Lecture 19 - Autoimmunity I Flashcards
What is the underlying cause of all autoimmune disease?
Loss of self-tolerance
What is the prevalence of autoimmune disease?
2-5% of the population suffer autoimmune disease
Incidence is rising in the developed world
Incidence increases with age
Describe, in general, current therapy and future goals for autoimmune diseases
Current therapy:
• General immunosuppression through anti-infammatories:
• e.g. Corticosteroids, anti-TNF
Future goals:
• Selective inhibition of offending lymphocytes
Outline the steps in the development of autoimmune disease
- Presence of self-reactive lymphocytes in the periphery
• Individual still healthy - Activation of self-reactive lymphocytes
• Loss of tolerance
• NB this activation is often just transient; followed by a return to a quiescent state. - Initial tissue damage
• Autoimmune response - Chronic autoimmune responses with ongoing tissue damage
• Autoimmune disease
Describe the determinants of autoimmune disease
- Genetic susceptibility
- Environmental triggers
• e.g. infection - Breakdown in tolerance mechanisms
“Environment can trigger autoimmunity in genetically predisposed individuals under conditions of immune dysregulation”
Briefly outline the various mechanisms of tolerance
Central:
• Deletion
• Receptor editing (B cells only)
• Generation of Tregs
Peripheral: • Anergy • Suppression; induction of Tregs (FoxP3+) • Deletion • Ignorance
Describe how self-reactive T cells can avoid the various mechanisms and cause injury
- Ag not present in thymus / low affinity, thus avoiding central tolerance
- T cells do not encounter Ag when naïve (i.e. Ag only in peripheral tissues), thus avoiding peripheral tolerance
‘Ignorant’ T cells can become activated (e.g. virus infection, molecular mimicry) and now enter tissue and cause damage through the normal effector mechanisms:
• CTL killing (perforin/granzymes)
• Cytokines
How do autoreactive B cells cause damage?
Auto-Abs directed against host Ag and bring about a variety of harmful responses
Compare autoimmune responses and autoimmune diseases
Autoimmune response: isolated immune targeting of self antigen
Autoimmune disease: sustained immune response against self-antigen
Differentiate between the different patterns of autoimmune disease
Give examples of each
Organ specific:
• Damage restricted to a particular organ in the body
• The auto-antigens are organ specific
• e.g. Hashimoto thyroiditis, IDDM
Systemic:
• Many tissues in the body are effected
• The auto-antigens are ubiquitous
• e.g. SLE, Rheumatoid arthritis
Outline the various mechanisms of autoimmune disease
- Auto-antibody to cell surface or matrix antigens
(Type II hypersensitivity reaction) - Immune complex disease
(Type III hypersensitivity reaction) - T cell mediated disease
Describe how autoantibody to surface / matrix Ag causes autoimmune disease
Give examples of autoimmune disease that are caused by this mechanism
- Abs directed against cell surface / matrix Ags
- C’ fixation on Fc region of auto-Abs, results in production of C3a and C5a, which recruits inflammatory cells to the tissue
• Neutrophils
• Macrophages - Inflammatory cell infiltrate
- ADCC, C’ mediated cell cytotoxicity, inflammation etc.
Examples:
• Autoimmune haemolytic anaemia (cell surface Ag)
• Pemphigus vulgaris (cell suface Ag; component of gap junction)
• Goodpasture syndrome (matrix Ag; collagen)
• Graves’ disease (cell surface Ag)
• Myasthenia gravis (cell surface Ag)
Describe the mechanism of immune complex mediated autoimmunity
- Improper clearance of immune complexes
• Low affinity complexes
• Excess Ag - Presence of immune complexes in circulation, deposition in the vascular wall and in glomerli
- C’ activation → recruitment of inflammatory cells
• Neutrophils, macrophages - Neutrophils and macrophages become frustrated:
• Release ROS and toxic enzymes - Vasculitis; glomerulonephritis
Examples:
• SLE
• Rheumatoid arthritis
Describe T cell mediated autoimmunity
Two sub-mechanisms:
