Mechanisms of Autoimmune Disease Flashcards
Definition of autoimmune disease
A breakdown of immunological tolerance to self, resulting in immune reactions against host ‘self’ antigens.
Mediated by antibodies (humoral) or T cells (cell-mediated) or both
What is the function of MHC class I
A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and cytotoxic t cells (CTLs) will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for the MHC:peptide complex will recognise and kill presenting cells.
What is the function of MHC class II
normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.
The antigens presented by class II peptides are derived from extracellular proteins (not cytosolic as in MHC class I). Antigens are presented to T helper cells
Loading of a MHC class II molecule occurs by phagocytosis.
Where does Central T cell tolerance occur and what happens
- Occurs during development in thymus
- Negative selection: cells that do not have any affinity to self MHC/self-antigens and those that have too high an affinity undergo apoptosis
- Those will low affinity migrate to peripheral lymphoid tissue
- Cells with intermediate affinity differentiate into Treg cells
What happens during peripheral T cell tolerance
- APCs express CD80/86 and MHC-peptide
- CD4 expresses CD28 and TCR
- Activation of CD4 requires signal 1 (MHC-peptide interaction with TCR) AND signal 2 (CD80/86 with CD28)
- Self reactive cells bind to APC inducing signal 1 but there will be no CD80/86 on the APC so no signal 2 so the CD4 cell becomes anergic
How to Treg cells help suppress resonses
- Have a high affinity to IL-2 (which activates T cells) to prevent T cell activation
- Produce IL-10 and TGF-b that downregulate CD80/86 of APCs
- Instead of CD28 they have CTLA-4 which downregulate CD80/86
Where does B cell central tolerance occur and what happens?
- Occurs in the bone marrow
- Self reactive B cells undergo apoptosis or receptor editing
What happens during peripheral B cell tolerance
- During hypermutation in germinal centre of lymphnodes another round of apoptosis occurs of self-reactive B cells
- Competition for antigen so those that do not bind also undergo apoptosis
Which genes are involved in self-tolerance or immune regulation in which mutations can cause autoimmune disease?
- autoimmune regulator gene (AIRE): drives negative selection
- CTLA-4: downregulates CD80/86
- Fas/fas ligand
- Foxp3
Which diseases can be caused by genetic issues with MHC?
Bechet’s Disease (HLA-B51)
Psoriasis (HLA-Cw6)
Systemic Lupus Erythematosus (HLA-DR3)
Rheumatoid Arthritis (HLA-DRB1)
What precipitating events can initiate autoimmunity?
- Molecular mimicry
- Innate Immune Response: e.g. SLE ligation of toll-like receptions and B cell receptor which can activate B cell without T cell help
What causes Rheumatoid Arthritis?
- Antibodies to citrullinated (post translational modification mediated by peptidylarginine deiminase (PAD)) proteins
- Also need NETosis to activate disease:
the release of neutrophil nuclear chromatin, citrullinated histones and enzymes (special type of cell death in response to inflammation)
this produces a Neutrophil Extracellular Trap which traps microorganisms to help clear foreign bodies
but this provides a target for autoantibodies
What causes SLE?
- ligation of toll-like receptions and B cell receptor which can activate B cell without T cell help
- This results in proliferation and differentiation into plasma cells
- These produce antibodies and form immune complexes
- Tissue damage through type II/III/IV hypersensitivity)
- Immune complexes may activate DCs and T cells amplifying response
