β cells

39. Clinical manifestation
Immune destruction of β cells
months to years
overt hyperglycemia
Clinical manifestation
Diagnostic Biomarkers

40. Biomarker and Diagnosis
ZnT8Ab autoantibody test (FDA approved)

41. Immunotherapy Autoantigen Therapy Monoclonal antibody therapy
DCs therapy (DV-0100, phase II)
Immunotherapy
Treg therapy
MSC Transplantation
Islet cell Transplantation

42. ? Autoantigen Therapy restore tolerance
induction of regulatory T cells ?
Autoantigen Therapy
restore tolerance

43. GAD-alum vaccine (phase III)
Glutamic acid decarboxylase 65 (GAD65) and DiaPep277 (a protein corresponding to amino-acid positions 437–460 of the human heat shock protein 60) are examples of antigen-specific therapies that aim to restore tolerance and achieve remission of autoimmunity in type 1 diabetes. The exact mechanism of how antigen-specific tolerance is achieved is not clear, but induction of regulatory T cells has been postulated94. Cytokine-targeted therapy with anti-tumour necrosis factor (TNF) therapy (for example, with etanercept) or anti-interleukin-1 (IL-1) therapy (for example, with anakinra) may downregulate pro-inflammatory responses that may maintain insulitis. In addition, anti-IL-1 therapy may help preserve pancreatic β-cell function. Cytotoxic T lymphocyte-associated antigen 4–immunoglobulin G1 (CTLA4–Ig; for example, abatacept) binds the CTLA4 ligands CD80 and CD86 and prevents T cell activation via co-stimulation of CD28. Normally, CTLA4 is expressed on the surface of CD4+ cells and delivers an inhibitory signal when it binds CD80 and CD86 on antigen-presenting cells (APCs). Rabbit anti-thymocyte globulin (rATG; also known as thymogobulin) is a purified polyclonal γ-immunoglobulin raised in rabbits against human thymocytes. The main mechanism of action of rATG is the depletion of T cells. Anti-CD20 therapy (for example, rituximab, a chimeric antibody that targets CD20 found on B lymphocytes) depletes B lymphocytes. For details on the mechanism of action of anti-CD3 therapies, see Fig. 3. MHC, major histocompatibility complex.

44. Teplizumab and otelixizumab are non-Fc receptor binding CD3-specific humanized monoclonal antibodies (mAbs) that act in a biphasic manner. Initially, there is a partial depletion of activated pathogenic T cells, and this effect is short-lived. The second durable response is postulated to involve the induction of regulatory T (TReg) cells. Interleukin-10 (IL-10)-producing and FOXP3+ CD4+ and CD8+ TReg cells have been described. The CD4+ TReg cell population is thought to act through the production of transforming growth factor-β (TGFβ) and IL-10. This induced TReg population may inhibit autoreactive T cells to pancreatic islet β-cells and thereby restore tolerance. APC, antigen-presenting cell; MHC, major histocompatibility complex.

45. down regulate pro-inflammatory responses
Etanercept (anti-TNF)
down regulate pro-inflammatory responses

46. Rabbit anti-thymocyte globulin (rATG

47. Rabbit anti-thymocyte globulin (rATG

48. Adoptive transfer of regulatory T cells
GAD65
GAD65-specific TR 1 cells

49. Hashimoto thyroiditis
Grave’s disease
Hashimoto thyroiditis

50. Hashimoto’s thyroiditis
Graves disease
Hashimoto’s thyroiditis
Autoimmune hyperthyroidism
Autoimmune hypothyroidism

51. Autoantigens in autoimmune thyroiditis
Thyroid Peroxidase (TPO)
TSH-R
Thyroglobulin (Tg)

52. Hashimoto’s thyroiditis Graves’ disease
During Hashimoto’s thyroiditis, self-reactive CD4+ T lymphocytes recruit B cells and CD8+ T cells into the thyroid. Disease progression leads to the death of thyroid cells and hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have been proposed to be responsible for autoimmune thyrocyte depletion. b | In Graves’ disease, activated CD4+ T cells induce B cells
to secrete thyroid-stimulating immunoglobulins (TSI) against the thyroid-stimulating hormone receptor (TSHR), resulting in
unrestrained thyroid hormone production and hyperthyroidism.

53. Cell-mediated immune response
Hashimoto’s thyroiditis
Graves’ disease
Cell-mediated immune response
Autoantibody
Autoantibody
During Hashimoto’s thyroiditis, self-reactive CD4+ T lymphocytes recruit B cells and CD8+ T cells into the thyroid. Disease progression leads to the death of thyroid cells and hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have been proposed to be responsible for autoimmune thyrocyte depletion. b | In Graves’ disease, activated CD4+ T cells induce B cells to secrete thyroid-stimulating immunoglobulins (TSI) against the thyroid-stimulating hormone receptor (TSHR), resulting in unrestrained thyroid hormone production and hyperthyroidism.
Blocking anti-TSHR
Activator anti-TSHR

