1. Prepared by: Shalimar Shadeed

2. 
 Blood flukes belonging to the genus Schistosoma are
important parasites of humans:
 Three species affect humans:
a. S. mansoni: large intestine
b. S. japonicum: small intestine
c. S. haematobium: urinary bladder
Flash Back- Schistosoma

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http://www.nature.com/icb/journal/v89/n3/images/icb2010152f1.jp
Central Role of Helper T-
cells in the Immune System

6. 
Innate Immunity
penetration of skin
Specific Immunity
 adults take on host antigens;
Soluble Egg Antigens (SEA) CD4+ Th2 (cytokines
according to the subtype activated) Complement system
(classical or alternative)
The most important aspect to be discussed throughout this
presentation is how this parasite can interfere with the
regulatory mechanisms of Th2 . Conseqently, the immune
system response.
Slippery Little Suckers Aren’t They…” ~ Julia
Roberts

7.  CD4+ is classified into different subsets depending on which
type of cytokines Th2 activates. Understanding the
mechanisms responsible for controlling T cell- dependent
events such eosinophilia and increased IgE levels that had for
some time been recognized as hallmarks of schistosomiasis,
led to the realization that schistosome infection induces a Th2
response.
 Analysis has shown the prominence of Th2 at the time of egg
production (SEA) are able to directly induce Th2 responses
when injected into mice.
The deposition of Schistosome eggs is
associated with the emergence of a strong Th2
response

8. 
 In animals infected with S. Mansoni , eggs trapped in tissue become
focal points for inflammatory infiltrates in which forms a
Cirucumova granuloma, these lesions reflect Th2 dominance; (CD4+
T cells, B cells and fibroblasts, and eosinophils).
 This was exp. proven when the granuloma developments was
impacted in mice lacking Th2 was analyzed; the findings shown that
inflammatory infiltrates around eggs were small and compromised.
 Granulomas serve an important role protective role in sequestering
the eggs away from the surrounding tissue.
CD4+ Th2 cells play a crucial host-protective role
during infection

9. 
 Mice T-cell depleted, infected with S. Mansoni were rendered unable to
form granuloma and developed necrosis in the liver and intestinal mucosa
between 6-7 weeks of infection. Additionally, these mice shown
microvesicular cytoplasmic damage with accompanying nuclear
pyknosis(irreversible mythelations of histones upon cell necrosis); this is
accompanied by elevated serum transaminase concentrations (indication of
liver damage).
 Granuloma formation around eggs that have been embolized to the lungs is
dependent on Chemokines and chemokine ligand, which is preferentially
expressed on Th2 cells). For example, CCL2 and CCR4 respectively.
Cont.

10. 
1- It’s thought that granuloma formation walls off the
eggs and prevent toxic molecules produced reaching
the surrounding tissue.
2- IL-4 regulates the proinflamatory and cellular
response. This was evident in mice lacking IL4; mice
died due to the excessive response of the above
mentioned mechanisms.
How are CD4 T cell protective (host)?

11. Data and observations implied that IL-4 suppresses the emergence of an INF-γ secreting CD4+ cell
and/or plays an important role in limiting access of TLR agonists into diseased tissues; the absence
of IL-4 as demonstrated:
Classical Pathway activation in the absence of IL-4:
TLR agonists & IFN-γ activates the Macrophage to produce( NO, ROS,TNF-α).
This pathway is implicated with the disease severity; Hence, we can appreciate the importance of
IL-4 in regulating the secretion of IFN-γ Secreting CD4 cells. Also, it’s hypothesized that that it
plays important role in limiting the access of TLR agonist into diseased tissue.
 The likely source of TLR agonists in this setting is the translocation of intestinal microflora into
the tissues and vasculature as a result of diminished barrier function in the intestinal
epithelium
IL-4

12.  Collected date and observations shows the importance of
macrophages protective role other than the INF-γ/TLR
agonists; IL-4 and IL-13 initiate a distinct “alternative
activation” (AA) pathway in macrophages that leads to the
expression of a characteristic panel of genes. Arginase 1
(Arg1) is a key marker of AA macs.
 L-arginine Arg1 L-ornithine (Urea Cycle)
Ornithine is precursor in proline synthesis, and proline and
hydroxyproline are major components of collagen, this
enzyme was originally suspected to play a role in the
development of hepatic fibrosis and, therefore, to play a role
in liver disease in schistosomiasis.
IL-4 and IL-13 role in activating the AA
pathway in Macrophage

