Parasite- Host interactions Flashcards
Some allergy statistics
- In the last decade, the cases of food allergies have doubled, and the number of hospitalisations caused by severe allergic reactions has increased 7-fold (EAACI, 2015)
- By 2025, asthma will represent the most prevalent chronic childhood disease and result in one of the highest causes of health care costs (EAACI, 2014)
- Up to 1 in 5 allergic people suffer a serious debilitating disease and are in fear of death from a possible asthma attack or anaphylactic shock (EAACI, 2011)
- UK hospital admissions for food allergies increased by 500% between 1990 and 2007 (Gupta, 2007) and are still rising (allergy and anaphalaxis 33% in 5 years to 2016)
- Asthma, Rhinitis and Eczema have trebled in the last 20 years (Allergy the Unmet Need, 2003)
- £900 million per annum spent by Primary Care is due to allergy - 10% of GP prescribing budget (Enquiry into Provision of Allergy Services, 2004)
- £68 million per annum is the cost of hospital admissions due to allergy (Enquiry into Provision of Allergy Services, 2004)
- The UK is one of the top three countries in the world for the highest incident of allergy (The Allergenic Invasion, 1999) 44% British adults (30% in pensioners, 50% under 35s)
Tell me about the incidence of immune disorders
- >80 different autoimmune diseases have been identified, affecting some 10% of the global population and representing a huge disease and financial burden.
- Most have no cure and are not, knowingly, preventable.
- Genetic predisposition is a key factor in susceptibility, but it can’t explain this recent surge in incidence.
Whats an immunoglobulin that is key in the pathways leading to acute and chronic allergic reactions?
IgE
What does IgE have an essential role in?
Why is it so important?
IgE has an essential role in type I hypersensitivity, which manifests various allergic diseases, such as allergic asthma, most types of sinusitis, allergic rhinitis, food allergies, and specific types of chronic urticaria and atopic dermatitis. IgE also plays a pivotal role in responses to allergens, such as: anaphylactic drugs, bee stings, and antigen preparations used in desensitization immunotherapy.
Although IgE is typically the least abundant Ig isotype, it can trigger the most powerful inflammatory reactions.
So why have we evolved such a potent and self-destructuve componenet of our immune system?
From an evolutionary point of view, IgE is conserved and can be found in all mammals. It therefore originated at least 160 million years ago, possibly even more than 300 million years ago when the major antibody class of early vertebrates, ancestral IgY, still found in birds, reptiles, amphibians, and lung diverged into IgG and IgE in mammals.
Evolution would be expected to select against individuals with a predisposition for anaphylaxis unless there were some stronger selective advantages conferred by the presence of IgE antibodies along with their family of receptors and dedicated effector cell lineages driving their persistence.
The nature of this evolutionary pressure is suggested by epidemiological observations of high IgE titers in helminth-infected populations indicating that IgE’s evolutionary role is defence against metazoan parasites.
What is the old friends’ hypothesis?
The “Old Friends” Hypothesis states that humans must be exposed to symbiotic microbes during childhood in order for adaptive immunity to properly develop. Children primarily encounter these bacteria through contact with others and the outdoors.
Tell me about the Old friends’ hypothesis and helminths
Helminths can survive in human hosts for years.
They achieve this by potent modulation of host immune responses
This host-parasite interaction has evolved over millennia.
A lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics) and parasitic protozoa and helminths, interferes with the natural (evolved) development of the immune system, leading to a dysregulated mucosal TH2 response manifesting as allergic diseases.
Redirecting the ability of helminths to modulate immune responses through live worms, worm secretions or synthetic analogues of worm molecules may help treat auto immune disease.
How is the TH2 response affected in affluent countries (rich)
NB: The Th2 immne response is the mediation of the activation and maintenance of the humoral, or antibody- mediates, immune response against extracellular parasites, bacteria, allergens an toxins. These cells also mediate the functions by producing various cytokines
In affluent, countries, with vaccination, sanitation and an increasing “hygiene-obsession” etc the TH2 response can’t do what it was designed and has evolved to do (as it is no longer exposed to those challenges) and so misbehaves.
So, what if we try to reverse the trend and we deliberately give our immune system something to occupy it, something which it has evolved to deal with (can this influence and moderate IgE/ Th2 related immune diseases?
I.e., What if we deliberately re-introduce parasitic helminths into the equation?
Infection with parasitic worms causes the immune response to polarise to a Th2 response, thus preventing Th1 /Th17 type immune responses.
What is Heligmosomoides polygyrus?
A naturally occuring intestinal nematode of rodents and a peanut antigen
What was the evidence of the old friend’s hypothesis using food allergy as an example…
What experiment was done?
Heligmosomoides polygyrus – naturally-occurring intestinal nematode of rodents and peanut antigen
Upon Ag challenge, mice previously fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine.
PN-specific IgE was not induced in helminth-infected mice fed PN without CT.
Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished.
What is the evidence for the old friends’ hypothesis in diabetes?
For Type 1 Diabetes
Cooke et al
- Examined spontaneous development of insulin-dependent diabetes mellitus in non-obese diabetic (NOD) mice infected with Schistosoma mansoni cercariae by injection or normal transcutaneous infection. Also injected eggs IP
- Diabetes defined by blood glucose level.
- Anti-insulin IgG and IgM measured – switch IgM to IgG associated with IDDM development
- Blood glucose measured after egg injection 12mmol/l = diabetes.
Zaccone et al
- Soluble worm or egg extracts also prevent IDDM but only if started when mice <4 weeks old.
- More IL-10, less IL-12, more NKT cells
What was the evidence for the old friends’ hypothesis in MS/ experimental autoimmune encephalomyelitis?
Multiple sclerosis (MS) is a neurodegenerative disease characterized by progressive impairment of mobility, vision, and coordination.
The immune system mediates the progression of MS, as the myelin sheaths, which insulate the nerve axons, are targeted by myelin-specific T cells and the resulting inflammation ultimately leads to neuronal damage.
Used model of MS where immunization of mice or rats with myelin proteins in the presence of a strong adjuvant leads to the development of self-reactive T cells.
TOP
A pre-established infection with the parasitic helminth, Schistosoma mansoni, significantly reduced the incidence
and delayed the onset of experimental autoimmune encephalomyelitis (EAE) in mice immunized with a myelin peptide. LATER AND LOWER
Showed decreased IFN gamma, NO, IL-10 TNF and IL-4 compared to uninfected, immunised mice across a range of antigen immunisation loads
BOTTOM LEFT
Showed decreased CNS inflammation / macrophage number infected mice
F = immunised uninfected,
g =immunised, infected,
e = uninfected, unimmunised.
The altered disease progression was not solely due to the induction of a strong Th2 response since intraperitoneal injection of schistosome eggs did not affect disease development.
So- INDICATIONS FROM ANIMAL MODELS, BUT WHAT ABOUT IN HUMANS?
What is the evidence of the old friends’ hypothesis in IBD (inflammatory bowel disease)?
Summers et al
- Problems of human derived helminths – co-transmission risk, public health risk
- Trichurus suis – 2500 porcine whipworm ova every 3 weeks – short-term self-limiting infection
- 29 patients most with longstanding disease and refractory to standard IBD therapy
- 5 withdrew
- Wk 12 22 responded 19 in remission
- Wk 24 23 responded 21 in remission
- CDA = crohn disease activity index - <150 = remission
Melon et al
- Hymenolepis diminuta tapeworm vs daily steroid for colitis in mice.
- dinitrobenzene sulfonic acid- (DNBS-) induced colitis
- Infection (5) vs daily dexamethasone
- Assessed 72h post DNBS by disease activity and histological damage scores, and spleen cell cytokine production
- Infected mice showed increased IL-4 and IL-10 production by spleen cells compared to other groups and were protected from DNBS-induced colitis.
- there was little benefit of dexamethasone in the treatment of colitis
What is the evidence of the old friends’ hypothesis in autism?
An exploratory safety and efficacy study of Trichus suis ova
Test group: high-functioning adults with autism, normal intelligence and good verbal skills.
Assessed: measures of rigidity, need for sameness and repetitive behaviors
Result: improved in individuals on TSO versus placebo, less discomfort and protest associated with interruption of restricted interests or deviation from expectations
Side effects: side-effect profile is low. Flatulence, stomach cramping and nausea or vomiting were more common with TSO, while loose stool, weight loss and knee pain were more common with the placebo
What work did Perales-Marin et al., do a study on in 2018 and what did the results show?
Perales-Marin et al. 2018
Evaluated the relationship between CS and autistic spectrum disorders (ASD) in childhood as an early indicator for ASD diagnosis.
A hospital-based nested case-control study in a retrospective cohort of births during 1996–2011.
251 mother-child pairs (53 cases, 198 controls) were studied.
The results suggest that the probability of ASD after a birth by CS is over three times that observed after unassisted vaginal delivery.
Yip et al. 2017
Emergency or planned CS is consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 when compared with vaginal delivery.
Stimson et al. 2018
We suggest that, while Cesarean delivery is certainly associated with alterations in the infant microbiome, the lack of exposure to vaginal microbiota is unlikely to be a major contributing factor.
The advent of Genome Wide Association Studies (GWAS) have enabled identification of predisposing genetic variants to allergic and autoimmune disease.
In the identification of allergy and autoimmune disease-associated loci, multiple overlapping loci have been identified with pathogen-induced positive selection - In this context, positive selection refers to genomic or Darwinian selection.
TSO limited to gut, self-limiting, so no systemic response?
Necator migrates through lung, long term residence in gut? More systemic response
Early days
Also, fact that many studies suggest early infection important
