PMI02-3001 Flashcards
What is an autoimmune disease?
Loss of immunological tolerance to self
What factors can predispose someone to autoimmune disease?
Gender bias (background)
T or B cells that are self-reactive
Genetics
How many autoimmune diseases have been described?
> 80
Give an example of an organ-specific autoimmune disease.
Type I diabetes
Multiple sclerosis (MS)
Give an example of a systemic autoimmune disease.
Rheumatoid arthritis
Systemic lupus erythematosus (SLE)
Which gender tends to be more susceptible for most autoimmune conditions?
Female
Give an example of an autoimmune disease that females are particularly more susceptible to than males.
Addison’s disease
Antiphospholipid antibodies
Hashimoto’s thyroiditis
Primary biliary cirrhosis
Sjogren’s syndrome
Which gender tends to have stronger immune responses and why?
Female
X chromosome carries a relatively high number of immune response genes (eg TLR7/8, CD40L)
Incomplete X chromosome inactivation (lyonisation) means ~20% of genes are still active (which aren’t supposed to be)
Results in bi-allelic expression of TLR7/8 in B cells and CD40L (CD154) in T cells
Also, oestrogen stimulates innate immune receptor expression (TLR3/7/8/9)
Which TLRs are found on the cell-surface?
TLR1/2/4/5/6/10
Which TLRs are found in intracellular membrane compartments?
TLR3/7/8/9
The expression of which TLRs are stimulated by oestrogen?
TLR3/7/8/9 (intracellular)
What does central tolerance mean?
Negative selection reduces but does not eliminate self-reactive T/B cells
Why do we have some self-reacting B/T cells?
Processes generating cell surface antigen receptors are RANDOM to produce diversity and results in some autoreactive receptors
Removing all autoreactive cells provides an opportunity for pathogens to evade immune response by mimicking human antigens
What percentage of T and B cells are self-reactive?
~20% of mature naive B cells
~4-10% of mature naive T cells
What do Aire and Fez2f do?
Transcription factors in thymus medulla
Promote expression of many proteins in medullary thymic epithelial cells during negative selection to increase exposure of cells to self-antigens
What would mutations in Aire or Fez2f result in?
Severe autoimmune disease
What cells maintain peripheral self tolerance?
Treg cells with specificity for self-antigens (MHC class II on APCs)
How do Treg cells maintain peripheral self tolerance?
Suppress activity of autoreactive T cells by:
- removing activating ligands (CD80, CD86) from APCs by CTLA-4 mediated endocytosis
- depleting IL-2 with a high affinity IL-2 receptor
- Fas ligand binding to Th cell Fas => apoptosis
- secreting inhibitory cytokines (IL-10, TGF-β)
Which factors are more important in development of autoimmune diseases: genetic or environmental?
Environmental
What genetic factors can contribute to autoimmune diseases?
Some show strong association with MHC/HLA (highly polymorphic)
Could enhance presentation of auto-antigens which increases the likelihood of activation of self-reactive cells
Could cause inefficient presentation of self-antigens in thymus medulla so impaired negative selection
Which enzyme contributes to rheumatoid arthritis and how?
Protein-arginine deiminase (PAD)
Converts arginine into citrulline normally in cells
Inactivation causes decreased presentation of citrullinated proteins during T/B cell selection
So antibodies to citrullinated proteins avoid negative selection and may react peripherally
What is molecular mimicry?
Antigens of infectious agents resemble self-antigens
Stimulates cross-reactive B/T cells leading to autoimmunity
Give an example of a bacteria that uses molecular mimicry and the disease it is associated with.
Porphyromonas gingivalis
Rheumatoid arthritis
How can P.gingivalis infection lead to autoimmunity?
Infection of oral cavity and use of PAD to release host and bacterial citrullinated proteins
Dendritic cells present citrullinated proteins to T cells
T/B cells do not tolerate bacterial citrullinated proteins so produce an immune response to these proteins
Persistent colonisation or repeated infection may result in somatic hypermutation of B cells specific to both host and bacterial citrullinated proteins (“epitope spreading”)
What is epitope spreading?
