Download Immunity to brucellosis

Rev. sci. tech. Off. int. Epiz., 2013, 32 (1), 137-147
Immunity to brucellosis
P. Skendros (1)* & P. Boura (2)
(1) First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of
Thrace, Alexandroupolis, Greece
(2) Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle
University of Thessaloniki, Thessaloniki, Greece
*Corresponding author: [email protected]
Summary
Resistance to intracellular bacterial pathogens such as Brucella spp. relies on
cell-mediated immunity, which involves activation of the bactericidal mechanisms
of antigen-presenting cells (macrophages and dendritic cells) and the subsequent
expansion of antigen-specific CD4+ and CD8+ T-cell clones. Brucella antigens
induce the production of T helper type 1 (Th1) cytokines, and an adequate Th1
immune response is critical for the clearance of Brucella infection. Studies
on experimental and human brucellosis indicate that interferon-γ (IFNγ) is the
principal cytokine active against Brucella infection. On the other hand, Brucella
has evolutionarily developed diverse evasion strategies to avoid the host’s innate
and adaptive immunity in order to establish an intracellular niche for long-term
parasitism. Disturbances of the Th1 response and anergy have been described
in patients with chronic brucellosis, and are associated with poor outcome.
Accordingly, chronic brucellosis represents a challenge for the study of immune
mechanisms against Brucella and the development of novel therapeutic or
vaccination approaches.
Keywords
Anergy – Brucellosis – Brucella – IFNγ – Immunity – Immune response – Macrophage
– T cell.
Background
Classically, the host immune response is functionally
divided into innate or non-specific and adaptive or
specific immunity. The innate immune system is the first
line of defence against invading pathogens. Its elements
include anatomical barriers (skin and internal epithelial
layers), secretory molecules (various chemokines and
cytokines, complement system and opsonins) and cellular
populations, such as phagocytes (neutrophils, monocytes/
macrophages, dendritic cells), and innate lymphocyte
subsets (natural killer [NK] and γδ T cells). The other arm,
adaptive immunity, consists of T lymphocytes, which are
involved in cytokine production and cytotoxicity (cellular
immunity), as well as antibody-producing B lymphocytes
(humoral immunity) (56).
Detection, in a non-specific manner, of microbial structures
called pathogen-associated molecular patterns (PAMPs) (e.g.
lipopolysaccharide [LPS], peptidoglycan [PG], lipoproteins,
DNA) by germline-encoded receptors of phagocytes that
are termed pattern recognition receptors (PRRs) (e.g. tolllike receptors [TLRs]), facilitates phagocytosis of microbes.
This leads to the activation of innate immune cells, and
the expression of pro-inflammatory mediators and costimulatory molecules that initiate adaptive immunity (32).
Macrophages and dendritic cells represent the professional
antigen-presenting cells (APCs). Upon activation, they
perform pathogen uptake and process the antigenic
material into peptides, presenting them in association with
major histocompatibility (MHC) class II and I molecules
to CD4+ T helper (Th) lymphocytes and CD8+ cytotoxic
T lymphocytes (CTLs), respectively. T cells recognise
peptide–MHC complexes via their specific receptors, T-cell
receptors (TCRs). Collectively, innate immune responses
aim initially to limit microbial spread using intracellular
bactericidal mechanisms and, in parallel, to induce a
dynamic adaptive immunity, which is mediated by antigenspecific lymphocyte clones responsible for the clearance of
the infection (32, 56).
Brucellosis is the commonest chronic bacterial zoonotic
disease worldwide (55). It is caused by facultative
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intracellular pathogens of the genus Brucella that have
domestic animals (cows, goats, sheep, pigs and dogs) and
wild animals as natural reservoirs (54). Brucellosis has long
been acknowledged as a model in the study of immunity
against intracellular bacterial infections. For the first time,
in 1958, Holland and Pickett demonstrated that Brucella
spp. extensively replicated inside murine macrophages in
a ‘silent mode’, without generating toxic effects (29). Later,
Mackaness confirmed the cellular basis of immunity in
brucellosis, suggesting the important role of the interaction
between T lymphocytes and macrophages in defence
against intracellular pathogens (41). It is noteworthy that,
two decades later, brucellosis was again used as the model
infection associated with interferon-γ (IFNγ) production
in the description of the Th1/Th2 dichotomy concept by
Mosmann (45). Since then, the pivotal role of cellular
immunity and Th1 cytokines (IFNγ, tumour necrosis factor
[TNF]␣) in the outcome of Brucella infection has been well
established not only in mice, but also in natural hosts and
humans (27, 66, 76).
