PMI02-3001 Mechanisms of Autoimmunity & Hypersensitivity Flashcards
What is autoimmune disease?
Loss of immunological tolerance to self
Disease may involve self-reactive T cells or B cells
What factors predispose autoimmune disease?
Gender
Genetics
Self reactive B or T cells
Why is there higher prevalence of autoimmune disease in females?
Incomplete X chromosome inactivation- there is a high number of immune response genes of X chromosomes that can escape inactivation
Hormones: oestrogen stimulates innate immune receptor expression
How does the potential for self-reactive B and T cells come about?
Through recombination of germ line DNA and mutagenesis
Because it is so random, it is likely that self antigen receipts may be generated
Where does Central T cell Torrance occur?
during development in the thymus
What transcription factors in the thymus medulla induce expression of proteins that mediates negative selection?
Aire
Fez2f
What are the mechanisms of central T cell tolerance?
Direct inactivation of effector T cells by clonal deletion
Conversion to Treg cells
Induction of anergy
How do Treg cells operate?
They remove activating ligands from the APC
The TCR complex with CTLA-4
Treg FAS ligand binds to Th Fas and undergoes apoptosis
Treg secretes inhibitory cytokines
Why is MHC strongly associated with autoimmune disease?
Enhanced presentation of auto antigens or insufficient presentation in the thymus
What are the precipitating events of autoimmune disease?
Molecular molecular mimicry: antigens of infectious agents may resemble self antigens and stimulate cross reactive B, T cells
Innate immunity: ligation of T cell receptors and BCRs which may prompt auto reactive B cells without the activation of T cells
What occurs to the nucleic acid complexes during production of antibodies?
Binding of nucleic acid complex to sIg induces the first signal
sIg traffics to endosome
Nucleic acid binds to TLR7, 9
TLR signal via nucleus triggers production of type I interferon
IFN binding to receptor provides second signal
B cell proliferates
How do activated B cells act as antigen presenting cells to T cells?
Activated B cells takes up nucleic acid/ protein complex
The protein component undergoes antigen processes and peptides are displayed on the MHC class II
CD4 Th cell recognises MHC II/ peptide- 1st signal from the B cell
The B cell delivers the 2nd signal via CD40
B cell secretes cytokines
Activated T cell stimulates other B cells, dendritic cells
What is a hypersensitivity reaction?
An exaggerated immune response that damages host tissues
What types of hypersensitivity are involved in autoimmune damage?
II, III, IV
What types are known as immediate type hypersensitive?
I-III
What type is known as delayed hypersensitivity?
Type IV
What is type I hypersensitivity mediated by?
IgE bound to high affinity Fc receptors on mast cells, basophils and activated eosinophils
What occurs during type I hypersensitivity?
Cross linking of IgE/ Fc receptor complex by antigen causes degranulation- release of histamine, serotonin, leukotrienes, proteases
Later there is cytokine release, which activates macrophages
This all induces vascular permeability, smooth muscle contraction, bronchoconstriction
Activates eosinophils, neutrophils, macrophages
What occurs during an extreme type I hypersensitivity reaction?
Anaphylactic shock
What is type II hypersensitivity mediated by?
IgG binding to an antigen on the individuals own tissues
What occurs during type II hypersensitivity?
IgG Fc binds to Fcy receptors of macrophages
IgG Fc also activates complement- opsonisation and activation of phagocytic cells
Degranulation or phagocytosis induces tissue damage
What is type III hypersensivity mediated by?
IgG forming an immune complex with soluble antigens
What occurs during type III hypersensitivity?
Accumulation of immune complexes in blood vessels, synovial fluid
This activates complement and attracts neutrophils
Degranulation. and increased vascular permeability
Is type III organ specific?
It is non-organ specific
