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Cutting Edge |
,
*
Department of Medicine, Division of Infectious Diseases, Boston University School of Medicine, Boston, MA 02118;
Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01665; and
Department of Pediatrics, Free University of Berlin, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B
nuclear translocation. This is the first demonstration of known vaccine
adjuvant to stimulate immune cells via TLR2. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism of the adjuvanticity of neisserial porins in vaccine formulations correlates with their ability to up-regulate the expression of the costimulatory molecule B7-2 (CD86) on the surface of B cells and other APCs (4, 10). The increased surface expression of B7-2 induces augmented costimulation of T cells through the interaction with its counterreceptor, CD28 (10). The effect of neisserial porins on B cells, including increased B7-2 surface expression and B cell proliferation, is not due to LPS, as studies were performed using the LPS-nonresponsive mouse strain C3H/HeJ (4, 10, 11). The lack of response to LPS in these mice is due to a natural point mutation in the gene encoding the Toll-like receptor (TLR)34 (12), necessary for LPS-mediated signal transduction (13).
Toll proteins, responsible for the dorsoventral development in
Drosophila (14), are involved in antifungal
responses in the adult fly (15). The mammalian orthologs
of Drosophila Toll, termed TLRs (16), are type
I transmembrane proteins belonging to the pattern recognition receptor
family. They are involved in the innate immune response by recognizing
microbial conserved structures called pathogen-associated molecular
patterns (PAMPs) (16), such as LPS, bacterial lipoprotein,
peptidoglycan, lipoteichoic acid, bacterial unmethylated CpG DNA,
mycobacterial lipoarabinomannan, and yeast mannans. The recognition of
PAMPs by the pattern recognition receptor leads to the activation of
various intracellular signaling cascades which modulate nuclear
translocation of the transcription factor NF-B (17),
induction of cytokines, and expression of effector molecules, such as
the costimulatory molecules B7-1 (CD80) and B7-2 (CD86)
(18). In this way, it has been suggested that signaling by
the TLRs bridges innate and adaptive immunity, allowing the host to
more efficiently combat microbial
infections.
The best-characterized TLRs, to date, are TLR2 (19) and
TLR4 (20). TLR2 is involved in the recognition of
Gram-positive bacteria and mycobacteria (21, 22) and
bacterial products such as lipopeptides (23, 24). TLR4
mediates the effect of Gram-negative bacteria by LPS (13, 25) together with CD14 (26). Recently, another
molecule, MD2, has been shown to interact with the ectodomain of TLR4
to confer LPS responsiveness, an essential prerequisite for TLR4
signaling (27). Engagement of TLRs by microbial products
results in homodimerization and recruitment of the adaptor molecule
MyD88 (28), the functional homolog of
Drosophila adaptor molecule Tube. In mammals, engagement of
MyD88 leads to NF-B nuclear translocation (19, 29).
Porins are of particular interest because they have been characterized as potent adjuvants and have great potential as a novel component of vaccines. Neisserial porins belong to the Gram-negative porin superfamily (30) and share significant structural similarities with other members of the family, resembling other PAMPs. Given the importance of mammalian TLRs in innate immunity, including their role in B7 up-regulation, and in the light of their ability to discriminate between different pathogens and bacterial products, their involvement in the response to neisserial porins was investigated. Thus far, the involvement of TLRs on the effect of immune adjuvants has only been theorized (16). However, one known immune adjuvant, unmethylated bacterial CpG DNA motifs, appears to induce its immunopotentiating effect through TLR9 (31).
Previous experimental evidence from studies using C3H/HeJ mice established that the immune response to neisserial porins is not abrogated in the absence of functional TLR4. Thus, the involvement of other TLRs in the cellular response to neisserial porins was investigated. Recent reports regarding the participation of TLR2 in response to Neisseria meningitidis (32, 33) suggested that outer membrane components of meningococcus can activate immune cells by engaging TLR2. However, the specific role of porins was not determined. B cells from TLR2 knockout mice (34) and MyD88 knockout mice (35) were used to elucidate the involvement of these molecules in the ability of the porin to stimulate B cells and induce increased surface expression of B7-2 and class II MHC. The data presented in this study directly demonstrate the importance of TLR2 in the adaptive immune response induced by potential vaccine adjuvants.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 wild-type mice and TLR2 knockout mice (34) or C57BL/6 and MyD88 knockout mice (35) were used.
