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Zpath term 2 > Helminths > Flashcards

Helminths Flashcards

1
Q

Wucheria bancrofti damage

A

Mostly immunopathology

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2
Q

Schisto damage

A

Mostly immunopathology

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3
Q

Geohelminths

A

Subtle morbidities, intestinal obstruction, rectal prolapse.

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4
Q

Cestodes

A

Subtle morbidities.

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5
Q

Onchocerca

A

river blindness

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6
Q

Guinea worms

A

Draculoniasis, immune component.

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7
Q

platyhelminths

A

trematodes and cestodes

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8
Q

WHO’s NTDs

A

8 are caused by parasitic worms. These are diseases of poverty. Include tape worm, guinea worm, liver flukes, filarial nematodes, schisto and gut nematodes.
About 1/5 of the world pop harbours an intestinal worm.

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9
Q

Helminth damage worldwide

A

Most cause chronic insidious disease rather than acute —> difficult to assess global impact on host population —> have to use DALYs which combine years of life lost to premature mortality and years lived with disability
NTDs collectively estimated to have caused around 26m DALYs worldwide with greatest contribution form helminths (exceed TB and malaria)

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10
Q

Helminth damage, classes

A

Direct
Subtle morbidities
Indirect immunopathology
Overdispersion

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11
Q

Helminth and host evolution

A

Until quite recently, the majority of Homo sapiens were colonized by at least one helminth —> close relationship led to the evolution of “disease tolerance” by the host —> mammalian host has evolved mechanisms to minimize the virulence of helminths, without necessarily reducing worm burden —> large proportion of infected individuals are relatively tolerant to colonization with helminths.

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12
Q

Ascaris

A 
Faeco-oral transmission
Highly prevalent
No clear antigen protection
Feed on luminal contents
Often asymptomatic.
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13
Q

Ascaris damage

A

Fatal intestinal blockage.
Damage to lungs during migration.
Allergic response to metabolites —> rashes, eye pain and asthma
decreased
Vitamin A absorption, lactose intolerance and malnutrition

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14
Q

Hookworm

A

Necator americanis. Active penetration, not faeco-oral.

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15
Q

Hookworm damage to hosts

A

worms feed on blood —> can lose up to 200ml a day —>iron/protein-deficiency anaemia and intestinal inflammation.
Intermittent abdo pain and loss of appetite
Larval invasion of skin —> intense, local itching and Cutaneous larva migrans (due to migration in torturous tunnels between stratum basal and corneum of skin)

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16
Q

Models of immunity to nematodes

A

Based on mouse models. Trichinella spiralis and trichuris muris.

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17
Q

Models of immunity to nematodes

A

Th2 response with high IgE, peripheral eosinophilia, gut mastocytosis and goblet cell hyperplasia
immunity transferable with CD4+ cells
IL-13 contributes to helminth expulsion

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18
Q

Immunity to nematodes with low egg dose.

A

low egg dose (like in wild) doesn’t generate protective Th2 response, instead get reinfection susceptible Th1 response —> chronic infection; but repeated low exposure will gradually lead to resistance

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19
Q

Subtle morbidies

A

Anemia, growth stunting, protein-calorie undernutrition, fatigue, and poor cognitive development —> hard to associate to single aetiology
Important due to prevalence in developing world.

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20
Q

Iron deficiency anaemia

A

most common and widespread nutritional disorder in world (>30%)
around half of pregnant women in the developing world —> contributes to to 20% of maternal deaths and associated with preterm birth and low birth weight —> mebendazole treatment reduces effect
similar distribution to helminthic diseases and positive correlation with severe anaemia

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21
Q

Malnutrition - effects, deworming

A

short term effects = wasting, long term = stunting
may be through increased TNFα production (trichuris)
After deworming with albendazole children showed increased weight for age and height

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22
Q

Physical fitness morbidity

A

Treatment with albendazole lead to significant increase in activity levels, decreased resting HR and quicker return to resting HR after exercise

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23
Q

Cognitive function subtle morbidity

A

Decreased performance with increased trichuris eggs but no control for school attendence
Verbal fluency increased much more with treatment of wasted compared to control than none-wasted

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24
Q

IgE to schisto

A

IgE raised
IgG:IgE balance important
IgE interaction with eosinophils in ADCC seems to be protective.

