Immunology of endocrine

1
Immunology of endocrine diseases Aetiology BS93
6 autoimmunity component Professor Nelson
Fernández
2
There are over 80 types of autoimmune diseases.
Many have overlapping symptoms. The most commonly
cited complaints amongst autoimmune disease
sufferers are fatigue, low-grade fever and sore
muscles. Autoimmune diseases can affect any part
of the body, including the nerves, muscles,
endocrine system and digestive system.
3

• Autoimmune disease results from a breakdown in
  immunological
• tolerance

4
(No Transcript)
5
Mechanisms hypothesized to be involved in the
breakdown of tolerance Failure to delete
autoreactive lymphocytes Central tolerance
failure Peripheral tolerance failure Molecular
mimicry Abnormal presentation of self
antigens Aberrant expression of major
histocompatibility complex class II
molecules Coupling of self and nonself
antigens Overproduction of self
antigens Disclosure of cryptic T-cell
epitopes Release of sequestered self
antigens Epitope spreading Polyclonal lymphocyte
activation
6

• Lymphocytes randomly generate the antigen
  receptors

7
(No Transcript)
8
Central tolerance thymic education
9
(No Transcript)
10
Anti-CD20 therapy and B cells in autoimmunity.
B cell depletion a novel therapy for autoimmune
diabetes? Hélène Bour-Jordan, Jeffrey A.
Bluestone J Clin Invest. 2007117(12)36423645
11
Autoreactive B cells play a role in autoimmune
diseases by production of circulating
autoantibodies and/or their role as
antigen-presenting cells for autoreactive T cells
after the capture of self antigens by cell
surface autoantibodies that increase their
antigen-presentation capabilities Rituximab and
other anti-CD20 mAbs cross-link CD20 on the
surface of B cells and induce B cell depletion
mainly through ADCC, although complement-dependent
cytotoxicity (CDC) and apoptosis have also been
implicated. Anti-CD20mediated B cell depletion
prevents interaction with autoreactive T cells
and reduces the amount of circulating
autoantibodies, although with much slower
kinetics.
12
Autoimmune endocrine diseases Thyroid Hashimoto
s disease (autoantibodies against thyroid
peroxidase) Primary myxoedema (atrophy of the
thyroid) Graves disease (autoantibodies against
TSH-R) Pancreas Type I diabetes Adrenal
Addisons disease (chronic endocrine disorder
adrenal glands produce
insufficient steroid hormones Gonads Autoimmun
e oophoritis (inflammation of the ovaries)
Autoimmune orchitis (testicular pain involving
swelling, inflammation and infection) Pituitary
Lymphocytic hypophysitis (low production of one
or more hormones by the pituitary gland due to
autoantibodies and autoimmunity)
13

• Aetiology of autoimmune disease
• Genes
• Environment

14
Thyroid autoimmunity Hypothyroidism Hashimo
tos disease Atrophic thyroiditis Hyperthyroid
ism Graves disease
15
(No Transcript)
16
(No Transcript)
17
AUTOIMMUNE THYROID DISEASES GENETICS 22
concordance in monozygotic twins Susceptibility
genes include HLA-DR3 and/or -DR4. CTLA-4
polymorphisms
18
HLA the human major histocompatibility
complex (MHC)
19
Antigen presentation by MHC molecules
20
CTLA-4 is an off-switch for T-cells
21
Nature of the associations   The MHC class II
HLA-DR gene products present antigenic peptides
to CD4 helper T-cells. The polymorphic variants
may present different autoantigenic
peptides.   CTLA-4 is a surface molecule on
T-cells which binds CD80 and CD86 on
antigen-presenting cells. Unlike CD28 on the
T-cell, which activates the T-cells when it binds
CD80 and CD86, CTLA-4 switches off the T-cell.
The polymorphisms may therefore influence T-cell
activation/inactivation.
22
AUTOIMMUNE THYROID DISEASES - ENVIRONMENTAL AND
ENDOGENOUS FACTORS   Female Male ratio 51. At
least partly due to modulation of the autoimmune
response by oestrogens. Thyroid autoimmunity
usually subsides during pregnancy, and rebounds
post-partum.   Stress. Bereavement, divorce, job
loss may proceed onset. Neuroendocrine pathways
affecting the immune system?   Smoking Weakly
associated with Graves disease and strongly
associated with development of opthalmopathy.   Io
dine In areas of iodine deficiency, iodine
supplementation associated with Graves disease.
23
TYPE I DIABETES GENETICS
Susceptibility genes include HLA-DQ8
Resistance genes include HLA-DQ6
24
TYPE I DIABETES ENVIRONMENT INFECTION C
oxsackie virus??? Echovirus??? DIET Wheat
protein???
25
Incidence of spontaneous diabetes in
geographically dispersed colonies of NOD mice at
20 weeks of age
26
(No Transcript)
27
(No Transcript)
28
Addisons disease Deficient
production of adrenocortical hormone Weakness,
anorexia, nausea, vomiting, weight loss,
hypotension
29
ADDISONS DISEASE GENETICS
FemaleMale ratio 41 Susceptibility
genes HLA-DR3 and/or DR4
30
Rheumatoid arthritis particularly affects the
small joints of the hands and feet
31
(No Transcript)
32
(No Transcript)
33
Typical rheumatoid joint deformities in the
hands. There is wasting of the small muscles of
the hand, swelling of the metacarpophalangeal
joints and a small subcutaneous nodule on the
little finger. The fingernail clubbing is
characteristic of the pulmonary fibrosis from
which this patient also suffered.
34
(No Transcript)
35
The knuckle joint shown here is inflamed and
swollen, and the range of movement and strength
of the joint are greatly reduced compared with a
healthy joint
36
The disease process starts with inflammation of
the lining of the joint -the synovium- and is
followed by destruction of the underlying
cartilage, and then the bone itself.
37
PATHOGENESIS
http//fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0
c.pdf
From Dr J. Martinez
38
PATHOGENESIS

• TYPE III IMMUNE COMPLEX DISEASE
• Rheumatoid Factor (RF) 80 of patients.
• RF IgM anti-IgG antibody
• TYPE IV T-CELL MEDIATED DISEASE
• RA synovial fluid is enriched with macrophages,
  neutrophils, Tlymphocytes dendritic cells.

From Dr J. Martinez
www.bio.davidson.edu/courses/immunology/Students/s
pring2006/Dresser/RA.html
39
PATHOGENESIS

• T-CELL MEDIATED DISEASE

en.sanofi-aventis.com/.../im/p_im_arthritis.asp
From Dr J. Martinez
40
PATHOGENESIS
From Dr J. Martinez
http//fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0
c.pdf
41
PATHOGENESIS

• Normal synovial membrane
• Film of 1-2 cells
• Type A and Type B cells
• RA synovial membrane
• Several cell layers (2-10)
• Type A cells gt Type B cells
• Subintima angiogenesis and infiltration by
  mononuclear cells

http//fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0
c.pdf
From Dr J. Martinez
42
CLINICAL FEATURES

• Onset Insidious
• Main symptoms
• Pain
• Stiffness on waking
• and following inactivity
• Other symptoms
• Fatigue and lethargy
• Low-grade fever
• Weight loss Progressive decline in physical
  function.

• From Dr J. Martinez

43
SUMMARY In the endocrine autoimmune diseases it
is thought that, in genetically susceptible
individuals, environmental factors lead to a
breakdown in immunological tolerance. The actual
environmental factors involved are
unknown. Ref. Most material from P. Delves (in
Roitt and Delves, Essential Immunology, 10th
Edition Blackwell)