Lymphocyte isolation, cell lines, and constructs
B lymphocytes were purified from splenocytes as described
(10). A Chinese hamster ovary (CHO-K1) reporter cell line,
clone 3E10 (36), stably transfected with human CD14 and an
NF-B-driven reporter construct, which regulates the surface
expression of Tac (CD25) Ag (22). Derivatives of 3E10 were
used: clone 7.19 (27) and clone 7.19-TLR2, which expresses
human TLR2 (P. Henneke, unpublished results) (23, 27, 36).
Human embryonal kidney (HEK) cells (HEK-293) were transiently
transfected with a pELAM-luciferase NF-B reporter construct
(13) plus either human TLR2 or the empty vector using the
Polyfect transfection reagent (Qiagen, Valencia, CA).
Neisserial porins and reagents
PorB was purified from N. meningitidis strain H44/76 lacking both PorA and RmpM (10, 37) as described (1). Purified neisserial LPS (kindly provided by Dr. M. Apicella, University of Iowa Medical Center, Iowa City, IA) was depleted of contaminating lipoproteins by phenol extraction method (38). The LPS inhibitor, compound E5564, was provided by Eisai Research Institute (Andover, MA; patent reference no. WO-9639411-A1). The following anti-murine mAbs were used for flow cytometric analysis: anti-rat IgG, anti-CD86 (B7-2), anti-class II MHC (IAb), and anti-CD25, all FITC conjugated (BD PharMingen, San Diego, CA).
Cell incubations and flow cytometric analysis
B lymphocytes (5 x 106/ml) were
incubated with 10 µg/ml PorB or 100 ng/ml N. meningitidis
LPS in the presence or absence of 10 µg/ml E5564. CHO reporter cell
lines (105/ml) were incubated with 20 µg/ml
PorB or with 5 ng/ml IL-1
. The expression of surface Ags was
examined by flow cytometric analysis (10, 36).
NF-B luciferase reporter assay
HEK/TLR2 cells (5 x 105/well) were
incubated for 16 h with 0.1, 1, and 10 µg/ml PorB, heat-killed
Listeria monocytogenes, or 5 ng/ml IL-1. Cell activation
was determined by measuring luciferase activity of the total cellular
lysate using an assay kit from Promega (Madison, WI) according to the
manufacturer’s instructions. The data are reported as the mean of
triplicate determinations ± SD.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified splenic B cells from C57BL/6 wild-type and MyD88 knockout
mice were incubated with purified meningococcal PorB or with medium
alone. After 24 h, the levels of surface expression of B7-2 and
class II MHC were measured by flow cytometry (Fig. 1
A). PorB failed to mediate
up-regulation of B7-2 or class II MHC on B cells from MyD88 knockout
mice. B cells from C57BL/6 wild-type mice are responsive to LPS, due to
the expression of intact TLR4 on their surface. In previous studies by
our group (10) we have found that neisserial porin
preparations do not appear to contain a significant amount of LPS,
which may account for the induction of B7-2 surface expression.
However, B cells from C57BL/6 wild-type mice and MyD88 knockout mice
were also incubated with PorB in the presence of E5564, a TLR4
antagonist (39). E5564 abrogated the effect of LPS on B
cells from C57BL/6 wild-type mice but did not modify the effect of
neisserial porins, as shown in Fig. 1, A and B.
Controls for LPS-mediated activation of B cells were performed by
incubating the cells with N. meningitidis LPS, which could
not induce expression of B7-2 or class II MHC in MyD88-deficient B
cells (Fig. 2A). Similar
results were obtained using purified Escherichia coli LPS
(data not shown). These data demonstrate that B cell activation by
neisserial porins is MyD88 dependent.