13. 
 Deletion of Arg1 in macrophages led to significantly greater granulomatous
inflammation, liver fibrosis, and portal hypertension. Arg1 expressing AA macrophages
can successfully compete with Th2 cells for arginine and, in so doing, limit T cell
proliferation. It was evident that in infected mice lacking Arg1 in immune cells also
develops more severe intestinal inflammation following infection with S. mansoni. This
is associated with the increased expression of classical macrophage.
 This is associated with the increased expression of classical macrophage activation and
the development of Th17-related IL-12/IL- 23p40-dependent neutrophil-associated
inflammation around eggs in the intestinal wall and resultant endotoxemia.
Mechanism-Arg(1)

14. 
 Interestingly, an additional AA macrophage product, RELM-α (FIZZ1), which is
additionally made by eosinophils and epithelial cells in sites of Th2-mediated
inflammation, appears to function in a somewhat similar manner to Arg1 since in
RELM-α-deficient mice, granulomatous inflammation and fibrosis around
schistosome eggs, as well as Th2 response intensity, are markedly increased.
Together, these findings point toward a strong, protective immunoregulatory role
for AA macrophages during schistosomiasis, in which the cells function to prevent
hyperresponsiveness within the Th2 cell compartment while promoting wound
healing within the intestine by antagonizing classical pro-inflammatory
macrophage activation.
Other AA pathways

15.  T cells has a very role important in helping the development of a B cell
response that protective at later stages during infection.
 previous study has shown that cytotoxic effects can be prevented in the
absence of T cells via passive immunization with antibodies from infected
immunologically intact mice or from mice immunized with egg antigens.
 The possible explanation for this is that the protective role of the T cell-
dependent cellular infiltrate around eggs is required only transiently until
the antibody response is able to develop to a point where it can neutralize
egg toxins.
Th2 & B-cells

16. 
 Recent studies have revealed the presence in the liver of F4/80+
macrophage-like cells that can be stained for IgG1 and it is possible that
these cells are “regulatory macrophages” which are able to play an anti
inflammatory role by responding to immune complexes by producing IL-10
and TGF-β1.
 As an extension on the body of evidence, IgG1+ F4/80+ cells (putatively
macrophages) in chronically infected mice are transcribing IL-10 in vivo and
secrete this cytokine ex-vivo.
F40+/80 and it’s protective role

17.  It was previously thought that the population of CD4+ T
cells making IL-4 elicited by infection is functionally
uniform, such that cells producing IL-4 to alternatively
activate macrophages in the liver would also be capable of
helping B cells within lymphoid organs.
 However, this is done by the B cell help is the specialized
role of T follicular helper (Tfh) cells and that the IL-4-
producing CD4+ Tfh cells that enter B cell follicles are
functionally distinct from the Th2 cells that migrate to
peripheral tissues.
 The extent to which either Tfh or Th2 cells retain the
plasticity to assume each other’s roles during infection
remains unclear, but is of considerable interest since, given
the protective role of antibody
More in the mechanism

18. 
 Age prevalence curves showed that patients living in a areas
endemic for schistosomiasis slowly develop resistance to
reinfection. This observation can be explained by the fact that
a protective response is initiated by the death of adult worms
and is boosted as worms naturally age and die.
 Successive rounds of chemotherapy accelerates this process,
especially when administered repeatedly over time to
individuals who are being continuously re-exposed; the
strongest correlate of resistance to further infection is the titer
of IgE, and specifically of IgE against adult worm antigens such
as Sm Tegumteal Allergen Like.
By inference, IL-4-producing Tfh cells play an important
role in resistance to reinfection

19. 
 As discussed before, the CD4 has a very important role in regulating Th2 response
in which protects form hepatic infections. However, it’s clear that there are
detrimental effects associated with strong Th2 responses in the context of
infection; Th2 responses are linked to the development of hepatic fibrosis, which
underpins severe morbidity in chronic Schistosomiasis.
 As a small revision on what have been discussed with regard IL-4 and IL-13, is that
both can stimulate fibroblasts to make collagen, it is IL-13 that plays a particularly
important pro-fibrotic role in Schistosomiasis. In the absence of this cytokine, or in
settings where the ability of IL-13 to bind to its cell-associated receptor is blocked,
hepatic fibrosis is very significantly reduced and the prognosis is improved.
Th2 cells cause pathologic
changes

20. 
 The outcome of inflammation and fibrosis is dependent not only on the
extent of collagen production but also on the regulation of degradation
through the expression of matrix metalloproteinases (MMPs) by AA
macrophages.
 In this context, MMP12 promotes the development of more severe
disease by regulating the expression of MMP2 and MMP13, both of
which act to degrade the extracellular matrix
Cont.