A. CTL mediated
1. CD8 T cells against auto-Ag become activated
2. CTL killing of self cells (perf/granzyme dep.)
B. Cytokine mediated
1. CD4/8 T cells against auto-Ag become activated
2. Release of cytokines
3. Recruitment of neutrophils and macrophages to the tissue
4. Tissue damage
• ROS
• Toxic enzymes
Examples:
• IDDM
• MS
• RA
State the role T cells and autoantibody play in the following diseases: • MS • Myasthenia gravis • IDDM • SLE
MS:
• T cells: pathogenic (cytokine release, CD4 T cells)
• Auto-Ab: present, but role unclear
Myasthenia gravis:
• T cells: help for Ab
• Auto-Ab: pathogenic
IDDM:
• CD8+ T cells: killing of beta islet cells
• CD4+ T cells: pathogenic - cytokine release
• Auto-Ab: present but not pathogenic (anti-insulin etc.)
SLE:
• T cells: pathogenic, help for Ab
• Auto-Ab: pathogenic
Describe the pathogenesis of Graves disease
Give the main features of the disease
Features:
• Thyroid over-stimulated leading to a ‘hyperthyroidism’-like disease
Pathogenesis:
- Abs against TSH-receptor on thyroid develop and bind
- TSH-receptor constantly stimulated
- Thyroid hormone constitutively released (continuous negative feedback on pituitary)
- High metabolic rate → hyperthyroidism
What is the role of the thyroid gland?
Regulation of metabolic rates through the production of thyroid hormones upon stimulation by TSH (from anterior pituitary)
Thyroid hormones feedback negatively on the pituitary to inhibit further release of TSH
Describe the pathogenesis of haemolytic disease of the newborn
- Rh- mother carrying Rh+ child
- During delivery of the baby, some of the baby’s blood enters the mother’s circulation
- Mother’s immune system recognises Rh Ag as foreign and makes Ab against it (mother now immunised against Rh)
– Second pregnancy –
- Anti-Rh IgG Abs cross the placenta and target the RBCs of the foetus
- RBCs in the foetus destroyed
Prevention:
• Mother given anti-Rh Abs immediately after delivery of the child, destroys all the baby RBCs before the mother’s immune system can launch its own response and thus form anti-Rh IgG
How can it be demonstrated that the auto-Abs are the primary driver of Graves disease?
Graves disease can be transferred from mother to foetus
- Anti-TSHR IgG from mother cross the placenta into the circulation of the newborn
- Newborn suffers from Graves disease
Furthermore, the disease can be cured by plasmapheresis, removing all of the anti-TSHR Ab
Describe the pathogenesis of myasthenia gravis
- Abs develop against nAChR
- Binding of Abs to the nAChR result in removal of the receptors from the surface (at the neuromuscular junction)
- ACh has no receptor to bind to; skeletal muscle can not contract
- Progressive myasthenia (muscle weakness)
Demonstration of primary role of auto-Abs in the pathogenesis of the disease:
When these anti-nAChR Abs are transferred to healthy mice, the mice develop the disease
Which lymphocytes survive central tolerance?
Those with low affinity for the Ag (self-Ag), such that they are not deleted in the central lymphoid organs
What are the requirements of the DCs for their activation of naïve lymphocytes?
The DC must be fully licensed and mature (i.e. expressing co-stimulatory molecules)
Characterise the onset of autoimmune diseases
Onset can take a number of years
Describe how autoimmune diseases can be induced in healthy mice
Immunisation with self Ag + an adjuvant
Adjuvant:
• Required for the maturation and licensing of DCs so that they up-regulate co-stimulatory molecules
• This step is required for DC activation of naïve lymphocytes
• DC Ag presentation to lymphocytes without Signal 2 results in anergy / deletion of the lymphocyte
Compare the effect of auto-Abs on the target receptor in the following diseases:
• Graves disease
• Myasthenia gravis
Graves disease:
• Binding of auto-Ab to the TSHR results in activation of the receptor
Mysathenia gravis:
• Binding of auto-Ab to the nAChR blocks the receptor and furthermore results in removal of the receptor from the surface of the myocyte
