KAMPALA INTERNATIONAL

UNIVERSITY
FACULTY OF BIOMEDICAL SCIENCES
DEPARTMENT OF MICROBIOLOGY &
IMMUNOLOGY

IMMUNOPATHOLOGY

BMS 3.1

ENDOCRINE IMMUNE DISORDERS

Course instructor: Reuben Maghembe (PhD)

 Coverage

• Objectives

• Overview of the endocrine system

• General endocrine disorders

Objectives

• To explain the effect of immune system on single or multiple organs

• To explain the role of autoimmunity against endocrine glands on

endocrine dysfunction

• To describe various cellular and humoral auto-immune mechanisms

involved in different endocrine disorders

• To suggest relevant diagnostics and management approaches

Overview of the endocrine system
Immune response against endocrine
tissues 
• Is organ-specific autoimmunity
• Both cellular and antibody
mediated immune responses are
involved

• Manifestations are usually related to

the organ involved (single or
multiple organ involvement)
Key issues
• Dysregulation of thymic selection events

• The role of intrinsic and extrinsic factors that enhance the expansion
and pathogenicity of effector T cells

• Defects which impair homeostasis and suppressor activity of FoxP3-

expressing regulatory T cells

• Properties of victim cells which contribute to islet inflammation.

Autoimmune polyendocrine syndrome
types
• It is characterized by dysfunction of multiple endocrine glands as a result of autoimmunity and is
associated with:
• Hypoparathyroidism (Hypocaclaemia)
• Addison’s disease (Hypoglycemia, hypotension)
• Hypothyroidism
• Hypogonadism and infertility
• Vitiligo (depigmentation of the skin)
• Alopecia(baldness)

• Malabsorption and pernicious anemia

• Chronic active (autoimmune) hepatitis
• Diabetes (Type 1)
DIABETES MELLITUS

• Type 1: Autoimune: Beta

cell depletion
• 10% of all DM cases globally
• Occurs earlier in life

• Type 2: Insulin resistance &

decreased insulin secretion
• Most prevalent
• Later in life
Etiological factors for DM1
Genetic, epigenetic and immunological
Environmental
• Genetic • Viruses (rubella, enteroviruses)
• HLA
• Insulin-VNTR • Diet (cow’s milk, cereals, omega-
• CTLA-4 3 fatty acids, vitamin D)
• Other genetic associations: (PTPN22, AIRE,
FoxP3, STAT3, IFIH1, HIP14, ERBB3) • Gut microbiota
• Immunological
•  Immune tolerance (central, peripheral,
Tregs)
•  Cellular immunity
•  Humoral immunity (GAD65, IA-2, IAA, ZnT8)
 Genetic factors for T1DM
• The HLA gene loci • CTLA-4 (Long arm of Chr 2, 2q33):
• Mutations of the MHCII: • SNPs limit the suppressive role,
• HLA-DR3, DQB1*0201 (aka DR3-DQ2) promoting overstimulation of CTL
• HLA-DR4, DQB1*0302 (aka DR4-DQ8) • Required for suppression of CTL by
anergy
• Insulin VNTR (short arm of chr 11)
• Class I
• Class III-protective
• Fetal thymic regulation of autoreactive
T cell
Key players in the immunopathogenesis of DM1

• T-lymphocyte-mediated insulitis

• Presence of one or more type of autoantibody (AAb) against:

• insulin
• glutamic acid decarboxylase (GAD)
• protein tyrosine phosphatase IA-2 or IA-2β
• zinc transporter 8 (ZnT8)
Immunopathogenesis of T1DM
 Immunopathogenesis of DM1
• Both innate and adaptive
immune arms

• Death of ß-cells
• Necrosis
• Necroptosis
• Apoptosis

Proinflammatory cytokines IL-1, TNF-α and

TNF-γ
Autoreactive antigens trigger apotoptic ß-cell
death by CTLs
 Autoimmunity to beta-cells