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25
Q

IgE raised in schistosomiasis.

A

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

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26
Q

Lymphatic filiariasis damage to host

A

In LF adult worms release Ag -> inflammation blcks lymph vessels –> oedema –> elephantiasis and hydroceles.

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27
Q

Onchocerca damage to host.

A

Microfilaria invade eye -> inflammation and fibrosis -> river blindness.

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28
Q

Hygiene hypothesis.

A

Helminths might be protective against autoimmunity

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29
Q

smTAL1

A

Allergen like protein in schisto with Ntd with EF hands. EF hands = structural motif shared with major fish and pollen Ags.

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30
Q

smTALs

A

smTAL1 = adult worm Ag released on rare occasions, smTAL2 = egg and adult ag released continuously as eggs die.

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31
Q

smTAL2

A

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)

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32
Q

Cross reactivity

A

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)

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33
Q

Allergen molecules

A

all from small number of protein families - most have homologues in metazoan parasites (5 of top 10 allergens) —> IgE didn’t evolve to target allergens but parasites to which are proteins are much more similar than bacteria

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34
Q

Evidence for relation between allergy and helminths

A

Types of allergens
Epidemiology
Intervention studies.
Mouse model

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35
Q

Anti-worm treatment and dust mite allergies.

A

Antiworm treatment in children shown to increase SPT results to dust mite Ags, and long term treated communities had twice SPT incidence as non treated —> in general allergic disease much less prevalent in less developed countries

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36
Q

Helminth infection suppressing allergy - mechanisms

A

increased IgE competing with anti-allergen IgE for Rs on cells
production of Tregs
production or regulatory cytokines IL-10 an TGFβ
Μοdified Th2 response seen in helminth infection seems to be important with alternatively activated macrophages stimulating Th2 response and IL-10 production —> IgG4 production; Tregs —> immunosuppression

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37
Q

Control of helminths

A

Chemotherapy.

Vaccines?

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38
Q

Chemotherapy for helminths.

A

Effective treatments are available for most e.g. praziquantal for schisto,
Problems: still get rapid post treatment reinfection, pathology remaining after elimination of parasites (e.g. filarial nematodes) and interruption of MDA due to war, famine, drought etc.

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39
Q

Vaccines for helminths

A

hookworm vaccin ASP-2 —> effective in animal studies and uninfected americans but in endemic brazil cause whole body urticaria —> reactions associated with pre-existing Asp-2 IgE —> histamine release
in natural infection don’t get same response as not systemic

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40
Q

Helminths immunopathology

A

Primary chronic manifestations
s.m. –> liver conditions, intestinal conditions, bladder.
w.b. elephantiasis and hydrocele.
Trichinella, trichuris and schistosome migration –> villous atrophy and diarrhoeia.

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41
Q

Anemia prevalence

A

 2 billion people

 40% school aged children

 1 in 2 pregnant women in the developing world

 20% maternal deaths!

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42
Q

Evidence for association of anemia in pregnancy with hookworm.

A

Correlation between hookworm egg count and fecal haemoglobin and IDA
Brooker: 12 studies light vs unifected (no sig difference), 7 studies light vs heavily infected (sig diff).
Mebendazole and Albendazole treatment during pregnancy appears to lower risk of still birth and increase mean birthweight

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43
Q

Assessment of poor nutritional status.

A

Assessed using Z scores , -2 is the cut off!

 Stephenson: Trichuris treatment increases weight 4 age, weight 4 height etc

 Positive correlation between treatment for hookworm ascaris trichuris and increase in
weight for height

 Increase in appetite : self reported, and no of kJ in 4 months post albendazole treatment

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44
Q

TNFa, worm infection and poor nutritional status.

