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Division of Geographic Medicine, Department of Medicine, and
Department of Ophthalmology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have developed a murine model for O. volvulus-induced keratitis, which is T cell-dependent and is characterized by the temporal recruitment of neutrophils and eosinophils into the cornea (4, 5). Our previous studies demonstrated that the severity of keratitis is determined by the number of inflammatory cells present in the cornea, and that recruitment of inflammatory cells, notably eosinophils, is regulated by IL-4 and can be modulated by rIL-12 (4, 6, 7). In the current study, we used B cell-deficient mice to examine the role of Ab in O. volvulus-mediated keratitis. We demonstrate that µMT mice fail to develop corneal disease, and that neutrophil and eosinophil migration into the cornea is dependent upon the presence of Ab.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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O. volvulus worms were obtained from nodules that had been surgically removed from patients in Cameroon, and were provided by Dr. Sara Lustigman at the New York Blood Center (New York, NY). Worms were isolated from s.c. nodules after digestion with collagenase (Sigma, St. Louis, MO), and parasites were homogenized in HBSS using a Dounce homogenizer, sonicated, and centrifuged to remove insoluble material as described previously (4). The soluble O. volvulus Ag preparation was adjusted to 1 mg/ml, filter-sterilized, and stored at -70°C.
Animals
Mice with a targeted disruption of the µ heavy chain membrane exon (µMT) were obtained from The Jackson Laboratory (Bar Harbor, ME). These mice were derived by Kitamura and Rajewsky (8) and backcrossed onto the C57BL/6 background. µMT mice are deficient in B cells and Ab. Age- and sex-matched C57BL/6 mice were obtained from The Jackson Laboratory as controls.
Immunization and intrastromal injection
Animals received three weekly s.c. immunizations with 10 µg of O. volvulus Ags in a 1:1 ratio with adjuvant containing squalene (Aldrich Chemical, Milwaukee, WI), Tween 80 (Fisher, Fair Lawn, NJ), and pluronic acid (BASF, Parsippany, NJ) (4). For intrastromal injections, the cornea was scarified with a 30-gauge needle, and 10 µg of O. volvulus Ags were injected into the corneal stroma using a 33-gauge needle attached to a Hamilton syringe (Hamilton, Reno, NV). Corneal opacification was monitored daily by slit lamp examination and evaluated as described previously (4). Briefly, clinical scores were graded on the intensity and extent of corneal opacity, measured in 0.5-U increments, using the following guidelines: 0, no pathology, cornea is transparent; 1, slight opacity; 2, moderate opacity; 3, severe opacity, underlying iris not visible.
For reconstitution experiments, sera were pooled from C57BL/6 or µMT mice that had been immunized three times with O. volvulus Ags. As control groups, sera were pooled from naive C57BL/6 or µMT mice. Sera were incubated with O. volvulus Ags in a 1:5 ratio at 37°C for 15 min before injection into the corneal stroma.
Immunohistochemistry
Eyes were removed, fixed overnight in 10% formaldehyde (Sigma),
processed by standard methods, and embedded in paraffin. To detect
eosinophils, 5-µm sections were immunostained for 2 h with
rabbit antisera to major basic protein
(MBP)3 that had been
diluted 1/1000 as described previously (5). Biotinylated
goat anti-rabbit Ig (Dako, Carpenteria, CA) was used as the
secondary Ab. Neutrophils were detected using the rat mAb 7/4 (Serotec,
Oxford, U.K.) diluted 1/100, followed by biotinylated rabbit
anti-rat Ig (BioGenex, San Ramon, CA). After incubation with a
secondary Ab, sections were incubated with alkaline
phosphatase-conjugated streptavidin (BioGenex). Positive reactivity was
visualized using Vector Red Substrate (Vector Laboratories, Burlingame,
CA) containing Levamisole (Sigma) and counterstained with modified
Harris’ hematoxylin (Richard-Allen, Kalamazoo, MI). Cells were
visualized by fluorescence microscopy and counted in a masked fashion.
To assess migration of cells to the central cornea, peripheral,
paracentral, and central regions of the cornea were defined as distance
from the peripheral (limbal) vessels in a manner similar to that
described by Hendricks et al. (9). Cell numbers for each
section were determined from limbus to limbus, which encompass two
peripheral regions (0 to 
500 µm from each limbus), two paracentral
regions (500–1000 µm from each limbus), and the central region of
the cornea (1000–1500 µm from each limbus). Values for each
region were combined.
Spleen cell proliferation and cytokine production
Spleens were removed 3 days after intrastromal injection and homogenized; erythrocytes were lysed using cold 0.01 M Tris (pH 7.2) containing 0.85% ammonium chloride. Cells were washed three times and resuspended at 1 x 107/ml in RPMI 1640 containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, 20 mM HEPES, 100 U/ml penicillin, and 100 µg/ml streptomycin.