Cross-talk between the host immune system and Brucella is
essential either for the eradication of the pathogen, or for the
development of intracellular parasitism and establishment
of chronic disease. Host protection against Brucella depends
on cell-mediated immunity, involving mainly activated
professional APCs, Th1 cells, and CD8+ CTLs (66) (Fig.
1). On the other hand, Brucella has developed various
strategies to evade innate and adaptive immune responses,
aimed at establishment of an intracellular niche for longterm survival and replication (3, 33, 42).
It should be mentioned that immune response mechanisms
to brucellosis may diverge, and they are dependent on the
host, and the species or strain of Brucella (27, 42). In this
Innate
immmunity
B7 co-stimulation
Antibody-mediated
opsonisation
Cellular
immmunity
Humoral
immmunity
Ag:
APC:
B7:
BCV:
CTL:
IFNγ:
antigen
antigen-presenting cell
CD80/CD86 co-stimulatory molecules
Brucella-containing vacuole
cytotoxic lymphocyte
interferon gamma
IL:
interleukin
MHC II: major histocompatibility complex type II
TCR: T-cell receptor
TLR: Toll-like receptor
TNFα: tumour necrosis factor alpha
Fig. 1
Simplified representation of immune response against Brucella
Phagocytosis and/or pattern recognition receptor (e.g. TLR) signalling lead to the activation of APC and the priming of naïve CD4+ T lymphocytes towards
a Th1 phenotype (innate immunity). The Th1 cytokines (TNFα, IFNγ) enhance the anti-Brucella mechanisms of macrophages (Mφ) and induce the CD8+
CTL-mediated cytotoxicity against Brucella-infected Mφ (specific cellular immunity). Innate lymphocytes are early producers of IFNγ, linking innate to
specific immunity. The Th2 response activates B lymphocytes (B) for antibody production, facilitating the phagocytosis of Brucella through opsonisation
(specific humoral immunity). The Th2 cytokines (e.g. IL-10) inhibit the action of Th1 cytokines (e.g. IFNγ) and vice versa
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paper the authors aim to summarise universal aspects of
immunity against Brucella infection using selected examples
of experimental models and human disease.
The innate immune
system and Brucella
Macrophages and dendritic cells
Macrophages and dendritic cells (DCs) play a fundamental
role in innate immunity, in recognition and in the induction
of robust adaptive immunity against intracellular bacteria
such as Brucella spp. Many lines of evidence support the
bidirectional relationship between these two cell types
and Brucella spp. Both cell types have various inducible
mechanisms to eliminate bacteria (Table I), while bacteria
can invade these phagocytic cells to avoid the cellular
immune response and establish infections for prolonged
periods. In order to establish chronic infection Brucella spp.
express virulence factors or PAMPs that interfere with, or do
not alert, the antimicrobial arsenal and antigen-presenting
potential of the host macrophages/DCs (Table II) (3, 33,
42, 66, 72). This stealthy strategy, characterised by low
stimulatory activity and toxicity for APCs, provides a ‘gap’
that permits the establishment of an intracellular replicative
niche before the activation of Th1 immune responses.
Brucella is uptaken via conventional zipper-like phagocytosis
through lipid raft interactions using various phagocytosispromoting receptors (FcR, C3bR, scavenger receptors
[SRs]). Following entry into macrophages and DCs, most of
the bacteria (approximately 90%) are killed within the first
few hours. However, some of them survive and reach their
replicative niche (42, 58, 74). Brucella ensures its survival
and virulence by diverting endocytic pathway trafficking,
and forming special phagosomes of endoplasmic reticulum
(ER) origin called Brucella-containing vacuoles (BCVs) –
these represent the intracellular replication compartments
(Fig. 1). The BCVs escape fusion with late endosomes and
lysosomes, before they move to ER and fuse with the ER
membrane (12, 61).
Autophagy is a dynamic cellular homeostatic process
in which cytoplasmic targets are sequestered within
double-membraned vesicles called autophagosomes and
subsequently delivered to lysosomes for degradation (38).