A

MacDonald 1994 showed an increase in the TNFa in plasma and produced by gut cells of

infected vs uninfected. Rats injected with TNFa have decreased apetite

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45
Q

Recovering height deficit cause by poor nutritional status.

A

Girls can recover the height deficit before menarche : menarche is later in more stunted populations: Norway 1860: 15.6 yrs, Norway 1940: 13.3yrs Morabia 1998
Leensha : puberty in Kenyan School girls 12yrs, menarche a 15 yrs
Callender : Growth and development 4 years after treatment for trichuris dysentery:

o Potential for catch up growth

o Still slower cognitive function

o Window period for both?

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46
Q

Poor nutritional status studies

A

Stephenson - weight for age.
MacDonald - TNFa
Callender - catch up growth.

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47
Q

Poor physical fitness studies

A

Adams 1994 treated vs untreated.
Stephenson linear regression.
Kenyan study.

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48
Q

Poor cognitive function study.

A

Simeon, but difficult to assess.

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49
Q

Poor physical fitness - Adams study.

A

Adams 1994 albendazole treated group much greater observed activity than untreated

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50
Q

Poor physical fitness - Stephenson study.

A

Stephenson showed that weight gain, appetite and worm count were all significant
predictors of physical activity in a linear regression model measuring the VO2 max in
school children in China

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51
Q

Poor physical fitness study, Kenyan study.

A

Kenyan study 2011 used a 20m shuttle run as a measure of fitness

o Easy low resource measure

o Exercise intolerance associated with anemia, stunting and wasting

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52
Q

Poor cognitive function, Simeon study.

A

School attendance, reading, arithmetic and spelling all drop

o Reading and arithmetic still significantly impacted when controlling for age, sex

SES and school attendance

o Treatment of Trichuris trichuria significantly improves scores if

 V heavily infected >7000 epg

 Or if v low Z score Z

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53
Q

Driving force behind interleukin gene selection

A

Fumagalli population genetic analysis showed that helminth infection has been the evolutionary driving force.

54
Q

Immunosuppressive qualities of hookworm.

A

o Tolerogenic DCs

o Alternatively activated macrophages

o iTregs

o Bregs

55
Q

Helminths and allergy; mouse model.

A

Infection with Heligmosomoides polygyrus decreases response to ovalbumin driven airway inflammation

56
Q

Helminths and allergy; intervention studies.

A

Flohr
Van de Biggelaar
Lynch
Endara.

57
Q

Helminths and allergy; intervention studies. Flohr

A

showed that following antihelminthic treatment in Vietnam for hookworm, trichuris and ascaris there was an increase in allergic sensitization

58
Q

Helminths and allergy; intervention studies. Van de Biggelaar.

A

2003 showed that long term treatment lead to an increase in sensitivity to dust mite

59
Q

Helminths and allergy; intervention studies. Lynch 1993.

A
  1. Increase in dust mite allergen sensitivity following treatment of a population in Venzuela
60
Q

Helminths and allergy; intervention studies. Endara

A

(Ecuador) Following 12 months treatment the treated communities has twice the SPT incidence of non-treated.
2010.

61
Q

Epi evidence about allergy and helminths.

A

Meta-analysis results not significant
Urbanisation, socio-economic status is related to SPT positivity in Ghana and Indonesia
Indonesia: Filariasis related to decreased %SPT to cockroach
Gabon: Schisto and decreased %SPT to dustmite
Ghana: schisto and STH and decreased response to dust mite

62
Q

Anti-schisto IgE levels

A

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.

63
Q

Effect of IgE

A

Binding to prevent invasion e.g. of larvae.
Stimulation of cell mediated cytotoxicity. IgE normally bound to highly avid FcεRI receptor which forms a trimer on APCs, and a tetramer on mast cells and basophils, with the B-chain leading to an amplification of the signal, which leads to a release of histamine and inflammatory signals.
Activates complement.