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B show that PorB was not able to induce increased surface
expression of B7-2 or class II MHC in MyD88-deficient B cells after
48 h of incubation. Incubation with LPS for 48 h also did not
induce increased surface expression of B7-2 or class II MHC in
MyD88-deficient B cells (Fig. 2B).
Neisserial porins induce TLR2-mediated NF-B nuclear
translocation
To investigate the interaction of neisserial porins with TLR2, two
different cellular reporter constructs were used to measure the
TLR2-mediated NF-B nuclear translocation induced by neisserial
porins. CHO cells, normally unresponsive to LPS, were transfected with
CD14 (36) and a reporter gene encoding CD25 (Tac)
(22). Among such transfectants, clone 7.19
(27), which had a negligible response to LPS
(36), was transfected with a plasmid containing human
tlr2 gene, and 7.19/TLR2 cells were incubated for 16 h
with PorB or IL-1 as a TLR2-independent control. Fig. 3A shows the level of CD25
surface expression, determined by flow cytometric analysis using
anti-CD25 FITC-labeled Ab. PorB induced increased expression of
CD25 on the surface of TLR2 transfected cells, while it failed to
induce CD25 expression in the cells that were not transfected with
TLR2.
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B-dependent luciferase reporter plasmid (13) and
with the human tlr2 gene. Cells were incubated with
different concentrations of PorB and, as a TLR2-dependent positive
control, with heat-killed L. monocytogenes. IL-1
incubation was also used as a control, and the naked vectors were used
as a negative control. Cell lysates were obtained and incubated in the
presence of luciferin as described. As shown in Fig. 3B,
PorB induced a dose-dependent increase in luminescence only in cells
transfected with TLR2. Increasing concentrations of meningococcal LPS
(up to 1 µg/ml) failed to stimulate those cells, while
TLR4/MD-2-expressing cells were stimulated by LPS but were not
stimulated by PorB (data not shown). These latter data confirm that the
presence of LPS in the porin proteosomes preparations was minimal and
its effect in these experiments was negligible. TLR2 is essential for neisserial porin up-regulation of B7-2 and class II MHC in B cells
B cells were isolated from spleens of TLR2 knockout mice
(34) in a C57BL/6 background and from C57BL/6 wild-type
mice, and were incubated with PorB or medium alone. After 24 h,
the level of surface expression of B7-2 and class II MHC was determined
by flow cytometric analysis. As shown in Fig. 4A, PorB failed to up-regulate
the surface expression of B7-2 or class II MHC on B cells from TLR2
knockout mice, as compared with B cells from wild-type mice, already
shown in Figs. 1 and 2. This indicates that the up-regulation of B7-2
and class II MHC surface expression was dependent on the normal
expression of TLR2 on the B cell.
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A), indicating that B
cell activation was not mediated by engagement of TLR4. These data have
been confirmed in another LPS-sensitive mouse strain, C3H/OuJ, in which
the up-regulation of B7-2 and class II MHC induced by neisserial porins
was not affected by the presence of this LPS inhibitor (data not
shown).
As a control for the involvement of TLR4-mediated LPS stimulation, B
cells from TLR2 knockout mice were incubated with purified LPS from
N. meningitidis in the presence or absence of E5564.
Up-regulation of B7-2 expression and class II MHC on the B cell surface
of TLR2 knockout mice induced by incubation with LPS was inhibited by
the cotreatment with E5564 (Fig. 4B). Virtually identical
results were obtained when E. coli LPS was used to stimulate
the B cells (data not shown). These data indicate that the TLR4 pathway
was not involved in the effect of neisserial porins on B7-2 or class II
MHC expression in B cells but is solely involved in the effect of LPS
on the expression of these ligands.
