Parasites, hypersensitivity and allergy Flashcards
What is a parasite
- an organism that lives in or on another organism (host), at the expense of that host
- Eg. Unicellular eukaryotes (protozoa), multicellular organisms such as helminths (worms) or arthropods
What is the life cycle of parasites
Infection
- The malaria parasite life cycle involves two hosts.
- During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the blood of the human host.
Liver stage
- sporozoites infect liver cells, where they proliferate via a schizont intermediate (multinucleated mega cell)
- Proliferated parasites mature into merozoites that are released into the blood
- Plasmodium vivax can become latent in some of the liver cells
- Resulting in chronic infection
Blood stage
- merozoites infect erythrocytes where they can go through several rounds of proliferation, red cell rupture and reinfection.
- It is the damage done by the blood stage parasites, and the immune response to it, that are responsible for the clinical manifestations of malaria.
Gametocyte production
- Some erythrocytes, the merozoites differentiate into the male and female gametocytes.
- These need to be ingested by another Anopheles mosquito during a blood meal.
Transmission
• Gametocytes can be taken up during a blood meal by a mosquito.
Sexual reproduction
• The sexual phase of the plasmodium lifecycle proceeds in the mosquito stomach, and results in sporozoites making their way to the mosquito’s salivary gland ready to infect a new host next time the mosquito feeds.
What are Residing RBC
merozoites after escaping from liver cells remain within cellular vesicles but lack immunogenic features, and remains undetected before infecting RBC
○ without a nucleus, they cannot activate transcription, which is the output of the innate sensors, such as TLRs, NLRs
○ red blood cells lack the MHCI antigen presentation system, effectively hiding the plasmodium from T cells.
How will parasites inform the immune system
○ after malarial parasites have consumed the haemoglobin in the blood cell, the bursting of the red cells releases intracellular components
○ Intracellular structures can represent danger-associated molecular pattern (DAMPs) when they are outside the cell thus activating immune responses, such as the waste metabolite of haemoglobin (calledhaemozoin) which indicates to the immune system that there is a parasitic infection of red blood cells.
What is the immune response to protozoa
At liver stage, plasmodium can be sensed by intracellular mechanisms similar to an intracellular bacterium, leading to a type I interferon response
At blood stage
• relies on immune cells such as macrophages and dendritic cells
• will lead to a pro inflammatory response, through activation of pro-inflammatory cytokines via TLR signalling and the inflammasome.
• Most important PAMP - glycophosphatidylinositol (GPI) - glycolipid anchoring proteins into the membrane
Both diverse and numerous on protozoa, thought to be recognised by TLR2 heterodimers
what are the main signals
- Generic microbial PAMPs (DNA,RNA)
2. Eukaryotic -specific PAMPs (GPI-anchored glyocoproteins sensed by TLR2, 1 heterdimers)
3. DAMPs sensed by NLRP3, triggering inflammasome activation
How does parasite evade immune system
- plasmodium species hide away in endosomal compartments
- Extracellular parasites can have constantly changing surface with over 1000 genes in its genome encoding a different variant of variant-surface glyocprotein (VSG)
- Same evasion mechanism as the antigenic variation
What is the problem with normal immune response with helminths
- Too big to be phagocytosed, so opsonisation is less likely to be useful
- Complement-mediated lysis could kill individual cells and eventually the whole parasite but generally does not seem to be adequate to destroy successful parasites
Primary immune defence against helminths
- Granulocytes releasing toxins to kill the parasite
• Neutrophils
• Eosinophils
• Basophils
• Mast cells
Physically disturbing the infected area so that the parasite can be ejected from the body. This can happen, for example, through coughing, sneezing, itching, vomiting, producing diarrhoea, or mucus.
What is the role mast cells, basophils, eosinpihils, granulocytes
Mast cells
• key roles in allergy and anaphylaxis.
• tissue-resident cells that upon activation (e.g. via complement activation or the binding of the IgE Fc region) release granular substances, such ashistamine.
• Activation of MCs is highly dependent on the release ofimmunoglobulin IgE, which binds to IgE-specific Fc receptors on the MC surface.
Basophils
• another IgE-responsive cell type that, in addition to their granule release, can act as anantigen presenting cell(APC).
Eosinophils
• motile phagocytic cells that release eosinophil cationic protein and peroxidase.
• They are central players in the host response to helminth infection.
Action of granulocytes
• basophils, eosinophils and mast cells all express an IgE-specific Fc receptor (FcεR - Fc[epsilon]R) on their cell surface
• when IgE molecules (bound to the antibody’s target antigen) binds to the Fcε receptors on one of these cells, it is activated and will release the contents of its granules
• degranulation of mast cells not only releases toxins to (hopefully) kill the parasite, but also triggers tissue level responses that have evolved to purge the parasite from the body
• include muscular tightening, constriction and/or spasm of the airways or gut, vomiting, diarrhoea or elevated mucus secretion.
• In the skin it induces itching, a trigger evolved to make us scratch a parasite out from its hiding place in the skin.
What happens when prolong inflammatory response fails to clear large parasite
formation of granuloma
• granuloma is made up of a cluster of tightly packed macrophages – packed so tightly that the cell membranes fuse to create enormous multinucleated cells
• cells can be surrounded by a cage of extracellular matrix proteins: a process calledfibrosis
• This can trap the parasite (or an area of pathogenic activity) and prevent its spread
• if it is not degraded or removed, the macrophages can continue to release inflammatory signals
§ resulting in ongoing inflammation that can lead to immunopathology.
What is hypersensitivity
- exaggerated immune response to a foreign substance, resulting in damage to a host’s own cells
- result in various pathologies, from collateral damage to cells in an antiviral response in one individual, to anaphylactic shock in response to peanut allergens in another
What are the four types of hypersensitivity
I over-reaction of the IgE response that is normal during helminth infections and insect bites
II antibody-mediated complement activation on cells
III mediated by antibody complexes activating cellular inflammatory responses (IMI8)
IV driven by inappropriate helper T cell activation of cellular responses.
What are Th1 and Th2 cytokines
- TH1 cytokines:IFN-γ, TNF-α, IL-6, IL-12
- NK cells, macrophages
- TH2 cytokines:IL-4, IL-5, IL-10
- Mast cells/ Basophils
Describe type 1 hypersensitivity
IgE-dependent degranulation of mast cells
- Triggered by antigen which leads tocrosslinkingof IgE bound to Fc receptors on a mast cell or basophil.
- This leads to the release of histamine from granules and causes symptoms of allergic reactions such as hay fever and asthma.
