Lecture 20 - Autoimmunity II Flashcards
Describe the pathogenesis of SLE
Immune complex mediated, systemic autoimmune disease
Auto-abs:
• Many different ones found
• Anti-nuclear protein Abs
• Anti-DNA Abs
- Dying cells and injured tissues release DNA and nuclear proteins
- Auto-abs continuously form ICs with these ubiquitous self-Ags
- Immune complexes are continuously produced, and improperly cleared in the spleen
- ICs deposit in walls of vessels in the kidney, joints, walls of blood vessels and skin
- Macrophages try to phagocytose the IC, but do not succeed since the IC are embedded in tissue
- Frustrated phagocytosis:
• Extracellular release of contents of lysosomes (ROS, lysozyme, hydrolytic enzymes) - Damage to walls of vessels
→
Lupoid rash; glomerulonephritis; vasculitis
Describe the pathogenesis of IDDM
List the key features of the disease
- Driven by autoreactive T cells
- Organ specific autoimmune disease
Pathogenesis:
- Activation of CD8 and CD4 T cells against Ag specific to β-islet cells of the pancreas
- CTL destruction of β islet cells (perf/granz. dep)
- CD4+ T cells infiltrate islets and produce cytokines
- Progressive loss of β islet cells and loss of insulin production
- Glucose intolerance due to insulin deficiency
Treatment:
• Insulin therapy
NB Auto-Abs against pancreatic Ags are present and diagnostic, but so far there is no evidence that they are pathogenic
NB α and δ cells of the islets are not affected; i.e. Glucagon and Somastatin are still produced
What is insulitis?
Lymphocyte infiltrate into the islets of Langerhans in the pancreas
Describe the NOD mouse model, and what it tells us about diabetes
Non-obese diabetic mouse
NOD mouse spontaneously develops T cell mediated insulitis, followed by diabetes
Mice experiences progressive decline in insulin secretion
Proof that the disease is autoimmune:
• Treatment of young NOD mice with anti-CD4 mAbs, which deplete the mouse of CD4+ T cells results in protection against diabetes
• Transfer of T cells from diabetic adult NOD mouse to young NOD mouse results in premature onset of diabetes
This is evidence that T cells are playing a primary pathogenic role in the disease
Describe the key features of MS
Describe the pathogenesis
Key features:
• Autoimmune disease of the CNS
• Organ specific autoimmune disease
• CD4+ T cell mediated
- Lymphocyte and macrophage infiltration of CNS
- Destruction of myelin sheaths by lymphocytes and macrophages
• Th1, Th17 release cytokines IFN-γ and TNF-α - Demyelinated neurons cannot fire by saltatory conduction
- Progressive paralysis
List the animal models for the following disease:
• IDDM
• MS
IDDM: NOD mouse
MS: EAE mouse (experimental autoimmune encephalitis)
Describe the features of the EAE mouse
(Experimental autoimmune encephalitis)
Similar pathology to MS:
• Inflammatory disease of the CNS
• Destruction of myelin sheaths
• Progressive paralysis
Generation of EAE mice:
• Immunisation with auto-Ag (myelin basic protein) + Adjuvant (Complete Freund’s Adjuvant)
• Delivery of Th1 and Th17 specific for MBP
What have twin studies shown about the role of genetics in autoimmune disease?
What is the implication of this?
Monozygotic twins: 20% concordance for autoimmune disease
→ environment is responsible for 80% of risk
Dizygotic twins: <5% concordance for autoimmune disease
Alleles of which genes are mostly commonly associated with autoimmune disease?
Explain why this is so
HLA class II alleles
Explanation:
• HLA polymorphism affects the peptide binding cleft
• This will affect presentation of both foreign and self Ag in the context of HLA
What is meant by relative risk of HLA II alleles?
Relative risk: comparison of the n° of people with the disease who have a specific HLA allele, compared with the prevalence in the general population
e.g. HLA-B27 allele carries 87.4 relative risk for Ankylosing Spondylitis, means that an individual carrying this allele has an 87.4-fold increased risk of developing the disease
Describe the genetic risk of IDDM
96% of individuals with IDDM have either HLA-DR3, HLA-DR4 or both
Compared with 64% in the general population
Furthermore:
39% of individuals with IDDM are DR3/4, compared with only 2.5% in the general population
How are susceptibility genes for the various autoimmune diseases identified?
Mapping studies
Describe how genes are important in the maintenance of self tolerance
Certain genes have been shown to be very important in the maintenance of tolerance against self-antigens
Examples:
1. AIRE
• Causes APECED, disease of endocrine glands
• Loss of the gene results in markedly decreased expression of tissue specific self ag in the thymus
• Developing thymocytes that are reactive to TSAs are not deleted in central tolerance
- CTLA4
• Associated with Graves disease, IDDM and others
• CTLA4 is an inhibitory molecule expressed by T cells that prevents and increases the threshold for activation
• KO results in reduced anergy and activation threshold of T cells - FoxP3
• Causes IPEX
• FoxP3 required for the induction of Tregs, an important immunosuppressive CD4+ T cell subset
List some other genes, of which certain polymorphisms have been associated with autoimmune disease
Genes involved with Ag presentation and clearance
• AIRE
• C4
Genes involved with co-stimulation
• CTLA-4
Genes involved with apoptosis
• Fas KO
Genes that control lymphocyte signalling
List the different ways that environment can play a role in the development of autoimmunity
- Tissue injury; inflammation
- Infection
a. Simulation of innate immune responses
b. Molecular mimicry
