Schisto Flashcards
Types of morbidity caused by schistosomiasis.
Acute infection
Primary chronic manifestations
Secondary chronic manifestations.
Acute infection.
Swimmer’s itch
Acute schistosoiasis.
Primary chronic manifestations (worms)
Subtle morbidities.
Primary chronic manifestations (eggs)
Deposition
Alteration of immune response
Species dependence
Primary chronic manifestations, eggs, species dependence
Mansoni and japonicum: hepatosplenamegaly or periportal fibrosis. Also intestinal schistosomiasis.
Haematobium: bladder pathology, female genital schistosomiasis.
Secondary chronic manifestations
Immune complexes, malignancy,
Types of morbidity caused by schistosomiasis.
Acute infection
Primary chronic manifestations
Secondary chronic manifestations.
Acute infection.
Swimmer’s itch
Acute schistosomiasis.
Primary chronic manifestations
Subtle morbidities, where eggs are.
Primary chronic manifestations (eggs)
Deposition
Alteration of immune response
Species dependence
Primary chronic manifestations, eggs, species dependence
Mansoni and japonicum: hepatosplenamegaly or periportal fibrosis. Also intestinal schistosomiasis.
Haematobium: bladder pathology, female genital schistosomiasis.
Secondary chronic manifestations
Immune complexes, malignancy,
Swimmer’s itch
o Urticarial rash and macropapular lesions.
o Exposure to non-human schistosoma cercaria in temperate areas develop active immune response leading to swimmer’s itch.
Acute schistosomiasis
Katayama fever, neurological disease.
Acute schistosomiasis - katayama fever.
Often in older people being infected for the first time: response to antigen load from worm maturation, egg production and seeing SEA, with florid host granulomatous response before immune modulation kicks in.
Acute schistosomiasis - neurological disease
Early in infection due to aberrant migration of adult worms to the brain or spinal cord, resulting in myelitis.
Primary chronic manifestations - subtleties.
Chronic inflammation: anaemia, growth deficiencies, physical fatigue, diminished cognitive development, chronic pain.
Difficult to disentangle due to other environmental factors (malnutrition, other infections).
Deposition of eggs.
Eggs have proteases and other toxic moieties –> necrosis –> granulomas –> fibrosis –> calcification, lack of contractility.
General alteration of immune response by eggs.
Active Type 2 cytokine suppression by eggs leads to expansion of innate based pro-inflammatory cytokine response. Nonetheless, most responses Th2.
Lack of Th2 –> expansion of pro-inflammatory. Tissue damage.
Alteration of immune response by eggs - detail.
Continual exposure to SEA Limitation of granulomatous disease by IL-10 and alternatively activated macrophages.
High levels of Th2 responses –> periportal fibrosis.
Active Type 2 cytokine suppression by eggs –> expansion of innate based pro-inflammatory cytokine response –> hepatosplenomegaly, associated with TNFa. Nonetheless, most responses Th2.
Primary chronic manifestation - liver.
o Depends on immune response
1) Hepatosplenomegaly (coincides with infection intensity). Associated with proinflammatory response.
• Portal hypertension
Ascites
Varices
• With gross hepatic portal fibrosis??
• Important with co-infection
2) High type 2 shifts towards periportal fibrosis (Symmer’s pipestem fibrosis) if poor immunoregulation.
3) Fibrotic disease irreversible, related to duration of exposure rather than age
Intestinal schistosomiasis.
o Egg deposition, granuloma formation, chronic schistosomal colitis.
o Mucosal hyperplasia and polyposis.
o Rarely: schistosomal appendicitis with egg deposition in appendix.
Bladder morbiditis
Eggs deposited in bladder wall –> released with ulceration and haematuria (considered sign of sexual maturity).
Formation granulomata, pseudoabscesses, fibrosis and ulceration. Healing of granulomata is with fibrosis leading to strictures and calcification.
If granulomata form at opening of ureter can block urine flow leading to hydronephritis and kidney damage.
Bacteriuria, malignancy.
Female genital schistosomiasis, general.
Eggs in vesical plexus migrate to genital tract, mostly vagina, cervix and fallopian tubes.
Leads to rubbery and sandy patches, and friable genital tissue. Can result in contact bleeding, superinfection and possibly decreased fertility.
Female genital schistosomiasis in pregnancy.
In pregnancy can possibly lead to placental incompetence and abortion. Certainly leads to low-birth weight babies due to maternal subtle morbidities.
Female genital schistosomiasis and HIV.
Association with HIV because increases presence of HIV-receptive immune cells bearing CCR5, an eotaxin receptor, and its expression, poor physical barrier. Also, men with high intensity active schistosomiasis may have more CD4+ cells in semen. HPV increased risk too.