64
Q

Effector mechanisms of Th2

A

Effector cells found in mucus membranes and skin - mast cells and eosinophils which release proteases and toxic proteins which can kill larval stages.
IgE

65
Q

IgE in evolution of Th2

A

Late mechanism; immune responses to helminths in avian hosts don’t even have IgE.

66
Q

IgG antagonism to IgE.

A
  • Doesn’t activate complement as well, competes for antigens
  • Binds inhibitory FcεRIIB  blocks IgE mediated eosinophil function. Most responses similar to those used for parasites: increased secretion of mucus, contraction of smooth muscle, itching and etc.
67
Q

Chief effects of Type 2 cytokines.

A

IL-4, IL-5 and IL-13 important in mastocytosis, eosinophilia and antibody class switching.

68
Q

Soluble worm antigen

A

Only released when adult worms die (e.g. on treatment, with time), so resembles seasonal allergenic stimulation. Stimulates production of IgE which is cross-reactive with antigens on cercaria, leading to immunity to reinfection. Explains age–dependent concomitant immunity.

69
Q

Cercarial penetration

A

Proteases are used. Traditionally thought not to usually induce much inflammation (if in correct host) in the skin, but histological evidence suggests otherwise.

70
Q

Radiation attenuated cercaria

A

Both innate and adaptive response. Much quicker resolution with normal larvae: cytokine production not sustained, no sustained TH-cell population.

71
Q

Cercarial modificataion of immune response.

A

• Rapid exit
• Downregulation.
o Excretory secretory products of cercariae induce IL-1 receptor agonist from keratinocytes. Possibly also induce IL-10.
o Parasite derived prostaglandins probably involved in promoting IL-10 production.
• Difficult to model multiple exposures, and mice don’t really do this.

72
Q

FceR

A

IgE binds cells through a low affinity CD23 receptor and a high affinity FcERI receptor
FcERI - trimer on monocytes and dendritic cells, tetramer on mast cells and basophils
The B chain present in the tetramer mediates a large amplification of the intracellular signal
Cross linking of occupied FCeRI on mast cells and basophils leads to the release of histamine, cytokines and inflammatory agents characteristic of allergic response

73
Q

T cell hyporesponsiveness in helminth infections.

A

Evidence
Manipulating induction
Manipulating regulatory mechanisms

74
Q

T cell hyporesponsiveness in helminth infections - examples of impaired responses.

A

Schistosome and onchocerca Infected individuals have an impaired Th1 respone to tetanus toxoid vaccine and to influenza virus
Intestinal parasites induce an impaired response to BCG or cholera vaccine

75
Q

T reg role.

A

Produce IL-10

Many Treg effects neutralised by blocking Abs to IL-10 or FoxP3

76
Q

T reg induction in onchocerciasis

A

Doetze showed increased levels of IL-10, TGFB and Treg

77
Q

T reg induction by Brugia Malayi (also causes lymphatic filiariasis).

A

Babu showed that infection with Brugia Malayi increases Foxp3 expression, TGFB and cytotoxic T cell antigen 4

78
Q

T reg induction in schisto patients.

A

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.

79
Q

Studies involving T regs

A

In vitro removal of Fox3p from PBMCs of schistosome or geohelminth infected individuals restored the BCG specific proliferation and IFNy production compared to controls

80
Q

Studies demonstrating T reg induction.

A

Animals models nematode infection induces FoxP3

Also onchocerciasis, brugia malayi and schisto.

81
Q

T regs in allergy

A

Populations with Foxp3 deficiency have increased allergy
In asthmatics the function of Tregs is often impaired
Successful immunotherapy is associated with the development of IL-10 producing Tregs and B cell modification: IgG4, IgA and decreased IgE.

82
Q

Roles of Bregs

A

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
MS patients with helminth infections have decreased disease activity, this is associated with increased IL-10 production from a sub-set of B cells: CD1 hi

83
Q

B reg induction in helminth infections.