Recently, substantial evidence has demonstrated autophagy
to be an important innate immune mechanism resulting in
direct elimination of various intracellular pathogens through
hydrolytic degradation in autophagolysosomes (xenophagy;
see Table I) (38, 65). Pathogen engulfment by APCs, TLR
signalling and IFNγ secretion by Th1 cells are potent
inducers of the autophagic machinery against intracellular
bacteria (65). Notably, recent experimental data on murine
macrophages suggest that B. abortus and B. melitensis
subvert autophagy or exploit autophagic machinery to
their advantage. In particular, BCVs that display structural
features of autophagy are required for B. abortus to complete
their intracellular lifecycle and spread from cell to cell (70).
Moreover, the pharmacological inhibition of autophagy in
vitro has been shown to significantly reduce the intracellular
replication of B. melitensis (28).
Recognition and signalling by TLRs is crucial for the
activation of APCs and the priming of adaptive immunity
(see Fig. 1). The TLRs detect a wide range of bacterial PAMPs,
including LPS, lipoproteins and nucleic acids, leading to
the activation of the principal transcription factors nuclear
factor (NF)-␬B, activator protein (AP)-1 and IFN regulatory
factor (IRF)3/IRF7. Thus, TLR signalling mediates the
production of several pro-inflammatory cytokines (TNFα,
interleukin [IL]-12, IL-6, IL-1β, type I IFNs) and the
expression of co-stimulation molecules (CD80, CD86),
ultimately bridging innate and adaptive immunity (31).
Various experimental models of TLR-deficient mice have
Table I
Basic mechanisms of action of antigen-presenting cells against Brucella
Effector mechanism
Mode of action
Phagocytosis and autophagy (xenophagy)
Degradation by hydrolytic enzymes of phagolysosomes/autophagolysosomes
Antimicrobial cationic peptides (defensins)
Direct killing
Oxidative burst
Direct killing by ROS
Cytokine production
TNFα
Strong enhancement of the bactericidal activity of phagocytes
IL-12
Priming Th1 immune response, leading to the production of IFNγ, the principal cytokine against Brucella infection
Chemokine secretion (macrophages) MCP-1,
RANTES, MIP1a/MIP1b
Migration of immune cells and maintenance of inflammation to limit infection
Antigen presentation
Priming of specific immune response, leading to IFNγ production and CTL-mediated killing (cytotoxicity)
CTL:
IL:
IFN:
MCP:
cytotoxic lymphocyte
interleukin
interferon
monocyte chemoattractant protein
MIP:
RANTES:
ROS:
TNF:
macrophage inflammatory protein
regulated and normal T cell expressed and secreted
reactive oxygen species
tumour necrosis factor
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Table II
How Brucella avoids or manipulates host immunity to its own benefit
Virulence factor or PAMP
Mode of action
Outcome
Type IV secretion system (virB)
Diversion of intracellular trafficking targeting
to replicative niche
Establishment of intracellular parasitism
BvrS/BvrR regulatory system
Control of several systems essential for intracellular trafficking
Establishment of intracellular parasitism
Periplasmic β-cyclic glucan
BCV biogenesis
Establishment of intracellular parasitism
Proline racemase PrpA
T-independent B cell mitogen that stimulates IL-10 secretion
Suppression of cellular immunity (anergy)
Btp1/TcpB
Interfere with TLR2 and TLR4 signalling, blocking of
MyD88-induced activation of NFkB
Subversion of innate immune recognition
and pro-inflammatory response (stealthy strategy)
Inhibition of CTL cytotoxicity
Evasion of adaptive immunity
Flagellum
Poor inducer of its cognate receptor TLR5
Escape from innate immune recognition (stealthy strategy)
Lipopolysaccharide (LPS)
Attenuated endotoxic response
Escape from innate immunity and establishment of
intracellular parasitism (stealthy strategy)
Inhibition of phagolysosome fusion
Establishment of intracellular parasitism
Inhibition of phagocytosis and bactericidal function
Subversion of innate immunity
Protection from complement attack
Subversion of innate immunity
Impairment of MHC II antigen presentation
Evasion of adaptive immunity
Induction of IL-10 production
Suppression of cellular immunity (anergy)
Interference with TLR4/MD-2 recognition inhibiting DC
maturation
Subversion of innate immunity, evasion of adaptive immunity
Inhibition of the expression of MHC-II molecules and antigen
presentation to CD4+ T lymphocytes in human monocytes
Evasion of adaptive immunity
Induction of human T-cell apoptosis
Evasion of adaptive immunity
Lipoprotein
Omp25
Down-regulation of TNFα production in human macrophages
and DCs
Escape from innate immunity and establishment of
intracellular parasitism (stealthy strategy)
?
