Immunity of

Filariasis
Filariasis limfatik :
Wuchereria bancrofti  Bancroftian filariasis (90%)
Brugia malayi
Brugia timori
Ditularkan melalui gigitan nyamuk
Siklus hidup :
Cacing dewasa  pembuluh limfatik aferen
Mikrofilaria  pembuluh darah perifer
Global health problem  2013 (WHO):
>1,25 milyar orang di 72 negara  berisiko
120 juta orang  terinfeksi
>40 juta orang  keluhan  elefantiasis

Siklus hidup  kompleks  respon imun yang

kompleks
Kompleksitas interaksi parasit-host  manifestasi
klinis yg bervariasi
 IgE
IgG4
IgG1
IL-5, IL-13
IgM
>>>>

Sumber: http://www.ozbiosciences.com/
The main characteristic of a chronic filarial
infection :
modified Th2 response
IL-10 dominated regulatory environment

Iin vivo data from mice deficient IgE 

increased worm burdens with B. malayi 
indicating an important role for IgE in host
defence
IgM  crucial for host protection against B.
malayi
In the lymphatics and lymph nodes as well as in the
circulation, filarial parasites are susceptible to
attack by the full range of host innate effector cells,
including macrophages, eosinophils and
neutrophils  ability to kill the parasites is often
dependent on one or more isotypes of specific
anti- body (often IgE but also IgM) and
complement.
Activated macrophages/ granulocytes  release
nitric oxide, damaging nitrogen intermediates
&reactive oxygen species  surface of the
parasites  but in vivo killing methods are not yet
fully understood.
Macrophages  special class of macrophages
(AAM):
expression enzyme arginase
nitric oxide  a key lethal hit in the host defence
against the parasite
increase activation of arginase-1 by IL-4 and IL-13
have a very specific gene expression profile 
upreguate arginase-1, chitinase 3-like proteins 3
&4 (also known as YM1 and YM2) & resistin-like
molecule a (RELMa)
important in wound healing
help limit tissue immunopathology
By virtue of expression of regulatory molecules such
as IL-10, TGFb and programmed cell death 1 ligand 2
(PDL2), these macrophages might play a
predominantly regulatory role in filarial infections (27).
Interestingly, these filarial-induced macrophages
appear to have the ability to expand locally and are
less dependent on influx of monocytes from the
bloodstream to perform their functions (28). While
filarial infection does induce expression of these cells
in humans, early interaction of parasites or parasite
antigens leads to a predominantly pro-inflammatory
response with expression of mainly pro- inflammatory
cytokines including TNFa, IL-6 and IL-1b, as well as
genes involved in inflammation and adhesion (29).
Characteristic of filarial infection : Blood
eosinophilia
mediated by IL-5
first cell  recruited to the site of infection, rapid 
eosinophilia characteristically early following
infection
morphological & functional changes :
cell density
increase surface expression of activation markers
enhanced cellular cytotoxicity
release of granular proteins, cytokines, leukotrienes
and other mediators of inflammation
 Filarial parasites  immunoregulatory effects on
the host immune system:
immunosuppression
immunological tolerance

immunoregulatory cytokine-induced
suppression of immune responses and a state of
immune tolerance in effector T cells
modification of stereotypical Th2 responses 
antibody isotype switching to the noninflammatory
isotype IgG4
 Immune evasion strategies  secretion of
products that modulate host immune function
Phosphorylcholine (PC)  one particular PC
containing molecule called ES-62 from filarial
worms
ES-62:
downregulate proliferation of CD4+ T cells and
conventional B cells
decrease IL-4 & IFNc production
upregulate proliferation & production IL-10
condition APCs to drive Th2 differentiation with
concomitant inhibition of Th1 responses
Recent analysis of the filarial parasite
genome has identified a remarkable
number of human cytokine and chemokine
mimics and/or antagonists :
IL-16 family
IL-5 receptor antagonist
Interferon regulatory factor, a homolog of
suppressor of cytokine signalling 7 (SOCS7)
other potential immunomodulators:
serpins and cystatins (modulation of antigen
processing and presentation to T cells),
indoleamine 2,3-dioxygenase (IDO) genes
(potent immunomodulatory molecule)
Wnt family of developmental regulators
Most of the immunological studies in filarial
infections have focused on filarial antigen-induced
immune responses
Live parasites cause a significant impairment of
both Th1 and Th2 cytokines in response to both L3
and Mf stages with diminished production of Th1
(IFNc and TNF-a) and Th2 (IL-4 and IL-5) cytokines 
impaired induction of T-bet (the master Th1 tran-
scription factor) and GATA-3 (the master Th2
transcrip- tion factor) mRNA and by significantly
increased expression of Foxp3, TGFb, CTLA-4, PD-1,
ICOS and IDO
Compromise of effector T-cell function  anergy
 the down modulation of immune responses in
patent filarial infectionmight have a potentially
vital role in the establishment of chronic,
asymptomatic infection
Figure 1. Role of regulatory T cells in the context of filarial
infection. Filarial parasite infective larvae (L3) deposited on
the skin during the bite of an infective mosquito actively
penetrate the skin following which they migrate to a
draining lymph node. During their migration, L3 contacts
and activates different cells such as keratinocytes (KC),
dermal dendritic cells (dDC), innate lymphoid cells (ILCs),
macrophages (MAC), dendritic cells (DCs), and basophils
(Baso). At this relatively early phase of infection the parasite
induces the differentiation of effector Th1, Th17, and Th2
cells, which together with IgE antibody may lead to attrition
of some of the parasites. However if there is failure to clear
the parasites, the infection evolves into a chronic
longstanding infection associated with IL-10-producing type
1 (Tr1), TGF-β-producing Th3, and Foxp3-expressing Tregs or
peripheral Tregs (pTregs), which together with the thymus-
derived Tregs (tTregs) can be found with increasing
frequencies in filarial infections. The high levels of IL-10
produced induce the production of IgG4 and together with
IL-4, IL-13, and/or TGF-β induce the differentiation of
alternatively activated macrophages (AAM) and inhibit the
function of a variety of other cells.