• Unlike protective immunity where

inflammation is terminated, autoimmunity
is sustained by chronic inflammation
 AUTOIMMUNE THYROID DISEASES
• Autoimmune thyroid diseases (AITD) are the most • Examples of AITD
prevalent organ-specific autoimmune diseases
(ADs) and affect 2 - 5% of the population.
• Hashimoto thyroiditis
• Gender bias: women 5–15% and men 1–5%)
• Painless thyroiditis
• Complex interaction between genetic and
environmental factors.
• Postpartum thyroiditis.
• Subacute thyroiditis.
• Genetics: HLA-DR, CTLA-4, CD40, • Graves' disease.
• Environment: iodine excess, selenium deficiency, use
of anovulatories, viral or bacterial infections
• Etc.
 Hypothyroidism
Hypothyroidism - deficient production of TH by the thyroid
gland and/or  their action to the tissue

A. Primary hypothyroidism is caused by:

1. congenital defects or loss of thyroid tissue

2. defective hormone synthesis - due to: autoimmune

thyroiditis, endemic iodine deficiency, antithyroid drugs

B. Secondary hypothyroidism is caused by:

1. insufficient stimulation of the normal gland

2. peripheral resistance to TH
 The major manifestations of hypothyroidism
and mechanism of their onset

- Hypothyroidism generally affects all body systems with the

extent of the symptoms closely related to the degree of
TH deficiency.

- The individual develops a low basal metabolic rate, cold

intolerance, slightly lowered basal body temperature

- A decrease in TH   production of TSH  goiter

- Characteristic sign of hypothyroidism is mixedema 

increased amount of protein and mucopolysaccharides

in dermis   water binding  nonpitting edema, thickening
of the tongue, and the laryngeal and pharyngeal mucous
membranes  thick slurred speech and hoarseness
 Other manifestations:

a) neurologic: - confusion, syncope, slowed thinking, memory loss,

lethargy, hearing loss, slow movements
- cerebellar ataxia

Mechanisms involved:
- decreased cerebral blood flow  cerebral hypoxia
- decreased number of beta-adrenergic receptors
b) endocrine: -  TSH production (in primary hypothyroidism)

-  serum prolactin levels with galactorrhea

-  rate of cortisol turnover, but normal cortisol levels

Mechanisms involved:
-  TH   TSH
- stimulation of lactotropes by TRH   prolactin
- decreased deactivation of cortisol
c) reproductive: -  androgen secretion in men
-  estriol formation in women due to altered
metabolism of estrogens and androgens
- anovulation, decreased libido

- spontaneous abortion

d) hematologic: -  RBC mass  normocytic, normochromic anemia

- macrocytic anemia due to vitamin B12 deficiency

and inadequate folate absorption

Mechanisms involved:

-  basal metabolic rate   oxygen requirement 

  erythropoietin production
f) pulmonary: - dyspnoea - due to pleural effusions
- myxedematous changes of respiratory muscles
 hypoventilation

g) renal: - renal blood flow   GFR  renal excretion of water

total body fluid  dilutional hyponatremia
-  production of EPO

Mechanisms involved: - hemodynamic alteration

- mucinous deposits in tissue
h) gastrointestinal:  appetite, constipation, weight gain
 absorption of most nutrients
 protein metabolism,  glucose uptake
 sensitivity to exogenous insulin
 concentration of serum lipids
 Hashimoto thyroiditis (HT)

• The body makes antibodies that attack the cells in the thyroid
• Leads to decreased thyroid hormone