A

CD1hi subset is increased in Gabonese patients with s haemotobium infection
Splenic B cells can be stimulated ex vivo with SEA
S mansoni infected mice produce fewer BAL eosinphils in an IL-10 dependent manner

84
Q

B regs and allergy

A

B cells responsible for the local inhalation tolerance following continuous allergen exposure by inducing T regs (Singh et al 2008)
Transfer of schistosome induced IL-10 producing B cells strongly decreases inflammation in the murine model
Another subset of B cells : CD23hi has been shown to induce IL-10 independent protection from allergic airway inflammation in H polygyrus infected allergen sensitized mice

85
Q

Trematodes

A

schistosomes

86
Q

Alternatively activate macrophages

A 
Arginase 1, YM1, FIZZ1 
IL-10, TGFB
Intermediate MHCII 
High mannose receptor 
High PD-LI and PD-L2
87
Q

aa-macrophages: evidence of role.

A

B malayi induced macrophages suppress T cell proliferation
Transwell expts show that this is dependent on cell: cell contact
SEA alternatively activates peritoneal macrophages
Arginase 1, Fizz-1, Mannose Receptor, PDL1

88
Q

PDL1/2 in alternatively activated macrophages.

A

PDL1/2 is a co-inhibitory signal, by upregulating PDL1 and PDL2 helminths control T cell expansion and proliferation
School children in Ghana S haemotobium infected expressed significantly higher lvels of PD1 (0.001) and CTLA-4 (0.005) mRNA.
CTLA-4 is another co-inihibitory signal.

89
Q

Helminths inducing cytokine homologues

A

H polygyrus excretory antigen can induce de novo expression of Foxp3 in murine T cells similar to that induced by TGF-B.
 Antigens like Omega-1 activate TGF-B pathways by inducing its production in DC cells.
 Some helminths express TGF-B homologues themselves.
 Hookworm TIMP protein seems to increase IL-10 production by B cells.

90
Q

SEA modulation of DC cells

A

SEA pulsed DC induce Th2 polarisation in vivo
When given with LPS SEA inhibits TLR induced IL-12 signalling
In absence of TLR stimulation, SEA upregulates CLRs in bone marrow derived DC

91
Q

Immunosuppressive qualities of hookworm.

A

o Tolerogenic DCs

o Alternatively activated macrophages

o iTregs

o Bregs

92
Q

T cell hyporesponsiveness in helminth infections.

A

Evidence
Altering induction
Altering regulatory mechanisms

93
Q

Immune responses to helminths - key themes

A

Host immune Th2 response causes expulsion.
Parasite downregulation of immune response to prevent expulsion.
Host downregulation of immune response to prevent pathology.

94
Q

Immune responses to helminths - key themes

A

Host immune Th2 response causes expulsion.
Parasite downregulation of immune response to prevent expulsion.
Host downregulation of immune response to prevent pathology.

95
Q

Studying the immune response to helminths.

A

Much of what we know is from mouse models, which are only acute.
Also studying cell populations in chronically infected humans.

96
Q

Immunity to helminths: host immune response causes expulsion. HOST GENETIC FACTORS.

A

Resistance usually strongly correlates to TH2 cytokines, IL-4, IL-5 and IL-13. Polymorphisms in these genes generally alter susceptibility. The cytokines induce effector responses via the class I and class II IL-4 receptors, which act via the JAK/STAT pathways.

97
Q

Models of immunity - infection of mice with…

A

Trichinella spiralis
Nippostrongylus brasiliensis
Trichuris muris.

98
Q

General immune responses to helminths.

A

 High serum IgE
 Peripheral eosinophilia
 Gut mastocytosis
 Goblet cell hyperplasia – make mucins for dynamic mucus barrier, also resistins.
 Increased contractility of gut  increased expulsion. CD4 T cell dependent. STAT6 KO mice have decreased contractility.
 Unique innate cells called ILC2 cells make IL-13
DEPENDS ON DIFFERENT ASPECTS FOR DIFFERENT HELMINTHS.

