12: Autoimmune diseases 🏁 Flashcards
Describe (self-)tolerance and autoreactivity
tolerance: unresponsiveness of immune system to self antigen
autoreactivity: reaction of immune system to self antigen (which is normal to a degree)
What is central T cell tolerance?
testing of immature T cells for reaction with self antigens in thymus
a) no self reaction -> naive T cell
b) self reaction -> deletion
c) self reaction -> development into Treg cells
What is peripheral T cell tolerance?
induced in mature T cells in peripheral tissue:
normal T cell response -> perfect
if self reaction:
a) anergy (functionally unresponsive/blocking of functionality) -> no function
b) suppression of T cell by Treg (Treg expresses always FoxP3, CTLA-4,antiinflammmatory cytokines))
c) deletion of T cell
How does B cell tolerance work?
central tolerance:
- in bone marrow
- receptor editing
- deletion
- anergy
peripheral tolerance:
- normal
- anergy
- deletion
- regulation by inhibition
What are the mechanisms of autoimmunity?
- Loss of T cell tolerance
- genetic basis
- environmental factors
- molecular mimicry
- immunological aberrations
What is the loss of T cell tolerance?
Escape, activation and proliferation of autoreactiv T cells
- genetic predisposition lowers the threshold for activation of…
- inflammatory environment supports the activation of…
- defects in Treg cell function leads to missing control over…
…autoreactive T cells
Genetic basis of autoimmunity
- most autoimmune diseases are polygenetic
- some polymorphisms are part of several diseases -> general immune regulation and control
strongest association: MHC genes
What are the environmental factors?
- infection -> triggers detection of self antigen upon the antigens of infective agent
- activation of APC by engagement of PRR -> cytokine activation of T cells
- molecular mimicry: cross reaction of microbial and self antigen (ex. Gillian-Barré syndrome: PAMP of C. jejuni is similar to patter of myelinated peripheral nerve -> acute demyelinating polyneuropathy possible)
What are other immunological aberrations that lead to loss of self tolerance?
- defects in T cell deletion
- defects in receptor editing in B cells
- defect number/function of Treg cells
- defective apoptosis
- „wrong“ identification of DAMPs as foreign and dangerous
Name hypersensitivity diseases
- systemic lupus erythematosus (antigen: DNA)
- rheumatoid arthritis (antigen: collagen)
- multiple sclerosis (antigen: myelin)
- type I diabetes mellitus (antigen: insulin)
Name single mutation diseases
- APS (mutation in AIRE (autoimmune regulator gene) gene) -> failure of central tolerance
- IPEX (mutation in FoxP3) -> deficiency in functional Tregs
Cause of systemic lupus erythematosus
- genetic background (polymorph)
- defective clearance of nucleic acids leads to overproduction of BAFF and IFN-α, that induces autoreactive B cell survival
Cause of rheumatoid arthritis
- genetic background in HLA gene
- initial innate immune response against a strong environmental impact (e.g. smoking)
- neoantigen formation (conversion of arginine to citrullin)
- anti-citrullin ABs induce joint damage
Cause of Granulomatosis with polyangiitis (GPA)
- ANCA associated vasculitis (AAV)
-> anti-neutrophil cytoplasmic autoantibodies against proteinase 3 - granulomatous inflammation of respiratory tract
-> necrotising systemic vasiculitis
-> development later in life
What are therapeutic approaches?
- broadly acting anti-inflammatory agents (corticosteroids)
- cytokine antagonists
- blocking of costimulation and signaling (pathways)
- tolerance inducing therapies
- antigen-specific immunotherapy (clearance of pathogenic AB/T cell)
Detection and elimination of autoreactive B cells/ABs
Neutralisation and reprogramming of autoreactive T cells