Defective IFNγ signal transduction in infected human
macrophages
Evasion from adaptive immunity
?
Subversion or exploitation of autophagy (xenophagy)
Subversion of innate immunity, establishment of intracellular
parasitism and promotion of infection (cell-to-cell spreading)
Lipoprotein
Omp19
BCV:
CTL:
DC:
IL:
MHC:
Brucella-containing vacuole
cytotoxic lymphocyte
dendritic cell
interleukin
major histocompatibility complex
been used in an attempt to describe the involvement of TLR
signalling in the host immune response against brucellosis
(3, 50). It seems that TLR9, in association with the MyD88
adaptor, has the most prominent role in host resistance,
because it is required for the clearance of B. abortus and
B. melitensis in infected macrophages and DCs. The TLR9 is
expressed intracellularly within endosomal compartments
and senses bacterial DNA rich in CpG motifs, leading to
the production of IL-12, which drives the Th1 immune
response (30, 40). Beyond TLRs, the role of other PRRs,
important in resistance to intracellular bacteria (such as
the NOD-like receptor family [NLR]), remains elusive and
needs further clarification (50).
Among the various PAMPs associated with innate immune
recognition of Brucella, lipopolysaccharide (Br-LPS) is the
most studied and best characterised. It is a non-canonical,
NF: nuclear factor
Omp: outer membrane protein
PAMP: pathogen-associated molecular pattern
TLR: Toll-like receptor
non-endotoxic LPS, in comparison with classical LPS from
Escherichia coli. The Br-LPS acts as an immunomodulating
factor critical for the survival and replication of Brucella spp.
in the host (11, 13). As demonstrated in Table II, Br-LPS has
a unique dual role during the course of brucellosis: at early
stages of infection it has low immunostimulatory activity,
‘masking’ the microbe from innate immune recognition,
whereas at advanced stages, it negatively modulates the
innate immune response to favour parasitism by the
pathogen and development of chronic disease.
Neutrophils
Neutrophils have a key role in innate immunity and
are the first cells recruited in vast numbers to the site of
inflammation. Neutrophils encounter and kill microbes
intracellularly upon phagocytosis, when their antimicrobial
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granules fuse with the phagosome. Furthermore, they release
lytic enzymes and reactive oxygen species (ROS) that destroy
pathogens (46). It has been shown that B. abortus promptly
activates human neutrophils and prolongs neutrophil
survival in vitro. This effect is associated with lipidated
outer membrane protein (L-Omp)19, indicating the proinflammatory role of lipoproteins in the innate immunity
against brucellosis (80). Brucella does not replicate within
neutrophils, although it seems to resist killing (4, 37).
Innate lymphocytes
Innate lymphocytes are at the interface between innate
and adaptive immunity, and include mainly natural killer
(NK) cells, natural killer T (NKT) cells and γδ T cells. In
comparison with conventional antigen-specific T cells
(αβTCR CD4+ and CD8+ T lymphocytes), they are a
smaller proportion of peripheral blood cell populations
and recognise non-peptidic antigens (glycolipids and
phospholipids) without MHC restriction. Many studies
support the important role of innate lymphocytes as rapid
and early producers of IFNγ in immunity to intracellular
pathogens, before the expansion of specific Th1 responses
(Fig. 1) (14, 39, 47, 60).
Data suggest an early protective role for γδ T cells in
murine, human and bovine brucellosis (6, 35, 68). This is
quite interesting because, in contrast to mice and humans,
in ruminants and neonatal calves γδ T cells are a major
lymphocyte subset (68).
In humans, Brucella phosphoantigens activate Vγ9Vδ2 T
cells at early stages of infection (6). Moreover, peripheral
blood Vγ9Vδ2 T cells increase significantly in patients with
acute brucellosis and decline after treatment (35). It has
been previously demonstrated that Vγ9Vδ2 T cells inhibit
the growth of Brucella in autologous macrophages through
a combination of contact-dependent and non-contactdependent mechanisms. These include granule- and Fas
ligand-mediated cytotoxicity, macrophage activation, and
bactericidal activity via IFNγ production and secretion of
the potent bactericidal factors granulysin and cathelicidin
(LL-37) (16, 49, 53). In addition, a recent study provides
new data for the inductive role of the NKG2D receptor in
the anti-Brucella effect of Vγ9Vδ2 T cells on infected human
macrophages (8).