99
Q

T spiralis expulsion depends on …

A

Mast cells - weep and sweep and mucus trap.

100
Q

Evidence that T spiralis expulsion depends on mast cells.

A

Mast cell deficiency leads to abrogation of expulsion, even if mast cells abrogated so contractility remains the same.

101
Q

Mechanism of action of T. spiralis expulsion.

A
  • Mode of action: mast cells produce mcp, mast cell protease. This prevents occluding localizing to the membrane, so the tight junctions between epithelial cells no longer have integrity. This results in ‘leaky gut’.
  • Since T. spiralis normally intertwine part of their body (or is it the tail) to anchor themselves, this causes expulsion. This is IgE independent. Weep and sweep.
  • Mucus trap. Trap in lumen and prevent them reaching niche. Also favours expulsion. Possibly mimic epithelial cells glycoproteins, preventing microbe attachment.
102
Q

Nippostrongylus brasiliensis expulsion basics.

A

IL-13 important.

But not necessarily useful as humans do not clear hookworm?

103
Q

Nippostrongylus brasiliensis - importance of IL-13

A

IL-13 KO mice don’t clear worms effectively. ILC2 cells appear important in IL-13 production. IL-13 important.

104
Q

Nippostrongylus brasiliensis - clearance mechanism.

A

• Intraepithelial cells respond chiefly to IL-13 acting via the IL-4Rα
o RELMβ KO don’t clear well: this resistin may act in several ways, but one hypothesis is that it acts by interfering with the chemosensory apparatus of the parasite.
o Mucus trap

105
Q

Trichuris muris immune response.

A

IL-13 essential.

Good model for whipworm.

106
Q

Trichuris muris role of IL-13

A

o Leads to increased cell turnover, meaning that the Trichuris muris anchoring system doesn’t work so well.
o Mucins are made by goblet cells. Mucin knockouts show delayed expulsion. Muc5 seems especially important as the worms excretory secretory products don’t really work against it, as they do on Muc2. Mucus trap.
• But this is in mice treated with a high dose. Low doses lead to Th1 dominated responses and chronic infections in all.

107
Q

Hyporesponsiveness of T cells in filiariasis.

A
  • Anergy strongly correlates to asymptomatic state. T cells derived from parasite containing subcutaneous granulomata express IL-10 and TGF-B, and have regulatory and suppressive phenotypes.
  • Early life exposure seems to promote asymptomatic “tolerant” state.
108
Q

Hyporesponsiveness of T cells in schistosomiasis

A

• 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.

109
Q

Tolerogenic dendritic cells - helminth activation.

A

Activation of TLR2.
Activation through unconventional receptors.
Inhibit classical activation with IL-10

110
Q

Tolerogenic dendritic cells - Activation of TLR2.

A

is perhaps central to producing the hyporesponsive state: TLR2 deficient mice show lower immune responses.

111
Q

Tolerogenic dendritic cells - activation through unconventional receptors.

A

Mannose dependent receptors.

Particularly CLR receptors such as dectins or DC-SIGN

112
Q

Activity of tolerogenic dendritic cells.

A

Suppression of TLR response, failure of DC maturation, impair the Th1 development and skew towards the Th2

113
Q

Phenotype of tolerogenic dendritic cells.

A

intermediate expression MHC II, low expression CD40, low expression CD80/86.

114
Q

SEA modulation of dendritic cells - molecules

A

Omega1
Lex
Mono-acetylated phosphatidyl serines.

115
Q

SEA modulation of dendritic cells - effects.

A

o can decrease responsiveness not only to itself but to P. acnes stimulation.
o Can decrease IL-12 production in response to TLR stimulation.

116
Q

Omega-1 basics

A

 Glycoprotein, cationic, N glycosylated with Lewis X, highly immunogenic and actively secreted by S mansoni eggs

117
Q

Omega-1 effects.

A

 Omega 1 pulsed DCs induce the Th2 response in vivo.

 Omega 1 induces the secretion of bioactive TGFB in bone marrow derived DC stimulated with LPS

118
Q

Alternative activation of macrophages - mouse models.

