Immunopathology Flashcards
Disorders of the immune system:
What are the 4 major catergories?
- Immune system is functioning normally even thouggh something has gone wrong (TB)
- Immune system isn’t functioning properly (allergy/cancer)
- Immune system is incomplete (immunodeficiency)
- Immune system reacts to ‘self’ (autoimmunity)
Immune system functions normally: Give an example
- Macrophages just doing their job but still can’t clear the pathogen that causes tuberculosis
- Caused by infection with the TB bacterium (Mycobacterium tuberculosis)
- Inhalation of bacteria via lungs (it is very small so can get into the alveoli of the lungs)
- Alveolar macrophages are stationed here, ready to repel invaders
What are the steps in phagocytosis?
- Macrophage detects bacterium
- Internalisation of bacterium in a phagosome
- Fusion of phagosome with lysosome creates the phagolysosome
- Degradative enzymes pumped into phagolysosome
- Excretion of digested bacterial particles
How is phagocytosis disrupted in TB?
- Macrophage detects TB (mycobacterium)
- Internalisation of bacterium in a phagosome
- TB modifies phagosome surface - prevents fusion with lysosome
- Multiplication of TB in phagosome
- Macrophage dies; multiple TB organisms are released
Explain how TB-infected macrophages die by necrosis
Macrophages full of miroplasma (bacteria) form a congregation of cells that are oxygen deprived (because they are so big) so become necrotic
- Necrosis causes tissue damage
- Necrosis initiates an inflammatory response
- Recruitment of immune cells to site – more tissue damage
- Cytokine release – hyperactivates macrophages
- Better killing but increased risk
- Granulomas form – macrophages full of bacteria
- Alveloli taken up by ganulomas compromises gas exchange- lung function decreases
The immune system isn’t functioning properly: Give an example
- Sometimes, the immune system responds to ‘safe’ as if it were dangerous
- Allergies are an immune response to common environmental antigens (called allergens)
- ⅓ of the UK population has an allergy
- Non-allergic people respond weakly to allergens with low IgG production – no problem
- Atopic (allergic) people respond with lots of IgE – allergic response
- Allergic asthma is caused by an allergen but can be triggered by non-specific stimuli as well
What do all alergens have in common?
Allergic reactions have two phases:
The early phase and the delayed phase
What is the difference between allergens and triggers?
Triggers make allergic symptoms worse even though they are not directly turning on your immune system
- Explain the early and late phases of an allergic response
Early phase:
- Antigen binds to the surface of mast cells
- Mast cells have IgE on their surface bound by their Fc (constant fragment)
- When the antigens crosslinks two IgE molecules the mast cell is full of granules
- The different granules e.g histamine, leukotrienes AND spasmogens confer allergen symptoms including bronchoconstriction
Delayed phase:
- Different cell types such as T cells (Th2), monocytes and eosinophils get involved
- Spasmogens are involed (LTC4 and LTD4)
- They cause another round of bronchoconstriction
Why make IgE and produce eosinophils if they are so bad for you?
- It’s not all bad – these cell types and IgE/FceR are needed and have evolved for defence against parasitic worms
- Release of granules from eosinophils breaks worms into ‘bite-size’ pieces for macrophages to eat
The immune response isn’t complete: Give examples
- Primary immunodeficiency diseases- (PID) Diseases you are born with
- Acquired immunodeficiency (HIV infection & AIDS)
Explain Primary immunodeficiency diseases (PID)
- Inherited; many X-linked (>100 types)
- General incidence 1:10,000 (considered rare diseases)
- Mostly irreversible & dominate in infancy (poor survival)
- Current treatments include:
- Immunoglobulin supplementation→ An injection approx every 6 weeks (you need a lot of blood donors then those immunoglobulins need to be harvested)
- Antibiotic therapy → leads to issues with antibiotic resistance
- Bone marrow transplants (cure but very risky)
- PID may affect innate or adaptive immunity
- PID are categorised according to the immunological component(s) involved:
- Lymphoid cell disorders may affect T cells, B cells or both
- Myeloid cell disorders affect phagocytes
- Defects early in haematopoiesis are most severe as they affect the entire immune system; usually fatal
Where does it all go wrong in PID?
Everywhere
The image shows the hierarchy of immune cells developing frim the haematopetic stem cell through either the myeloid or lymphoid progenitor down to the more specific and mature cell types
The further down, the less severe the disease but it also depends on what cell types are being affected
Explain Acquired immunodeficiency (AIDS)
- Infection with HIV initially causes an influenza-like illness, then a latent, asymptomatic phase.