In vitro studies on human cells have also indicated
the contribution of NK and CD4+ invariant NKT cells
(iNKT) to antibacterial immunity against Brucella through
cytotoxic activity and IFNγ release (7, 15). Additionally,
recent data from mice immunised with heat-killed
B. abortus (HKBA) suggest a role for NK cells in the
induction of polyclonal antibody production by B cells (23).
In humans, peripheral blood mononuclear cells (PBMCs)
of patients with acute brucellosis transiently demonstrate
deficient NK cytotoxicity but revert to normal function
after effective treatment, suggesting that the efficiency
of NK responses could be important for the evolution of
brucellosis (62).
Adaptive immunity
in brucellosis: the pivotal
role of the Th1 response
Specific T-cell immunity
Adaptive immunity expands after the activation of innate
immunity in order to mount and sustain an antigen-specific
response aimed at eradicating bacteria and protecting the
host. The Th1 nature of adaptive immunity in brucellosis is
clearly demonstrated by:
– the susceptibility to infection of mice deficient in key
Th1 elements such as IFNγ, IFNγ regulatory factor-1 (IRF1) and IL-12 (10, 42)
– the protection that is elicited in mice by the administration
of Th1-related cytokines (IFNγ and IL-12) (42)
– the predominant secretion of IFNγ by murine splenocytes
and CD4+ T cells (21, 52, 79), bovine CD4+ T cells (75),
and human PBMCs and T cells (24, 57, 78) after in vitro
stimulation by various Brucella antigens
– the display of Th1 responses in patients with brucellosis
and the correlation between reduced Th1 responses and
chronic/relapsing disease (1, 24, 57, 59)
– human genetic studies that associate disease susceptibility
or outcome with polymorphisms and mutations of
molecules involved in Th1 cellular immunity (66).
The Th1 immune response against Brucella leads to
IFNγ secretion by antigen-specific T lymphocytes
(see Fig. 1). Most studies indicate that CD4+ T lymphocytes
are the major producers of IFNγ, although other cell subsets
such as CD8+ T lymphocytes, γδ T lymphocytes and NK
cells also participate in IFNγ production (3, 77). The
IFNγ activates the bactericidal machinery of macrophages,
promotes the expression of antigen-presenting and costimulatory molecules on APCs, stimulates CTL-mediatedcytotoxicity and potentiates the apoptotic death of infected
macrophages (3, 66, 77). The bactericidal efficiency of IFNγactivated murine macrophages against Brucella is hampered
by the Th2 cytokine IL-10. It has also been reported that
Br-LPS induces the expression of IL-10 by human PBMCs
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(20, 34). Data suggest that Brucella disturbs IFNγ signal
transduction in infected human macrophages, although the
aetiological mechanism has not yet been clarified (9) (see
Table II).
Substantial evidence demonstrates the protective role of
CD8+ CTLs in several models of experimental brucellosis.
Activated CTLs contribute to protective immunity against
Brucella through Fas- or perforin-mediated cytotoxicity
and IFNγ secretion (Fig. 1) (17, 18, 51). Recent data
obtained in IFNγ and IL-12/β2-microglobulin knockout
mice demonstrate that lack of endogenous IFNγ is more
important to control of brucellosis than CTLs (10).
However, in the murine brucellosis model, CTLs were
found to increase during the chronic stage of infection
(22). In a similar manner, human clinical studies have also
demonstrated increased numbers of CTLs in the peripheral
blood of patients with chronic/relapsing brucellosis (43, 44,
63, 71). It could be presumed that this phenomenon is a
compensatory effect for the defective CD4+ T-cell responses
that are characteristic of chronic disease. Recent data from a
murine model of chronic brucellosis indicate that CTLs also
display a low quality responding capacity, characterised by
suppression of Th1 cytokines (IFNγ, TNFα and IL-2). This
deficit is associated with the B. melitensis Toll/IL-1 receptor
(TIR)-domain-containing protein (TcpB), which inhibits
CD8+ cytotoxic killing of target cells expressing antigenic
peptides and constitutes a novel strategy for Brucella to
evade adaptive immunity (18) (Table II).
