Genetic and environmental factors contributing to autoimmune diseases
Classification of autoimmune diseases
Selected examples for autoimmune diseases
Term coined by Ehrlich when he conceived the idea of antibodies
Inherent problem of random creation of antigen receptors
Self reacting lymphocytes are randomly and constantly generated
Normally, autoreactive lymphocytes are either removed by apoptosis or tolerance is established
Discrimination of Self and Non-Self Mechanism Self antigens Non-self antigens Timing of antigen receptor signaling Strong signals in immature developing lymphocytes in central lymphoid organs (central tolerance) Activation of antigen receptor in mature lymphocytes in peripheral (secondary) lymphoid organs Antigen concentration Continuous and high Sudden increase of previously low concentrated antigen Co-stimulatory signals Absent Present
Layers of Self Tolerance
Self tolerance depends on the concerted and synergistic action of a variety of mechanisms
Succession of checkpoints
Develop when multiple layers of self tolerance are dysfunctional
Response to endogenous self antigen that leads to tissue damage
Since antigen cannot be eliminated response is sustained
Results from a combination of genetic susceptibility, break down of natural tolerance mechanisms and environmental triggers
Requirements of the Development of Autoimmune diseases Tolerance
Defects in Central Tolerance Development
Defective AIRE gene
Transcription factor “autoimmune regulator”
Allows thymic epithelial cells to express peripheral genes
Absence leads to lack of elimination of self reactive lymphocytes and development of severe autoimmune disease
Activation of Ignorant Lymphocytes
Ignorance develops when self antigen is monovalent or of low affinity for antigen receptor
Under normal circumstances, no reaction to self antigen.
However, ignorant lymphocytes are potentially self reactive under certain circumstances:
High concentration of antigen
Immune complexes with formation of multivalence
In the context of inflammation and infection
Co-stimulation through TLRs
When a Monovalent Selfantigen Becomes Multivalent
Example rheumatoid factor
Normally, B cells specific for Fc of IgG are not activated as Fc of IgG is a monovalent antigen.
When immune complexes are formed Fc moieties of complexed IgG becomes multivalent.
BCR of self-reactive B cells can be cross linked.
In the presence of co-stimulatory signals self reactive B cells become activated and begin to secrete anti-IgG.
TLR Ligands Can Activate Autoreactive B Cells Increased liberation of host DNA during infection with tissue damage + Additional co-stimulatory signals Unmethylated CpG DNA sequences are enriched in apoptotic cells.
Antigens in Immunologically Privileged Sites Can become Target
Immunologically privileged sites are not under constant immune surveillance
Extracellular fluid does not pass through lymphatic system
No naïve lymphocytes around those tissues
Presence of inhibitory cytokines like TGF
Expression of fas ligand in these tissues
Post trauma and infection
Tissue barrier disrupted
Access of self reactive lymphocytes to the sites
Infection/inflammation provide co-stimulatory signal
Immune response against self
Example: sympathetic ophthalmia
Control of Autoimmune Responses by Regulatory T Cells
Regulatory T cells can suppress self reactive lymphocytes that react to an antigen different from those recognized by themselves.