- For the most part HIV viruses are picked up by dendritic cells so they can be actively infected by HIV.
- When the dendritic cell enters the lymph node, it allows the virus to also infect (CD4) T cells
- Once the CD4 T cell is infected the virus will insert its genome into the cells DNA and take oer the cell to turn it into a HIV factory
- When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS
- This is characterized by a deficiency in cell-mediated immunity
- The result is increased susceptibility to opportunistic infections and certain forms of cancer.
Loss of CD4 T cells eventually means the loss of adaptive immunity.
What is Highly active antiretroviral therapy (HAART)?
The use of multiple antiretroviral drugs hitting multiple targets in an attempt to control HIV infection. Useful because the virus has few proofreading mechanism so is likely to become resistant to drugs.
- Reverse transcriptase inhibitors (first to be discovered- tested as a cancer drug before)→ Genomic RNA of the virus turns into DNA so cant make copies of itself
- Protease inhibitors→ HIV makes one long peptide from its genome and it needs a protease to chop it up to get the useful bits of protein that it needs to assemble itself- inhibiting the HIV protease prevents it from assembling new virus particles
- Ingegrase inhibitors → Keeps viral DNA away from human DNA (virus not able to intergrate itself therefore not able to hide in the cell for very long)
- Fusion/ entry inhibitors→ Blocks co-receptors like CCR5 so HIV cant get into the cell initially so will be delt with by the complement system
Explain tumour antigen expression
Tumours can express tumour antigens that are recognized by the immune system and may induce an immune response
•Tumour-specific antigens (TSA) are antigens that only occur in tumour cells
- products of oncoviruses like E6 and E7 proteins of human papillomavirus or EBNA-1 protein of Epstein-Barr virus
- abnormal products of mutated oncogenes (e.g. Ras) and anti-oncogenes (e.g p53)
•Tumour-associated antigens (TAA) are present in both healthy cells and tumour cells, but differ in quantity, location or time of expression
- examples: oncofoetal antigens such as α-fetoprotein, carcinoembryonic antigen, HER2/neu, EGFR and MAGE-1
How can the immune response be suppressed?
How is TGF-β involved?
- Decreased MHC expression
- Co-stimulatory molecule expression
- Infiltration of different types of immune cells e.g. macrophages and if they are alternatively activated they can produced a lot of mediators TGF-β which is an immunosuppressant (can suppress T cells and cause them to differentiate into regulatory cells instead of actively killing T cells
- TGF-β can also induce epithelial to mesenchymal transition (EMT) in which the epithelial cells loose their conections to each other and become more migratory which leads to metastasis into bone, brain, lung etc
Describe Adoptive chimaeric antigen receptor (CAR) T cell therapy
- Adoptive T cell therapy involves isolation of tumour-specific T cells from patients and their expansion ex vivo – provides a (hopefully) large number of tumour-specific T cells
- These T cells are then engineered to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens
Explain the importance of Immune checkpoint modulators
- Many checkpoints are present in the immune response to ensure that the cells of the immune system do not mistakenly destroy healthy cells during an immune response (autoimmune reaction)
- Cancer cells have adapted to exploit these immune checkpoints as way to evade immune detection and elimination
- By using checkpoint inhibitors (blocking PD-1, PD-L1 and CTLA-4 with monoclonal antibodies), the immune system can overcome the cancer’s ability to resist the immune responses and stimulate the body’s own mechanisms to remain effective in its defences against cancer
Explain cancer vaccines:
What are they efficient for?
What do they consist of?
What do they target?
- Vaccines may be particularly efficient for low mutational burden tumours, where anti-PD1 monotherapy efficiency is limited by low levels of T cell clones primed for tumour antigens
- Cancer vaccines consists of the administration of tumour-associated antigens – for example melanoma-associated antigen-A3 (MAGE-A3) – in the form of either peptides or recombinant proteins in the presence of adequate adjuvants (an additional component that stimulates the immune response)
- Targeting biologically relevant antigens via vaccination in animal models has resulted in both tumour inhibition and modulation of the biology of the tumour to make cancer more amenable to standard treatments
- The vaccines are effectively reprogramming dendritic cells. They can be harvested, loaded with antigen and given another stimulant (adjuvant) that hyperactivates the dendritic cell which get sent back into the patients body.
- The dendritic cells are already programmed to present antigen to T cells so they migrate to the lymph node and activate T cells which will seek out and destroy tumours.
