Transcript BS963 (Autoimmunity) 2011

Immunology of endocrine
diseases
Aetiology
BS936 autoimmunity component
Professor Nelson Fernández
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.
Autoimmune disease results from a
breakdown in immunological
tolerance
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
Lymphocytes
randomly generate
the antigen
receptors
Central tolerance
=
thymic education
Anti-CD20 therapy and
B cells in autoimmunity.
B cell depletion: a novel therapy for
autoimmune diabetes? Hélène BourJordan, Jeffrey A. Bluestone
J Clin Invest. 2007;117(12):3642–3645
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-CD20–mediated B cell depletion
prevents interaction with autoreactive T cells and
reduces the amount of circulating autoantibodies,
although with much slower kinetics.
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
Addison’s disease (chronic endocrine disorder; adrenal glands
produce insufficient steroid hormones
Gonads
Autoimmune 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)
Aetiology of autoimmune
disease
Genes
Environment
Thyroid
autoimmunity
Hypothyroidism
Hashimoto’s disease
Atrophic thyroiditis
Hyperthyroidism
Graves’ disease
AUTOIMMUNE THYROID DISEASES – GENETICS
22% concordance in monozygotic twins
Susceptibility genes include: HLA-DR3 and/or -DR4.
CTLA-4 polymorphisms
HLA – the human major histocompatibility complex (MHC)
Antigen presentation by MHC molecules
CTLA-4 is an ‘off-switch’ for T-cells
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.
AUTOIMMUNE THYROID DISEASES - ENVIRONMENTAL
AND ENDOGENOUS FACTORS
Female: Male ratio 5:1. 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.
Iodine: In areas of iodine deficiency, iodine supplementation
associated with Graves’ disease.
TYPE I DIABETES –
GENETICS
Susceptibility genes include: HLA-DQ8
Resistance genes include:
HLA-DQ6
TYPE I DIABETES –
ENVIRONMENT
INFECTION
Coxsackie virus???
Echovirus???
DIET
Wheat protein???
Incidence of spontaneous diabetes in geographically
dispersed colonies of NOD mice at 20 weeks of age
Addison’s
disease
Deficient production of adrenocortical
hormone
Weakness, anorexia, nausea, vomiting, weight
loss, hypotension
ADDISON’S DISEASE –
GENETICS
Female:Male ratio 4:1
Susceptibility genes:
HLA-DR3 and/or DR4
Rheumatoid arthritis particularly affects the
small joints of the hands and feet
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.
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
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.
PATHOGENESIS
From Dr J. Martinez
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdf
…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/spring2006/Dresser/RA.html
…PATHOGENESIS
T-CELL MEDIATED DISEASE
From Dr J. Martinez
en.sanofi-aventis.com/.../im/p_im_arthritis.asp
…PATHOGENESIS
From Dr J. Martinez
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdf
…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 > Type B cells
 Subintima – angiogenesis and
infiltration by mononuclear cells
From Dr J. Martinez
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdf
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
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)