The increased surface expression of B7-2 and class II MHC on B cells from TLR2 knockout mice or C57BL/6 wild-type mice induced by purified neisserial lipopeptide (a gift from P. Fisette and Dr. R. Ingalls, Boston University School of Medicine, Boston, MA), a common TLR2 ligand, was compared with the effect of neisserial porin preparations. Using high doses of purified lipopeptide, stimulation of B cells was achieved. Low doses of purified lipopeptide (comparable to the lipopeptide content of neisserial porin preparations, as demonstrated by immunoblot analysis) failed to induce increased expression of B7-2 and class II MHC on the B cell surface (data not shown), suggesting that the up-regulation of these molecules was due to the immune modulatory properties of neisserial porin and not due to potential lipoprotein contamination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MyD88 is an effector molecule associated with TLR-mediated response in lymphoid cells. The use of MyD88 knockout mice has shown that the activation of B cells by neisserial porin is strictly MyD88 dependent. It has been demonstrated that MyD88-deficient DCs are still able to respond to LPS via TLR4, but with delayed kinetics (40), due to the presence of a new TLR adaptor protein, termed TLR/IL-1R-associated protein (42). To investigate the possibility of a MyD88-independent pathway for neisserial porin signaling, we used meningococcal PorB or LPS for extended time points. However, we could not detect up-regulation of B7-2 or class II MHC even after 48 h of incubation, suggesting that their signaling is strictly dependent on MyD88. These data suggested involvement of TLR in the immune stimulation of neisserial porins.
The role of TLRs, specifically TLR2 and TLR4, in the innate and
adaptive immune responses has been examined in detail by several
investigators (43, 44). In the past few years, the
activation of B cells and DCs in response to different pathogens and
bacterial products has been correlated to the presence of different
TLRs on the cell surface. Specifically, TLR2 and TLR4 can recognize a
series of ligands, such as bacterial lipopeptides, LPS, and other outer
membrane bacterial components (17, 19, 23, 24), thus
initiating signaling pathways which affect the immune response, such as
up-regulation of B7 molecules on the surface of B cells and DCs or
nuclear translocation of the transcription factor NF-B. The evidence
that TLR4 is not critical for the signaling pathway initiated by
neisserial porins preceded many of the fundamental discoveries of the
TLRs. Neisserial porins induce increased surface expression of B7-2 on
B cells from C3H/HeJ mice, which are unresponsive to LPS because of a
TLR4 mutation (12), as well as in their LPS-sensitive
counterpart, C3H/OuJ mice (10, 11). The possibility that
TLR2 might be involved in response to neisserial porins was
investigated, because this TLR appears to have an extraordinarily broad
repertoire of ligands. All the lines of evidence suggested a central
role for TLR2 in porin recognition.
TLR2 is known to be a receptor for bacterial lipoproteins and their interaction has been shown to induce B7-2 surface expression on B cells (16). Outer membrane preparations may contain variable amounts of lipoproteins. Biochemical analysis and in vitro studies comparing neisserial porin preparations with purified neisserial lipopeptide indicated that the effect of porin was not related to the presence of lipopeptide, supporting our hypothesis that the TLR2-mediated up-regulation of B7-2 and class II MHC on B cells surface by neisserial porins mediates their adjuvant activity on the immune response.
In conclusion, this work demonstrates that the effect of neisserial porins on the surface expression of B7-2 and class II MHC on B cells, which mediates the effect of these proteins, is dependent on the interaction of porins with TLR2 on the cell surface. Also, the presence of the effector molecule MyD88 is required for the activity of the porin. Furthermore, we have shown that the effect of neisserial porin on B cells is dependent on MyD88, and that a delayed response to neisserial porins or LPS was not detectable in B cells, as compared with previous reports regarding the effect of LPS on MyD88-deficient DCs (40). As we have demonstrated that the adjuvant activity of neisserial porins is specifically related to their ability to induce increased B7-2 surface expression on APCs, this work suggests that their adjuvant effect is, therefore, dependent on porin-mediated TLR2 signaling events.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lee M. Wetzler, Department of Medicine, Division of Infectious Diseases, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118. E-mail address: lwetzler{at}bu.edu
3 Abbreviations used in this paper: TLR, Toll-like receptor; DC, dendritic cell; PAMP, pathogen-associated molecular pattern; CHO, Chinese hamster ovary; HEK, human embryonal kidney.
Received for publication November 2, 2001. Accepted for publication December 21, 2001.