B lymphocytes and Brucella infection
The B lymphocytes govern the humoral arm of adaptive
immunity, characterised by production of antigen-specific
antibodies (see Fig. 1). In addition to their neutralising
effect, antibodies act as opsonins that facilitate the
phagocytosis of bacteria by APCs, activate complement and
promote antibody-dependent cell-mediated cytotoxicity
(ADCC) by macrophages, neutrophils and NK cells. Under
certain circumstances, B cells perform antigen presentation
which can activate cellular immunity (3).
The role of humoral immunity against intracellular bacterial
infections is limited and not protective. Antibody-mediated
opsonisation (by immunoglobulin [Ig]M, IgG1, IgG2a and
IgG3) enhances phagocytic uptake of bacteria, limiting the
level of initial infection with Brucella (see Fig. 1), but has
little effect on the intracellular course of Brucella infection
(3, 5). From a clinical perspective, detection of antibodies
against Br-LPS is commonly used for the diagnosis of
brucellosis (using seroagglutination tests) in livestock and
humans (2).
Recently, a study of B-cell-deficient mice provided new
insight into the regulatory role of B cells in brucellosis,
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illustrating the critical role of Th1 responses in host
resistance. During the early phase of disease, B cells produce
IL-10 and transforming growth factor (TGF)β, which
attenuate IFNγ-mediated Th1 responses and promote
persistence of infection. Absence of B cells is associated
with marked, antibody-independent resistance to Brucella
(26). The proposed immunoregulatory role of B cells in
brucellosis is supported by experimental data showing that:
– opsonised B. abortus infects and survives inside primary
murine B cells (25)
– B. abortus expresses the virulence factor proline racemase
PrpA, a strong B-cell mitogen that induces secretion of high
levels of IL-10 (69).
Brucellosis-acquired cellular anergy:
lessons from patients with chronic brucellosis
Approximately 10% to 30% of patients with brucellosis
develop chronic disease, characterised by an atypical
clinical picture, high frequency of complications (focal
disease), chronic fatigue syndrome and relapses (63, 64).
Patients with chronic brucellosis display defective Th1
responses and T-cell anergy, probably due to modulation of
host cellular immunity by Brucella spp. (Table II) (19, 24,
36, 57, 63, 64, 67). In particular, several clinical studies
have reported:
– disturbance of phagocytosis and migration against nonspecific and disease-specific antigens
– reduced skin reactivity to bacterial antigens
– protracted resistance of monocytes and lymphocytes to
apoptosis
– low proliferative responses of lymphocytes to mitogens
or Brucella antigens
– diminished in vitro production of Th1 cytokines (IFNγ,
IL-2) by PBMCs, and elevated TGFβ1 in serum
– reduced CD69+ early activated T lymphocytes
– an increased proportion of CTLs (CD4/CD8 ratio
inversion) (66).
Related to the aforementioned data, patients with chronic
relapsing brucellosis present a diminished percentage of
CD4+ T lymphocytes expressing the IL-2 alpha receptor
(CD25) in the peripheral circulation when compared with
acute brucellosis cases (63), and they retain this ‘defect’ even
after potent in vitro stimulation of PBMCs with mitogen and
E. coli LPS (67). Interleukin-2 is a growth factor for antigenstimulated T lymphocytes and is critical for Th1 clonal
expansion. Efficient priming of T cells by APCs also requires
CD28/CD80 co-stimulation to enhance TCR signalling
(see Fig. 1). However, patients with chronic brucellosis,
as compared with those who are acutely infected, present
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low frequencies of CD4+/CD28+ T lymphocytes after
stimulation of PBMC cultures with mitogen and E. coli LPS.
In addition, stimulation of patients’ PBMCs with killed
Brucella (HKBA) resulted in a significant, dose-dependent
reduction in CD80+ monocytes (64, 67). Similarly, whole
blood HKBA cultures resulted in significant reduction in
T cells expressing IFNγ, followed by an increase in CD3+/
IL-13+ T cells during disease prolongation (Th2 switch)
(57). Collectively, these data on human primary cell/HKBA
cultures illustrate the immunosuppressive effects of Brucella
PAMPs, which may contribute to chronicity of the disease.
