Immunology 4 - Autoimmunity Flashcards
What is immunologic tolerance?
Unresponsiveness to an antigen that is induced by previous exposure to said antigen
What are tolerogens?
Antigens that induce tolerance
What is Self-tolerance?
System that prevents the immune system to react to itselfa
How are autoimmune diseases avoided?
T + B cells bearing self-reactive molecules are eliminated or downregulated
What are the mechanisms for downregulation of self-reactive B and T cells?
- Thymic destruction
- Clearing of antigens which are normally only present in cells via complement
- Physical barriers
- Inhibition by T-regulatory cells
Outline Central tolerance?
Thymus destroys T-cells with high affinity to self-antigens
Outline Peripheral Tolerance
Mature Lymphocytes which recognise self-antigens in peripheral tissues become incapable of activation or die
What are the mechanisms of peripheral tolerance?
- Anergy (unresponsiveness)
- Antigen recognition without co-stimulation
- Treg suppression
- Deletion (by apoptosis)
- Anatomical barriers
What are the responses of immature lymphocytes to recognition of self-antigens?
Apoptosis
Change in receptors (B-cell editing)
Development of regulatory T cells
How can peripheral tolerance be overcome?
- Inappropriate access to self-antigens
- Increased expression of co-stimulatory molecules
- Alterations in how self-molecules are presented
Overcoming peripheral tolerance is more likely to happen when?
Inflammation/tissue damage is present or Increased proteolytic enzymes leading to high concentrations of peptides being presented to T-cells
- Tolerance breaks down leading to further inflammation
- Immune response broadens (epitope spreading)
What is the major source of antoantibodies?
B1 cells
How can natural antibodies become autoantigens?
- Cross-reaction with inherited A and B antigens (normal - forms Anti-A and Anti-B antibodies)
- Can bind to cellular constituents (by-products of normal apoptosis)
What factors lead to the breakdown of T-cell tolerance?
Inheritance of HLA with poor binding to self-antigens
Poor expression of self-antigens in the thymus
Infections/drugs
What is the role of HLA?
Encode MHC
What are the genetic factors associated with autoimmunity?
MHC alleles (HLA-B27, DR2,3,4)
Familial clusters
Polymorphisms
AIRE genes
What is the role of the AIRE protein?
Autoimmune regulator
Transcription facotor medullary epithelial cells in the thymus
Failure in AIRE leads to failure of negative selection
What are the environmental factors for autoimmunity?
Infections
- Molecular mimicry
- Antigen breakdown & presentation changes
Drugs
- Molecular mimicry
- Genetic variation in drug metabolism
UV radiation
- skin inflammation –> modification of self-antigen
What autoimmune diseases are associated with microbial antigen molecular mimicry?
Rheumatic fever (Group A strep)
T1DM (Cocksackie B4)
Guillain-Barre (Campylobacter jejuni)
Non-organ specific autoimmune diseas are assocaited with what?
Autoimmune responses against Intracellular (self)-molecules
Self-antigens can targets what things in the body?
(everything)
Hormone receptors
Neurotransmitter receptors
Cell-adhesion molecules
Plasma proteins
Intracellular enzymes
DNA
What is the pathophysiology of Celiac disease?
Autoantibodies against endomysium (connective tissue surrounding smooth muscle)
Tissue transglutaminases bind to gliadin and creates Glutaminic acid
What is the pathophysiology of SLE?
IgG attacking DNA after exposure to DNA fragments
Inheritance of impaired DNA clearance
How are autoimmune diseases treated?
Suppression of damaging response (immunosuppresants)
Replacement of function of damaged organ/tissue
Anti-inflammatory drugs