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K. O. Omueti, J. M. Beyer, C. M. Johnson, E. A. Lyle, and R. I. Tapping Domain Exchange between Human Toll-like Receptors 1 and 6 Reveals a Region Required for Lipopeptide Discrimination J. Biol. Chem., November 4, 2005; 280(44): 36616 - 36625. [Abstract] [Full Text] [PDF]
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R. Ramphal, V. Balloy, M. Huerre, M. Si-Tahar, and M. Chignard TLRs 2 and 4 Are Not Involved in Hypersusceptibility to Acute Pseudomonas aeruginosa Lung Infections J. Immunol., September 15, 2005; 175(6): 3927 - 3934. [Abstract] [Full Text] [PDF]
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J. Zhang, G. Li, A. Bafica, M. Pantelic, P. Zhang, H. Broxmeyer, Y. Liu, L. Wetzler, J. J. He, and T. Chen Neisseria gonorrhoeae Enhances Infection of Dendritic Cells by HIV Type 1 J. Immunol., June 15, 2005; 174(12): 7995 - 8002. [Abstract] [Full Text] [PDF]
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S. Borsutzky, K. Kretschmer, P. D. Becker, P. F. Muhlradt, C. J. Kirschning, S. Weiss, and C. A. Guzman The Mucosal Adjuvant Macrophage-Activating Lipopeptide-2 Directly Stimulates B Lymphocytes via the TLR2 without the Need of Accessory Cells J. Immunol., May 15, 2005; 174(10): 6308 - 6313. [Abstract] [Full Text] [PDF]
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Y. Maeda, T. Mukai, J. Spencer, and M. Makino Identification of an Immunomodulating Agent from Mycobacterium leprae Infect. Immun., May 1, 2005; 73(5): 2744 - 2750. [Abstract] [Full Text] [PDF]
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T. E. Singleton, P. Massari, and L. M. Wetzler Neisserial Porin-Induced Dendritic Cell Activation Is MyD88 and TLR2 Dependent J. Immunol., March 15, 2005; 174(6): 3545 - 3550. [Abstract] [Full Text] [PDF]
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G. Hajishengallis, R. I. Tapping, M. H. Martin, H. Nawar, E. A. Lyle, M. W. Russell, and T. D. Connell Toll-Like Receptor 2 Mediates Cellular Activation by the B Subunits of Type II Heat-Labile Enterotoxins Infect. Immun., March 1, 2005; 73(3): 1343 - 1349. [Abstract] [Full Text] [PDF]
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S.-H. Lee, K.-K. Kim, and B.-K. Choi Upregulation of Intercellular Adhesion Molecule 1 and Proinflammatory Cytokines by the Major Surface Proteins of Treponema maltophilum and Treponema lecithinolyticum, the Phylogenetic Group IV Oral Spirochetes Associated with Periodontitis and Endodontic Infections Infect. Immun., January 1, 2005; 73(1): 268 - 276. [Abstract] [Full Text] [PDF]
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M. J. Binnicker, R. D. Williams, and M. A. Apicella Gonococcal Porin IB Activates NF-{kappa}B in Human Urethral Epithelium and Increases the Expression of Host Antiapoptotic Factors Infect. Immun., November 1, 2004; 72(11): 6408 - 6417. [Abstract] [Full Text] [PDF]
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O. Levy, K. A. Zarember, R. M. Roy, C. Cywes, P. J. Godowski, and M. R. Wessels Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-{alpha} Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-848 J. Immunol., October 1, 2004; 173(7): 4627 - 4634. [Abstract] [Full Text] [PDF]
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G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease J. Immunol., May 15, 2004; 172(10): 6324 - 6329. [Abstract] [Full Text] [PDF]
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T. Guthrie, S. Y. C. Wong, B. Liang, L. Hyland, S. Hou, E. A. Hoiby, and S. R. Andersen Local and Systemic Antibody Responses in Mice Immunized Intranasally with Native and Detergent-Extracted Outer Membrane Vesicles from Neisseria meningitidis Infect. Immun., May 1, 2004; 72(5): 2528 - 2537. [Abstract] [Full Text] [PDF]
