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Immunology of endocrine diseases
Aetiology
BS936 autoimmunity component
Professor Nelson Fernández
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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.
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Autoimmune disease results from a breakdown in immunologicaltolerance
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Mechanisms hypothesized to be involved in the breakdown of tolerance
Failure to delete autoreactive lymphocytesCentral tolerance failurePeripheral tolerance failure
Molecular mimicryAbnormal presentation of self antigensAberrant expression of major histocompatibility complexclass II moleculesCoupling of self and nonself antigensOverproduction of self antigensDisclosure of cryptic T-cell epitopesRelease of sequestered self antigensEpitope spreadingPolyclonal lymphocyte activation
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Lymphocytes randomly generate the antigen receptors
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Central tolerance=
thymic education
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B cell depletion: a novel therapy for autoimmune diabetes? Hélène Bour-Jordan, Jeffrey A. BluestoneJ Clin Invest. 2007;117(12):3642–3645
Anti-CD20 therapy and B cells in autoimmunity.
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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.
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Autoimmune endocrine diseasesThyroid
Hashimoto’s disease (autoantibodies against thyroid peroxidase)Primary myxoedema (atrophy of the thyroid)Graves’ disease (autoantibodies against TSH-R)
PancreasType I diabetes
Adrenal Addison’s disease (chronic endocrine disorder; adrenal glands
produce insufficient steroid hormones
GonadsAutoimmune oophoritis (inflammation of the ovaries)
Autoimmune orchitis (testicular pain involving swelling, inflammation and
infection)
PituitaryLymphocytic hypophysitis (low production of one or more hormones by the pituitary gland due to autoantibodies and autoimmunity)
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Aetiology of autoimmune disease
Genes
Environment
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Thyroid autoimmunity
HypothyroidismHashimoto’s diseaseAtrophic thyroiditis
HyperthyroidismGraves’ disease
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AUTOIMMUNE THYROID DISEASES – GENETICS
22% concordance in monozygotic twins
Susceptibility genes include: HLA-DR3 and/or -DR4. CTLA-4 polymorphisms
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HLA – the human major histocompatibility complex (MHC)
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Antigen presentation by MHC molecules
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CTLA-4 is an ‘off-switch’ for T-cells
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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.
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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.
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TYPE I DIABETES – GENETICS
Susceptibility genes include: HLA-DQ8 Resistance genes include: HLA-DQ6
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TYPE I DIABETES – ENVIRONMENT
INFECTIONCoxsackie virus???Echovirus???
DIETWheat protein???
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Incidence of spontaneous diabetes in geographically dispersed colonies of NOD mice at 20 weeks of age
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Addison’s disease
Deficient production of adrenocortical hormone
Weakness, anorexia, nausea, vomiting, weight loss, hypotension
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ADDISON’S DISEASE – GENETICS
Female:Male ratio 4:1
Susceptibility genes: HLA-DR3 and/or DR4
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Rheumatoid arthritis particularly affects the small joints of the hands and feet
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Typical rheumatoid joint deformities in the hands. There iswasting of the small muscles of the hand, swelling of themetacarpophalangeal 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.
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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
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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.
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PATHOGENESIS
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdfFrom Dr J. Martinez
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…PATHOGENESIS
TYPE III: IMMUNE COMPLEX DISEASERheumatoid 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.
www.bio.davidson.edu/courses/immunology/Students/spring2006/Dresser/RA.html
From Dr J. Martinez
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…PATHOGENESIS
en.sanofi-aventis.com/.../im/p_im_arthritis.asp
T-CELL MEDIATED DISEASE
From Dr J. Martinez
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…PATHOGENESIS
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdfFrom Dr J. Martinez
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…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
http://fds.oup.com/www.oup.co.uk/pdf/0-19-262922-0c.pdfFrom Dr J. Martinez
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CLINICAL FEATURES
Onset: InsidiousMain 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
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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)