Secondary chronic manifestations.
Immune complexes –> kidney damage. Mansoni.
Malignancy.
Increased mutations Increased cell turnover Downregulated anti-cancer responses Indirect. Epidemiology.
Malignancy - increasing mutations.
Promote carcinogenesis by causing inflammation, a pro-oncogenic environment. Inflammatory cells such as macrophages and eosinophils produce free radicals leading to DNA damage. Aids production of N-nitrosamines.
Inflammatory cells may activate pro-carcinogens such as aflatoxin.
Malignancy - increased cell turnover.
Damage by parasites/eggs –> restorative hyperplasia –> increase propagation of cells, even those with mutations. Macrophage migration inhibitory factor may also contribute by partially suppressing p53 in inflammatory environments.
Malignancy - anti-cancer responses.
Because immune system shifted to Th2 response, anti-cancer responses are downregulated.
Malignancy - epidemiology
Bladder cancer common in areas with endemic S. haematobium.
Little evidence that S mansoni/japonicum cause cancer (e.g. poor epidemiological evidence to date, not taking into account confounding factors) but some case reports.
Malignancy - indirect hypothesis.
Damage to genitalia allowing entry of carcinogenic agents e.g. HPV.
General increase in schistosomiasis due to
Large and small scale irrigation, with invasion of snail hosts.
Population increase
Widespread drought so concentration of hosts to infected water sources.
Discovery of schisto immune evasion.
1966; host antigens acquired by adult schistosomes. A monkey immunized against antigens from a different mouse will be immune to worms transferred from the mouse.
Egg expulsion.
Eggs in the intestinal wall are expelled by the immune system into the lumen: necessary for transmission. Expulsion only occurs when larvae start pumping out antigens through the egg shell.
Prevalence patterns
After teenage years, prevalence and intensity begin to drop, due to lack of reinfection (although this is difficult to quantitatively assess) and death of adult worms. Studies from around the world show peak levels of infection at around 12.
Reasons for decreased reinfection after puberty.
Patterns of exposure
Immunity
Arguments for acquired immunity against schisto.
Would relate to duration of exposure (given multiple immune evasion mechanisms).
Damming of Senegal river.
Measuring immune responses.
Anti-fecundity immunity.
Argument for innate immunity change at puberty.
Precipitous fall at puberty suggests hormonal changes –> possible affects parasite metabolism, induction of physiological/anatomical changes in host such as skin thickness, or induction of immunological changes in the host.
Potential candidates for hormonal cause of immunity at puberty.
Potential candidates: adrenal androgens or gonadotrophins. Adrenal androgens seem to be suggested in experiments which raise them in mouse models.
Th2 in immunity
Measuring immune responses in infection and reinfection studies shows that resistance to reinfection is correlated with TH2 responses. Eosinophilia, IL-4 and IL-5, anti-schistosome IgE. Latter the best. Decreases acquisition.
Susceptibility correlated with host locus including TH2 cytokine genes IL4, IL5 and IL13. Genetic polymorphisms in these genes affected susceptibility.
Anti-fecundity immunity
S. haematobium and some animal schistosomes: TH cell dependent anti-fecundity immunity, reducing egg production. In adults, urinary egg excretion to worm burden ratio is lower than for children: antifecundity effect. Appears to result from transmission-dependent humoral immune response.
Immunity in animals
o Acquired resistance important in regulating infection intensity in cattle.
o Pigs eliminate within a few months, and are relatively resistant to later challenges.
Mechanisms of immunity in the skin
IL-13 involved in induction of TH2 response
Mechanisms of immunity in the lung
IL-13 critical for eosinophil entry and survival.
Mechanisms of immunity in the intestine
IL-13 important in egg destruction
Mechanisms of immunity in the bladder
IL-13 has mixed results: increases eosinophil migration and hence pathogenesis, but also pro-fibrinogenic.
R0 for worms
Work out the dynamics for the different stages. R0 = all the gain terms / all the loss terms. But only works in absence of density dependence or other regulatory constraints.
dm/dt
Rate of change of mean number of schistosomes per person.
dm/dt = αNy - γm
where α is number of schistosomes produced per snail per unit time.
N = number of snails in unit area.
H = number of humans in unit area.
y = proportion of snails releasing cercaria
γ = per capita mortality rate of snails.
m = mean number of schistosomes per person.
dy/dt
dy/dt = β*H*m(1 - y) - u-h*y β = probability that one schistosome causes a snail to be infected. α = number of schistosomes produced per snail per unit time. N = number of snails in unit area. H = number of humans in unit area. y = proportion of snails releasing cercaria γ = per capita mortality rate of schistosomes. m = mean number of schistosomes per person. u-h = per capita mortality rate of infected snails.