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M. M. Estabrook, D. L. Jack, N. J. Klein, and G. A. Jarvis Mannose-Binding Lectin Binds to Two Major Outer Membrane Proteins, Opacity Protein and Porin, of Neisseria meningitidis J. Immunol., March 15, 2004; 172(6): 3784 - 3792. [Abstract] [Full Text] [PDF]
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T. J. Murphy, H. M. Paterson, J. A. Mannick, and J. A. Lederer Injury, sepsis, and the regulation of Toll-like receptor responses J. Leukoc. Biol., March 1, 2004; 75(3): 400 - 407. [Abstract] [Full Text] [PDF]
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E. Latz, J. Franko, D. T. Golenbock, and J. R. Schreiber Haemophilus influenzae Type b-Outer Membrane Protein Complex Glycoconjugate Vaccine Induces Cytokine Production by Engaging Human Toll-Like Receptor 2 (TLR2) and Requires the Presence of TLR2 for Optimal Immunogenicity J. Immunol., February 15, 2004; 172(4): 2431 - 2438. [Abstract] [Full Text] [PDF]
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M. Galdiero, M. Galdiero, E. Finamore, F. Rossano, M. Gambuzza, M. R. Catania, G. Teti, A. Midiri, and G. Mancuso Haemophilus influenzae Porin Induces Toll-Like Receptor 2-Mediated Cytokine Production in Human Monocytes and Mouse Macrophages Infect. Immun., February 1, 2004; 72(2): 1204 - 1209. [Abstract] [Full Text] [PDF]
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P. Henneke and D. T. Golenbock Phagocytosis, Innate Immunity, and Host-Pathogen Specificity J. Exp. Med., January 5, 2004; 199(1): 1 - 4. [Full Text] [PDF]
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 M. B. Drennan, D. Nicolle, V. J. F. Quesniaux, M. Jacobs, N. Allie, J. Mpagi, C. Fremond, H. Wagner, C. Kirschning, and B. Ryffel Toll-Like Receptor 2-Deficient Mice Succumb to Mycobacterium tuberculosis Infection Am. J. Pathol., January 1, 2004; 164(1): 49 - 57. [Abstract] [Full Text] [PDF]
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P. L. Fisette, S. Ram, J. M. Andersen, W. Guo, and R. R. Ingalls The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-{kappa}B Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner J. Biol. Chem., November 21, 2003; 278(47): 46252 - 46260. [Abstract] [Full Text] [PDF]
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T. Al-Bader, M. Christodoulides, J. E. Heckels, J. Holloway, A. E. Semper, and P. S. Friedmann Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis Infect. Immun., October 1, 2003; 71(10): 5590 - 5597. [Abstract] [Full Text] [PDF]
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K. A. Heldwein, M. D. Liang, T. K. Andresen, K. E. Thomas, A. M. Marty, N. Cuesta, S. N. Vogel, and M. J. Fenton TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG J. Leukoc. Biol., August 1, 2003; 74(2): 277 - 286. [Abstract] [Full Text] [PDF]
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E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]
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A. C. Pridmore, G. A. Jarvis, C. M. John, D. L. Jack, S. K. Dower, and R. C. Read Activation of Toll-Like Receptor 2 (TLR2) and TLR4/MD2 by Neisseria Is Independent of Capsule and Lipooligosaccharide (LOS) Sialylation but Varies Widely among LOS from Different Strains Infect. Immun., July 1, 2003; 71(7): 3901 - 3908. [Abstract] [Full Text] [PDF]
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 A J Kvalsvig and D J Unsworth The immunopathogenesis of meningococcal disease J. Clin. Pathol., June 1, 2003; 56(6): 417 - 422. [Abstract] [Full Text] [PDF]
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 R. Girard, T. Pedron, S. Uematsu, V. Balloy, M. Chignard, S. Akira, and R. Chaby Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow granulocytes via Toll-like receptor 2 J. Cell Sci., January 15, 2003; 116(2): 293 - 302. [Abstract] [Full Text] [PDF]
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