54. Lymphocyte infiltration
ectopic follicle (germinal center)
Hashimoto’s thyroiditis

55. Main histopathological feature Hashimoto’s thyroiditis
massive lymphocyte accumulation

57. Transient Graves’ disease
Antibody-mediated autoimmune diseases can
appear in the infants of affected mothers as a consequence
of transplacental antibody transfer. In pregnant women, lgG
antibodies cross the placenta and accumulate in the fetus before
birth (see Fig ). Babies born to mothers with lgG-mediated
autoimmune disease therefore frequently show symptoms
similar to those of the mother in the first few weeks of life.
Fortunately, there is little lasting damage because the symptoms
disappear along with the maternal antibody. In Graves' disease,
the symptoms are caused by antibodies against the thyroidstimulating
hormone receptor (TSHR). Children of mothers making
thyroid-stimulating antibody are born with hyperthyroidism, but
this can be corrected by replacing the plasma with normal plasma
(plasmapheresis), thus removing the maternal antibody.

58. Graves’ ophthalmopathy
Orbit Fibroblast

59. Graves’ ophthalmopathy
Orbit Fibroblast
hyaluronic acid
secrete cytokines and chemokines
adipogenesis
Inflammatory response
restriction of extraocular eye movements
edema and swelling

60. optic-nerve compression

61. following surgical orbital decompression and rehabilitative surgery

63. Environmental factors
Smoking
Iodine
Stress
Successful treatment of HIV with HAART (highly active antiretroviral therapy)
Infections e.g., hepatitis C

65. Autoimmune polyendocrine syndromes
Autoimmune polyendocrine syndrome type I (APS-I) Autoimmune polyendocrine syndrome type II (APS-II) IPEX
Autoimmune polyendocrine
syndrome type I (APS1), also called autoimmune polyendocrinopathy
candidiasis ectodermal dystrophy (APECED), is a rare disease
in which patients develop multiple autoimmune diseases,
often beginning in childhood.7 While candidiasis and ectodermal
dystrophy (including involvement of enamel and nails, as
well as keratopathy) are features of the disease, the syndrome
is characterized by striking autoimmunity directed against multiple
different target tissues. Autoimmune processes include autoimmune hypoparathyroidism, Addison disease, autoimmune
gastritis with pernicious anemia, type I diabetes, thyroid disease,
autoimmune hepatitis, celiac disease, and gonadal failure. The genetic basis of APS1 was mapped to
a gene on chromosome 21q22.3, subsequently termed AIRE (for
autoimmune regulator). AIRE expression is highest in the thymus,
where it is expressed in medullary thymic epithelial cells.
Several predicted structural features of the AIRE protein, and its
localization in nuclear dots, suggested that the protein might
be a transcriptional regulator, and significant evidence for this
proposal was obtained in vitro. Several AIRE-deficient mouse
models were subsequently generated, which allowed the definition
of important pathogenic pathways in APS1 that are likely
broadly relevant to the mechanisms of autoimmunity in general.
Thus, mice deficient for AIRE developed various autoimmune
phenotypes, resembling those found in human APS1. These included
multiorgan lymphocytic infiltration and autoantibodies,
as well as autoimmune eye disease. In an elegant series of experiments,
Mathis and colleagues demonstrated that AIRE regulates
expression in thymic epithelial cells of various peripheral autoantigens
normally expressed exclusively in endocrine target tissues.
9 Similarly, thymic expression of the mouse lung protein
vomeromodulin is also AIRE-dependent, and loss of tolerance
to this antigen is sufficient to cause interstitial lung disease in
wild type mice.10 Thus, AIRE appears to regulate the ectopic
expression in the thymus of tissue-restricted autoantigens, and
provide an antigen source against which to establish central
tolerance.

66. Abbreviations: APS, autoimmune polyglandular syndrome; CTLA4, cytotoxic T lymphocyte associated
antigen 4; FOXP3, forkhead box P3 gene; GAD, glutamate decarboxylase; HLA, human leukocyte antigen;
IPEX, immune dysfunction, polyendocrinopathy, enteropathy, X‑linked; MICA5.1, MHC class I‑related gene A;
IA‑2, islet antigen 2; PTPN22, protein tyrosine phosphatase, non‑receptor 22; TPO, thyroid peroxidase;
Tg, thyroglobulin; TTG, tissue transglutaminase; VNTR, variable number tandem repeat in the 5' promoter of
the insulin gene; ZnT8, zinc T8 transporter.

67. Pathogenic model for the autoimmune polyglandular syndromes
HLA-II molecules predispose to tissue specific targeting

68. Autoimmune polyendocrine syndrome type I (APS-I)
autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) manifests during infancy
a child has at least two of the following pathologies:
1) mucocutaneous candidiasis
2) Hypoparathyroidism (hypocalcemia)
3) Addison disease (Hypotension or fatigue)
Eighteen percent of patients develop type 1A diabetes

69. transcription factor AIRE (autoimmune regulator)
Central Tolerance

70. APS-2
presence of at least two of three diseases in the same patient: T1DM Addison disease and autoimmune thyroid disease

71. APS-2
Schmidt syndrome the most frequent autoimmune polyglandular syndrome the incidence is two to three times higher in females than in males

72. Autoantibodies in APS2: anti‑21OH in Addison disease Anti-glutamic acid decarboxylase in T1DM Anti-IA‑2 in T1DM

73. Autoimmune Addison disease
primary adrenocortical insufficiency (autoimmune disease)
Individuals with type 1A diabetes have a 100 times greater risk of developing Addison’s disease
This significant increase justifies anti-21-hydroxylase autoantibody screening in type 1A diabetics.