Immune response diversifies in response to a persistent/repeated pathogen to be able to react with different epitopes/proteins than the original invader
How might persistent P.gingivalis infection affect joint inflammation?
P.gingivalis results in epitope spreading to citrullinated proteins (specific antibodies)
Joint inflammation causes damage and release of intracellular citrullinated proteins which become targets for the new antibodies
Results in formation of immune complexes and further tissue damage in joints
What mechanism is used to bypass T cell help in activation of B cells?
TLRs/innate immune receptors
What is SLE characterised by?
Production of antibodies that recognise nucleic acid(-protein complexes)
Describe how nucleic acid can activate B cells without T cell help.
- Nucleic acid bind to surface receptors/immunoglobulin on B cells to induce the first signal
- Surface Ig traffics nucleic acid to endosome
- Nucleic acid transferred to TLR7 or TLR9, producing a signal that causes type 1 interferon production
- Type 1 interferon secreted and binds receptors to deliver second signal in an autocrine manner for B cell activation
- Activated B cell proliferates to give plasma and memory cells
Why can the ability of nucleic acid being able to activate B cells via innate receptors an issue?
B cells may be able to react with viral nucleic acid that has cross-reacted with host DNA
~8% of human genome is derived from retroviral DNA so some may be recognised as virus-derived
Retroviral DNA usually degraded by nucleases but can be release by necrotic tissue = autoimmunity
How do activated B cell act as APCs for T cells?
- B cell takes up nucleic acid (complex) and becomes activated and also presents proteins from the complex on its surface with MHC class II
- CD4+ Th cells recognise the complex which generates the first activation signal
- B cell delivers the second signal via CD40 (binds CD40L/CD154 on T cell)
- B cell secretes cytokines (IL-2/4/6)
- Activated T cell stimulates other B cells and dendritic cells to spread autoimmunity
What are the “names” given to each of the hypersensitivity reactions?
Type I = allergic
Type II = cytotoxic
Type III = immune complex
Type IV = delayed cell-mediated
What are hypersensitivity reactions?
Exaggerated immune responses that damage host tissues
Usually requires previous exposure to an antigen to mount a strong response
Describe a type I hypersensitivity reaction.
Develops in minutes to hours
IgE (formed from a previous exposure) bound to high affinity Fcε receptors on mast cell basophils, eosinophils
Cross-linking of two IgE/Fcε receptor complexes by antigen causes degranulation
Release of histamine, serotonin, leukotrienes, proteases in minutes and cytokines in hours
Leukotrienes and histamine = increased vascular permeability, smooth muscle contraction, bronchoconstriction, mucus secretion
Cytokines attract and activate eosinophils, neutrophils, macrophages
Extreme reactions can lead to anaphylactic shock
Give a possible antigen that can cause a type I hypersensitivity reaction.
Peanut allergens
Highly immunogenic substances that induce high levels of IgE
Describe a type II hypersensitivity reaction.
Develops in 2-24 hours
IgG binds to antigen on cell surface of host
Fc portion of IgG:
- binds Fcγ receptors on macrophages, NK cells, neutrophils
- activates complement
- causes phagocytosis or degranulation
Give an example of a condition with type II hypersensitivity involvement.
Grave’s disease
Rhesus antibodies (pregnancy)
Describe a type III hypersensitivity reaction.
Develops in hours to days
IgG binds to a soluble antigen
Immune complexes deposit in blood vessels, synovial fluid and other tissues and are not removed
Cause continuous complement activation and neutrophil, mast cell recruitment via Fcγ receptor (local inflammation)
Tissue damage as a result of complement and degranulation
Describe a type IV hypersensitivity reaction.
Develops in 2-3 days
T cell-mediated
Activated T cells secrete chemokines, cytokines (IFN-γ, TNF) to recruit and activate macrophages to secrete mre pro-inflammatory cytokines (IL-12, TNF)
Degranulation causes tissue damage
Cytotoxic T cells kill cells
Granuloma formation if pathogen persists to wall off pathogen but in autoimmunity, antigen is not cleared => multiple granulomas form