Manifestation
Pathogenesis
• Gradual loss of thyroid function, goiter, or both • Two major clinical forms of HT are:
due to autoimmune–mediated destruction of
the thyroid gland through apoptosis of the 1) Goitrous autoimmune thyroiditis
thyrocytes. 2) Atrophic autoimmune thyroiditis
• Mechanisms: • Lab tests:
• Molecular mimicry
• Non specific lymphocyte activation by virus-thyroid
• TSH, fT4, TPOAb, and TgAb.
gland inflammation-thyroiditis via IL-1 expression • The usual findings in patients with
•  thyroid cell expression of HLA antigens and antigen hypothyroidism include high TSH
presentation
and low fT4 levels.
• Apoptosis by Th1-induced expression of Fas and Fas
on thyrocytes. i.e. self depopulation
Hyperthyroidism is a condition in which thyroid hormones
(TH) exert greater-than-normal response
Causes:
- Graves disease
- exogenous hyperthyroidism (iatrogenic, iodine induced)
- thyroiditis
- toxic nodular goiter
- thyroid cancer

  All forms of hyperthyroidism share some common characteristic:

· metabolic effect of increased circulating levels of thyroid

hormones   metabolic rate with heat intolerance and increased tissue
sensitivity to stimulation by sympathetic division of the autonomic
nervous system;
 The major manifestations of hyperthyroidism
and mechanisms of their onset

a) endocrine:
- enlarged thyroid gland (TG) with systolic or continous bruit over
thyroid due to blood flow
-  cortisol degradation – due to metabolic rate
- hypercalcemia and decreased PTH secretion - due to excess bone
resorption
- diminished sensitivity to exogenous insulin- due to hyperglycemia
(glycogenolysis and gluco-neogenesis)

b) reproductive:
- oligomenorrhea or amenorrhe due to hypothalamic or pituitary
disturbances
- impotence and decreased libido in men
c) gastrointestinal:
- weight loss and associated increase in appetite due to increased catabolism
- increased peristalsis  less formed and more frequent stools - due to
malabsorption of fat
- nausea, vomiting, anorexia, abdominal pain
- increased use of hepatic glycogen stores and adipose and protein stores
- decrease of tissue stores of vitamins
- hyperlipid – acidemia (due to lipolysis)

d) integumentary:
- excessive sweating, flushing, and warm skin
- heat loss
- hair faint, soft, and straight, temporary hair loss
- nails that grow away nail beds

All these signs and symptoms are due to metabolic effect of TH

 Graves’ disease
 Key features: Hyperthyroidism, diffuse goiter, ophthalmopathy (GO), and dermopathy

Causes and pathogenesis Manifestation and diagnosis

• Circulating TRAb bind and • Blood TSH, T3, T4

activate the TSH receptor
• Thus stimulating follicle
hypertrophy and hyperplasia as
well as increasing the synthesis of
thyroid hormones and the fraction
of T3 relative to T4
• People with Graves' disease usually
have lower than normal levels of TSH
but higher levels of T3 or T4.
• Ultrasound and MRI
• Enlarged thyroid
• Radioactive iodine uptake
 Common clinical signs of Graves disease

Enlarged thyroid
Widespread enlargement of the thyroid can expand the
gland well beyond its typical size (left) and cause a Graves' ophthalmopathy
noticeable bulge in the neck (right). Graves' ophthalmopathy signs and symptoms include
bulging eyes, redness and retracting eyelids
Graves' dermopathy
• Rarely, people who have Graves' disease develop a
reddish thickening of the skin that resembles the texture
of an orange peel (Graves' dermopathy)

• This results from a buildup of protein in the skin.

• It often occurs on the shins and on the tops of the feet.

Treatment of hyperthyroidsm
1. Beta blockers
• Propanolol
2. Anti-thyroid drugs:
• Propylthiouracyl
• Methimazole
3. Surgery
Study questions
1. Write short notes on the Jod basedow phenomenon
2. Differentiate between primary and secondary hyperthyroidism
3. Under what circumstances hyperthyroidism can be transient or chronic?
4. How about chronic hypothyroidism?
5. State the function of the following in thyroid physiology:
• Iodine
• Thyroglobulin
• TPO
• Deiodinase
6. What environmental factors could trigger hyperthyroidism
7. Explain the immunological aetiology of hyperthyroidism and show how it differs from that of
hypothyroidism
8. When would you associate choriocarcinoma and struma ovarii with hyperthyroidism?