Conclusions
mechanisms in order to ‘hide’ from, or manipulate,
cellular immunity, and to achieve intracellular persistence
(Table II). Brucella can cause asymptomatic latent disease
and late reactivation (48, 73). Symbiosis of Brucella
spp. with the host is related to T-cell unresponsiveness
(anergy) caused by pathogen-mediated disturbances in
cellular immunity. Despite the heterogeneous and protean
phenotype of human brucellosis (54), chronic/relapsing
disease remains a challenge for the study of protective
immunity to intracellular pathogens such as Brucella spp.
Understanding protective immunity against brucellosis
could provide insights for the development of novel
therapeutic and vaccination strategies for livestock and
humans.
Over the last 50 years, brucellosis has served as a model
for the study of cross-talk between host immunity
and intracellular bacterial infections. Despite host- and
pathogen-dependent differences in the immune responses
against Brucella infection, APC activation and antigen-specific
Th1 responses, characterised mainly by the production of
IFNγ, are mandatory for overcoming disease (Table I and
Fig. 1). Brucella has developed sophisticated evolutionary
L’immunité vis-à-vis de la brucellose
P. Skendros & P. Boura
Résumé
La résistance aux bactéries pathogènes intracellulaires telles que Brucella
spp. repose sur l’immunité à médiation cellulaire, qui consiste en une activation
des mécanismes bactéricides propres aux cellules présentatrices d’antigènes
(macrophages et cellules dendritiques) avec par la suite une prolifération
de clones des cellules T CD4+ et CD8+ effectrices spécifiques de l’antigène.
Les antigènes de Brucella induisent une production de cytokines T helper de
type 1 (TH1). Cette réponse immune TH1 est cruciale pour venir à bout
de l’infection à Brucella. Des travaux effectués sur la brucellose chez
l’homme et sur la brucellose induite expérimentalement ont montré que
l’interféron-γ (IFNγ) est la cytokine la plus active contre l’infection à Brucella.
Cela étant dit, Brucella a développé au cours de son évolution plusieurs stratégies
d’évitement visant à contourner l’immunité innée et acquise de l’hôte et à établir
une niche intracellulaire permettant d’installer un parasitisme de longue durée.
Une perturbation de la réponse de type TH1 et une anergie ont été décrites chez
des patients atteints de brucellose chronique et sont souvent associées à une
issue défavorable. En conséquence, la brucellose chronique représente un défi
pour l’étude des mécanismes de l’immunité vis-à-vis de Brucella et un enjeu pour
la mise au point de méthodes thérapeutiques ou vaccinales innovantes.
Mots-clés
Anergie – Brucella – Brucellose – Cellule T – IFNγ – Immunité – Macrophage – Réponse
immune.
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Inmunidad a la brucelosis
P. Skendros & P. Boura
Resumen
La resistencia a patógenos bacterianos intracelulares como las brucelas pasa
por mecanismos de inmunidad celular, que suponen la activación de los sistemas
bactericidas de las células presentadoras de antígeno (macrófagos y células
dendríticas) y la subsiguiente multiplicación de linajes clónicos de células
específicas de antígeno que son los linfocitos T CD4+ y CD8+. Los antígenos de
Brucella inducen la síntesis de citoquinas por los linfocitos T reguladores (helper)
de tipo 1 (Th1). Para eliminar la infección por Brucella es indispensable una
adecuada respuesta inmunitaria de estas células. Los estudios sobre brucelosis
experimental y humana indican que el interferón gamma es la principal citoquina
activa contra la brucelosis. Por otro lado, Brucella ha adquirido evolutivamente
diversas estrategias de evasión para zafarse de la inmunidad tanto innata como
adaptativa del hospedador y establecer un nicho intracelular de parasitismo
duradero. En pacientes con brucelosis crónica se han descrito perturbaciones de
la respuesta mediada por Th1 y estados de anergia, que se traducen en un débil
rendimiento inmunitario. La brucelosis crónica representa en consecuencia un
terreno de pruebas para estudiar los mecanismos inmunitarios contra Brucella y
dar con nuevos planteamientos terapéuticos o de vacunación.
Palabras clave
Anergia – Brucella – Brucelosis – Inmunidad – Interferón gamma – Linfocito T – Macrófago
– Respuesta inmunitaria.
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