A

• This is found in mouse models; not yet been identified in humans but likely to exist in humans. SEA alternatively activates macrophages. Stimulated by IL-4 and IL-13. Possibly IL-21 has a role too.

119
Q

Arginase-1 in alternatively activated macrophages.

A

Outcompetes inducible nitric oxide synthase. Associated with fibrosis and healing response – granuloma formation – rather than clearing, as downstream product proline is important in fibrosis, and polyamines are important in stimulating cellular proliferation

120
Q

T cell hyporesponsiveness in helminth infections - manipulating induction

A

Tolerogenic DCs

Alternatively activated macrophages.

121
Q

T cell hyporesponsiveness in helminth infections - manipulating regulatory responses.

A

Alternatively activated macrophages,
Tregs,
Bregs.
Cytokine production and homologues

122
Q

Helminth infections - downregulation of response to decrease pathology

A

Lymphatic filiariasis
Onchocerca volvuli
Schistosomiasis
Gastrointestinal nematode infections.

123
Q

Helminth infections - downregulation of response to decrease pathology; lymphatic filiariasis.

A

 Tolerant phenotype has little pathology. TGF-B and IL-10. Tregs important, B cells produce IgG4. Limited T cell proliferation.
 Chronic pathology: parasite at low levels, but elephantiasis due to Th1 and Th17 leading to inflammation and fibrosis. Lots of IgE. Deficient in Tregs.

124
Q

What alters helminth and allergy interactions?

A

Timing
Intensity
Host genetics
Type of infection/allergy

125
Q

What alters helminth and allergy interactions? Timing.

A

o Treating pregnant mothers for hookworm increases chance of eczema in child.
o The earlier the infection is in childhood, the more likely it is to cause a fixed deviated immune phenotype.
o A chronic infection is more likely to modulate the immune system than a transient one.

126
Q

What alters helminth and allergy interactions? Intensity.

A

Some studies demonstrate an inverse relationship between intensity of helminth infections and allergic disorders.

127
Q

What alters helminth and allergy interactions? Host genetics.

A

Atopic individuals more common in some ethnic groups?

128
Q

What alters helminth and allergy interactions? • Type of helminth infection, type of allergy

A

o Trichuris, hookworm and schistosomes associated with allergen skin reactivity, hookworm also with asthma.
o Ascaris seemed to potentiate asthma.
o Short-term treatment does not seem to increase allergic reactions, but long-term treatment studies have reported that it does.

129
Q

Immunity to worms - basics

A

Immunity not always obvious - may be absent or just reduce disease burden rather than incidence altogether —> due to evasion of immunity or failure of immune system to mount adequate response
Would be very unusual if no immunity at all —> parasite would overwhelm susceptible host and cause death —> loose evolutionary bias
lack of complete immunity evolutionary compromise between limiting worm burden and preventing immunopathology?
reinfection studies prove that immunity not complete

130
Q

Problems with studying immunity via epidemiology

A

Problems with studying immunity via epidemiology
Presence of worms from existing infection dying at unknown rate —> difficult to assess level of new infection —> have to do reinfection studies
Lack of reinfection can just be lack of exposure —> control for exposure
Difficult to detect even partial immunity
Most studies = reinfection studies where chemotherapy use to remove exitsting worm populations, measure degree of exposure of each individual in study and do quantitative measurements of rates of infection (e.g. counting parasite eggs produced)

131
Q

Despite chemotherapy, reinfection. This suggests…

A

Not complete immunity

132
Q

Age intensity curves intestinal worms

A

trichuris and ascaris intensity decrease after peaking in childhood —> fewer worms establishing infection/surviving = evidence for immune response
hookworm has peak in 30-40s with no evidence for immunity in adults in low transmission areas, in high transmission areas there is some drop which may be due to increased dose exposure needed
but for N. americanis there is evidence for decreased fecundity with increasing specific IgE

Zpath term 2 (14 decks)

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