74. Steroidogenic enzymes
Adrenal Glands
steroid 21-hydroxylase
(CYP21)
Cortisol
Aldosterone
Steroidogenic enzymes
steroid 17‑α-hydroxylase

75. Stages in the development of Addison disease
Stages in the development of Addison disease. Adrenocortical function is
lost over a period of years. In the first stage, genetic predisposition is conferred
through human leukocyte antigen (HLA) genes. In the second stage, unknown
events precipitate anti‑adrenal autoimmunity. In the third stage, which involves
presymptomatic disease, steroid 21‑hydroxylase autoantibodies production predicts
future disease. Finally, overt Addison disease develops. An increased plasma renin
level is one of the first metabolic abnormalities to occur and is followed by the
sequential development of other metabolic abnormalities (a decreased cortisol
level after cosyntropin stimulation, an elevated ACTH level and a decreased basal
cortisol level). Finally, symptoms of adrenal insufficiency, such as fatigue,
hyperpigmentation and hypotension, manifest. Abbreviations: ACTH,
adrenocorticotropic hormone.
Stages in the development of Addison disease

77. IPEX syndrome
immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
Extremely rare disease
mutations in the forkhead box P3 (FOXP3) gene
results in the absence or dysfunction of regulatory T cells
Main manifestation:
type 1A diabetes mellitus
that can develop as early as 2 days after birth
Children affected with IPEX syndrome usually die in the first 2 years of life

78. An overview of the common, less common and rare autoimmune and/or endocrine diseases and their affected organs that are discussed in this article. Abbreviations: AIT, autoimmune thyroid disease; APS2, autoimmune polyendocrine syndrome type 2; APS1, autoimmune polyendocrine syndrome type 1; IPEX, immune dysfunction, polyendocrinopathy and enteropathy, X‑linked; SLE, systemic lupus erythematosus; T1DM, type 1 diabetes mellitus.

79. Case
Billy was born at full term and developed atopic dermatitis shortly after birth.
local application of hydrocortisone and antihistamines to control itching, the treatment being only partly successful.
At 4 months of age, Billy developed an intractable watery diarrhea
his weight had fallen below the third centile for his age.
At 6 months old, Billy started to develop high blood glucose levels and glucose in the urine
Eczematous rash on the face
He was diagnosed with type 1 diabetes

80. His cervical and axillary lymph nodes and spleen were enlarged
Laboratory tests revealed a normal white blood cell count
Autoantibodies were found against glutamic acid decarboxylase (the GAD65 antigen) and against pancreatic islet cells.
a duodenal biopsy revealed almost total villous atrophy-an absence of villi in the lining of the duodenum-with a dense infiltrate of plasma cells and T cells
An endoscopy was ordered, to ascertain the cause of his persistent diarrhea, and
When Billy's mother was questioned, she revealed that there had been another son, who had died in infancy with severe diarrhea and a low platelet count.

81. On the basis of Billy's symptoms and the family history, IPEX (immune dysregulation, polyendocrinopathy, enteropathy X-linked) was suspected
A FACS analysis of Billy's peripheral blood mononuclear cells revealed a lack of both CD4 CD25 cells and CD4 Foxp3-positive cells.
Sequencing of Billy's FOXP3 gene revealed a missense mutation, confirming the diagnosis.

82. With the diagnosis established, immunosuppressive therapy, including cyclosporine and tacrolimus, was started
After several months, however, his symptoms began to return
and he stopped gaining weight. Shortly afterwards, he developed thrombocytopenia (a deficiency of blood platelets) and anti-platelet antibodies were detected.
The decision was made for Billy to be given a bone marrow transplant from his 5-yearold HLA-identical sister.

84.  Case 15.1 Graves' disease
A 29-year-old woman presented with a 3-month history of increased sweating and palpitations with weight loss of 7kg. On examination, she was a nervous, agitated woman with an obvious, diffuse, non-tender, smooth enlargement of her thyroid, over which a bruit could be heard. She had a fine tremor of her fingers and a resting pulse rate of 150/minute. She had no evidence of exophthalmos (contrast with figure which shows exophthalmos). A maternal aunt had suffered from 'thyroid disease'.
On investigation, she had a raised serum T3 of 4.8nmol/l (NR ) and a T4 of 48nmol/l (NR 9-23). Measurement of her thyroid-stimulating hormone showed that this was low normal, 0.4mU/l (NR 0.4-5_mU/l). The biochemical findings pointed to primary thyroid disease rather than pituitary overactivity. Circulating antibodies to thyroid peroxidase (titre 1/3000; 200iu/ml) were detected by agglutination. A diagnosis of autoimmune thyrotoxicosis (Graves' disease) was made. She was treated with an antithyroid drug, carbimazole, to control her thyrotoxicosis, and surgery was not required.