WEEK 3 - Immune-related diseases and harnessing the immune system to treat cancer Flashcards
primary immunodeficiency diseases
results from:
the result of a gene defect and can affect almost any component of the immune response
many are X-linked and cause disease in males
primary immunodeficiency diseases
include deficiencies in
complement system
cytokine/cytokine receptors
B and T cells
primary immunodeficiency diseases
characterised by:
opportunistic infections
primary immunodeficiency diseases
treatment:
- antibiotics
- intravenous
- immunoglobulin (antibody)
- haematopoietic stem cell transplantation
- potentially gene therapy
examples of primary immunodeficiencies
- selective IgA deficiency
affects 1 in 500 individuals
recurrent respiratory and gastrointestinal infections
primary immunodeficiency diseases
- common variable immunodeficiency (CVID)
affects 1 in 25,000 to 50,000 individuals
low antibody levels
recurrent infections
caused by mutations in lymphocyte membrane proteins or cytokine receptors
primary immunodeficiency diseases
severe combined immunodeficiency (SCID)
e.g. bubble boy
affects 1 in 60,000 individuals
defective T and B cells
severe bacterial, viral or fungal infections requiring treatment by bone marrow transplant
most cases due to mutations in the IL-2 receptor common gamma chain, a protein shared by the receptors for interleukins IL-2,4,7,9,15,21 involved in the development of T and B cells
autoimmune disease
intro
a low level of autoimmunity in individuals is normal and does not generally result in disease
however 5-8% of the population do develop autoimmune disease characterised by autoreactive T cells and/or autoantibodies that result in pathology
- Normal checks have broken down
the tissue distribution of the autoantigen dictates whether the disease is organ-specific or non-organ-specific
main causes of autoimmune disease
autoimmunity is genetically programmed
most autoimmune diseases involve multiple susceptibility genes
hormones - 75% of autoimmune diseases is found in women
(due to the hormonal effect)
example of organ-specific thyroid autoimmune diseases
graves’ disease
- increases TSH (thyroid-stimulating hormone receptor) leads to hyperthyroidism
(producing too much hormones)
hashimoto’s disease
- destruction of the thyroid cells leads to hypothyroidism
thyroid too small
not producing enough hormones
example of non-organ-specific systemic lupus erythematosus
- process
apoptic cell with necleosome
–> defective clearance
–> dysregulated autoimmune response
–> activated histone-specific T-cell
–> anti-DNA specific B-cell
–> Synthesis of anti-DNA
–> Antibody/nucleosomes/complement immune complex
–> binding to glomerulus
–> immune complex-mediated gloerular nephritis
Recognises the apoptic belbs as foreign
example of non-organ-specific systemic lupus erythematosus
- common symptoms
painful and swollen joints
fever
chest pain
hair loss
mouth ulcers
swollen lymph nodes
feeling tired
red rash (most commonly on face)
example of non-organ-specific systemic lupus erythematosus
- cause
unclear
example of non-organ-specific systemic lupus erythematosus
- treatment
teated with immunosuppressants
to try and dampen down the immune system
harnessing the immune system to treat cancer
cancer introduction
development
cancer development is a multistep process
Series of mutation over many years
Cells overcome check points of normal cell regulation
Cells divide uncontrollably
Metastatic spread
cancer is a state where cells escape the normal controls on cell division and longevity
harnessing the immune system to treat cancer
cancer introduction
problem for treatment
solid tumours have considerable genetic heterogeneity
this can pose a problem for treatment
harnessing the immune system to treat cancer
cancer introduction
what may be critical to the instigation of robust immune responses against tumours
tumour-derived damaged-associated molecular patterns (DAMPs)
immune system can kill tumour
–> Dendrites pick up antigens from cancer cells and display them as peptides and recruit t cells
immune system cannot kill tumour
–>Dendrites may pick up antigens, but do not display warning (or recognised as self) allows tumours to keep growing
mature dendritic cells (DCs) express B7 molecules to provide costimulaion (to T cells)
harnessing the immune system to treat cancer
cancer introduction
naive T cells require…
co-stimulation for activation
mature dendritic cells (DCs) express B7 molecules to provide costimulaion (to T cells)
harnessing the immune system to treat cancer
immune checkpoint inhibitors
what
immune checkpoints are molecules in the immune system that either
- turn up a signal (e.g. co-stimulatory CD28)
OR
- turn down a signal (e.g. CTLA-4, PD-1)
harnessing the immune system to treat cancer
immune checkpoint inhibitors
what do tumour cells do
tumour cells often utilize immune checkpoint molecules to suppress and evade an immune system attack
harnessing the immune system to treat cancer
immune checkpoint inhibitors
- CTLA-4
a potent T cell inhibitor
- CTLA-4 binds B7 but with higher affinity than CD28 does
- CTLA-4 inhibits T cells
- CTLA-4 is expressed by regulatory T cells and activated conventional T cells
- CTLA-4-deficient mice suffer from fatal lymphoproliferative disease and die by 3-4 weeks of age
harnessing the immune system to treat cancer
immune checkpoint inhibitors
PD-1
PD-1 also inhibits T cells when it engages its ligand PD-L1
harnessing the immune system to treat cancer
immune checkpoint inhibitors
CTLA-4 and PD-1 immune checkpoints
CTLA-4 is the immune checkpoint that can inibit T cells during the priming phase
PD-1 is a secondary checkpoint because it is expressed later during the effector phase
harnessing the immune system to treat cancer
immune checkpoint inhibitors
immune checkpoint inhibitors (therapeutic antibodies) promote tumour clearance
Antibodies blockers
Binding antibody to T4? stops it from recognising T7?
T cell can kill cancer cell
in the last 10 years several have been approved to treat a variety of tumour types