21.  This cytokine inhibits dendritic cell (DC) activation and, in such action, it limits
their ability to activate T cells. Thus, the production of IL-10 by Th2 cells,
regulatory T cells, and innate cells such as macrophages was seen as a
compelling mechanism for the inhibition of Th2 responses; this is well
documented as an exaggerated immune response in case of mice lacking this
cytokine during late stages of the infection.
 On the other hand, immunomodulation was seen to occur normally in
chronically infected IL-10−/− mice.
 It is apparent that the mechanism is ultimately cell autonomous in that the
cells remain hypoproliferative even when transferred into acutely infected
mice (where resident Th2 cells are proliferating strongly) [86]. Increased
expression over time of grail (gene related to anergy) [86], and of inhibitory
CD200 receptors [13], possibly as a result of repetitive stimulation with
antigen (a common theme in chronic infection), is implicated in the loss of
Th2 proliferative capacity late in infection
Regulation of Th2 responses by IL-10

22.  Treg compartment expands during infection following schistosome eggs.
Expansion is dependent on TLR2; in the absence of this pattern recognition
receptor, immunopathologic changes are more severe, and there is a
prolonged Th1 response during acute infection.
 Loss of Th2 responsiveness at week 8 of infection in schistosomiasis is
interesting because the decline occurs despite the fact that parasitic worms
live for years, continuing to produce eggs such that there is effectively an
ongoing increase in the amount of antigen to which the host is being
exposed.
The regulation of Th2 responses by
Treg cells and the overall pic

23.  In this regard, immunoregulation in schistosomiasis is reminiscent of T cell exhaustion in
chronic viral infections where the interaction of PD-1 on T cells with its receptors (PD-L1/PD-
L2) on other cells plays an important role in inhibiting T cell function. Nevertheless, in other
worm infections, PD-L2 expression by AA macrophages has been implicated in the loss of
responsiveness within the responding T cell population, and consistent with this, in
schistosomiasis, PD-L2 expression is linked to the development of less severe disease. It is
also possible that PD-L1 is playing a role in T cell non-responsiveness during schistosomiasis .
 The production of IL-10 by Treg cells has been implicated in limiting the development of
immune mechanisms, measured as the increased production of Th1, Th17, and Th2
cytokines, increased IgE, IgG2b, and IgG1, and increased eosinophilia, that are correlated
with the expression of resistance to reinfection in infected mice following chemotherapy.
Cont.

24. 
 Studying how Schistosoma has the ability to interfere with the Treg in such
the development of Treg cells and the effects of schistosome antigens on
dendritic cells and macrophage.
 the outcome of allergic and autoimmune disease. Infection with S.mansoni, or
the injection of schistosome eggs, or of SEA, in settings where animals have
been manipulated to develop autoimmune diseases or are genetically
predisposed to do so have, in some cases, had notably beneficial effects.
Exploiting schistosomiasis-associated immune
responses to treat other diseases

25. 
 Many studies have shown that schistosoma eggs induces Th2
response. The response becomes most noticeable after egg
production begins during infection, and eggs isolated from
infected mice are able to strongly induce a Th2 response when
injected, without adjuvant, into naïve mice.
 A SEA is similarly immunogenic. DCs are also crucially important
in the induction of Th2 responses during infection since following
their deletion the immune response becomes dominated by IFN-
γ production. However, SEA fails to activate DCs in the classical
way, but rather is able to inhibit TLR-initiated activation and
generally appears to maintain DCs in an immature state.
The mechanisms underpinning Th2 response
induction during schistosomiasis

26.  Intriguingly, Omega-1 (produced by the parasite) is a molecule that has
hepatotoxic properties and is the major target of antisera that protect
infected T cell-deficient mice against liver damage.
 Recent findings indicate that Omega-1 is taken up by DCs via its glycans
through the CTL (C-Type Lectin) mannose receptor (MR) and thereafter
inhibits protein synthesis by degrading RNA and that these processes
result in DCs that preferentially induce a Th2 response.
 MR has also been implicated in the response of DCs to glycans from the
infectious stage of the parasite that leads to the suppression of IFN-γ
production by T cells. Other possible mechanisms for the inhibition of DC
activation by schistosome products have been reviewed recently [26]
and include the degradation of TLRs within endosomes by endocytosed
schistosome protease or engaging CTL that modulate canonical NF-kB
translocation following TLR stimulation
Cont. how does the Parasite
inactivates IR?

27. 
 During a primary infection of S. mansoni, the immune system responds vigorously,
especially once significant tissue damage associated with egg production begins,
however this response doesn’t eliminate the parasite. Nevertheless, the response
protects the liver against toxic molecules released by eggs and promotes healing
in the intestinal epithelium that is being continuously perforated by eggs as they
pass from the vasculature into the intestinal lumen. These beneficial mechanisms
are a key for the survival of this parasite for a long periods of time (chronic).
 Understanding how Th2 responses are induced and regulated in schistosomiasis
(and relating this to the regulation of other Th2-mediated diseases) remains a
priority.
Summary

28. 
Questions?