IgE to schisto
IgE raised
IgG:IgE balance important
IgE interaction with eosinophils in ADCC seems to be protective.
IgE raised in schistosomiasis.
both polyclonal and specific —> binds both to helminth and immune cells (macrophages, DCs, mast cells and basophils) through FcεRI —> cross linking gives release of histamine and inflammatory cytokines (egg stage responsible for induction) —> IgE to worm age correlates with protection from reinfection
IgG4:IgE balance in schisto
seems to be important —> IgG4 positively correlates with reinfection —> binds inhibitory FcγRIIB and competes with IgE for Ags —> blocks IgE mediated basophil and mast cell degranulation
smTAL1
Allergen like protein in schisto with Ntd with EF hands. EF hands = structural motif shared with major fish and pollen Ags.
smTALs
smTAL1 = adult worm Ag released on rare occasions, smTAL2 = egg and adult ag released continuously as eggs die.
smTAL2
probably protective = tolerance to allergen that is encountered repeatedly in small doses to prevent long term tissue inflammation and damage which would be fatal to host —> resembles allergen immunotherapy (repeated subcutaneous injections of small doses of allergen over a period of time —> increases IgG4, IL-10 and TGFβ maybe due to Tregs)
Cross reactivity
larval smTAL5 doesn’t induce specific response but binds smTAL3-Ige due to cross-reactivity —> could explain age-dep concommitant immunity (immunity induced by existing worms that prevents new incoming infection)
Epi evidence about allergy and helminths.
Meta-analysis results not significant
Gabon: Schisto and decreased %SPT to dustmite
Ghana: schisto and STH and decreased response to dust mite
Anti-schisto IgE levels
o As age increases, so does IgE (graph), but rapid increase at puberty coincides with drop in reinfection rates.
o Normally IgE is at low levels in plasma, but this rises with helminth infections.
T cell hyporesponsiveness in helminth infections - examples of impaired responses.
Schistosome and onchocerca Infected individuals have an impaired Th1 respone to tetanus toxoid vaccine and to influenza virus
T reg role.
Produce IL-10
Many Treg effects neutralised by blocking Abs to IL-10 or FoxP3
T reg induction in schisto patients.
Watanabe showed increases in CD4+CD25hi and CD4+CD25Foxp3 expression in schistosomiasis patients compared to uninfected individuals in Gabon and Kenya
Controversy with some schistosomiasis studies showing induction of Fox3p and some not, an increase in CD103 on Tregs occurs in either case, indicating that they become more active.
Omega 1 and anti –CD3 can force T reg development.
Roles of Bregs
Adoptive transfer studies in IL-10 deficient mice has illustrated that B cells can also produce IL-10 to regulate T cell responses
These have been identified in chronic schisto and filiariasis patients
Hyporesponsiveness of T cells in schistosomiasis - cause
• Lack of responsiveness can be for different causes. See reinfection after chemotherapy treatment studies.
o SWA due to lack of exposure.
o SEA due to active downregulation.
Lack of response to cercariae due to rapid exit and active downregulation.
Age intensity curves schisto - pattern
Both age intensity and age prevalence curves in human population show typical rise and fall with age —> but immunity or pattern of exposure?
Study in the Gambia by Wilkins and Hagan –> dramatic change in susceptibility to schisto at around 12 yo —> worm burden accumulates from first water contract through childhood and then worms start to die and are replaced at slower rate in adults.
Age intensity curve schisto - due to exposure?
Even when increased water exposure of children taken into account by studying fishing community where adults exposed just as highly still get pattern of higher reinfection in children —> not exposure based
Effect of puberty on schisto infection
Puberty = good indicatory of resistance:
could be hormonally induced innate resistance—> women have less infection than men despite increased water contact e.g. increased skin thickness/fat deposition that prevents cecarial penetration
or age-dependent acquired immunity
Age dependent acquired immunity
changes to immune system that increase the likelihood of acquiring protective immunity: adrenal androgens especially DHEA may affect immune system and they increase with puberty —> shown to inversely correlate with no of worms in mice
measure immune responses in reinfection studies —> shows Th2 correlates to reinfection e.g. eosinophilia, IL-4/5 and IgE —> immunity gene near Th2 cytokine ten cluster on chromosome 5
Best marker for resistance to reinfection.
Best marker for resistance to reinfection = IgE specific to schist proteins with structural similarity to food and environmental allergens e.g. mTAL1
Anti-fecundity in S haematobium
Appears to be anti fecundity immunity in S. haemotobium —> fewer eggs lead to reduced morbidity (can measure CAA = gut associated Ag released by worms to assess worm burden and compare to eggs produced)