Duplicate wells containing 1 x 106 cells
were incubated with 10 µg/ml parasite Ags for 72 h at 37°C in
5% CO2. Cell culture supernatant was removed and
assayed for IL-4, IL-5, and IFN-
by two-site ELISA. The following
mAb pairs were used: for IL-4, BVD6 and BVD4; for IL-5, TRKF-5 and
TRKF-4; and for IFN-, R46A2 and XMG1.2 (PharMingen, San Diego, CA).
Standard curves were generated with recombinant cytokines: IL-4, IL-5
(PharMingen), and IFN- (Genzyme, Cambridge, MA).
After removal of supernatant for cytokine measurement, cells were pulsed with 0.1 µCi of [3H]thymidine (ICN, Costa Mesa, CA) and harvested 18 h later onto glass fiber filters (Cambridge Technology, Watertown, MA). Liquid scintillation fluid was added, and cpm were determined using a Matrix 96 Direct beta counter (Packard Instruments, Meriden, CT).
Differential leukocyte counts
Blood was collected retro-orbitally, and total cells were counted using a hemocytometer. For differential counts, blood smears were stained with modified Wright-Giemsa stain (Diff-Quik; Dade Diagnostics, Aguada, Puerto Rico).
Measurement of Ab responses
Sera were collected at the time of sacrifice and assayed for Ab by ELISA. Immulon-4 ELISA plates (Dynatech, Chantilly, VA) were coated overnight with 50 µl of 1 µg/ml parasite Ags. After blocking with 1% FBS, dilutions of mouse sera were incubated for 2 h at room temperature, washed, and incubated with biotinylated goat anti-mouse isotype-specific Abs (Southern Biotechnology Associates, Birmingham, AL). Reactivity was determined after incubation with peroxidase-labeled anti-goat IgG (Santa Cruz Biotechnology, Santa Cruz, CA), and tetramethyl benzidine (Zymed, San Francisco, CA) was used as a substrate. The reaction was stopped after 10 min with 1N HCl. Absorbance was measured at 450 nm on a kinetic microplate reader (Molecular Devices, Sunnyvale, CA).
Statistics
Statistical significance was determined using an unpaired Student’s t test (Prism Graph Pad Software, San Diego, CA). A value of p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Earlier findings demonstrated that immunocompetent animals develop
severe corneal opacification after intrastromal injection of helminth
Ags (4). To determine whether B cells and Ab are required
for the development of O. volvulus-mediated keratitis,
C57BL/6 and µMT mice were immunized s.c. and injected intrastromally
with O. volvulus Ags. As shown in Fig. 1
, C57BL/6 mice develop severe corneal
opacification, which is evident by day 1 after intrastromal injection
and remains elevated through day 3. In contrast, µMT mice developed
only a mild, transient opacification that resolved by day 2.
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), opacification was still prominent through day 8, consistent
with our previous observations (4, 5). µMT corneas
remained transparent throughout this study period. These data
demonstrate that B cells and/or Ab are essential for the development of
O. volvulus-mediated keratitis. Absence of corneal pathology in µMT mice is associated with impaired eosinophil migration to the central, but not the peripheral cornea
Given that inflammatory cell recruitment into the cornea correlates with the development of keratitis, we subsequently determined whether there was altered migration of eosinophils into the cornea. Previous studies demonstrated a biphasic recruitment of neutrophils and eosinophils into the cornea after intrastromal injection of O. volvulus Ags, with neutrophils predominant at 1 day postinjection, neutrophils and eosinophils present after 3 days, and eosinophils predominant after 7 days (5). Eyes from C57BL/6 and µMT mice were recovered 3 days after intrastromal injection, and 5-µm sections were immunostained with Abs to eosinophil MBP.
The distribution of eosinophils in the corneas of C57BL/6 and µMT
mice is shown in Figs. 2 and
3. In C57BL/6 mice, eosinophils were
present throughout the corneas on day 3, with 63.1% in the periphery,
22.3% in the paracentral region, and 14.6% in the central cornea. In
contrast, µMT corneas had significantly fewer eosinophils than
C57BL/6 corneas (596.6 ± 235.8 vs 326.6 ± 130.9,
p = 0.0188); of those present, 90% were in the
periphery, with only 9.2% in the paracentral region and 0.7% in the
central region.
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Neutrophil recruitment to the peripheral and central cornea is impaired in µMT mice
To determine the effect of Ab on neutrophil recruitment to the
cornea, C57BL/6 and µMT mice were sacrificed 1 day after intrastromal
injection. As shown in Fig. 4, neutrophil
recruitment to all regions of the cornea was significantly impaired in
µMT mice compared with C57BL/6 mice. In addition, of those
neutrophils detected in the corneas of µMT mice, 83.6% were in the
periphery, whereas neutrophils were observed in all regions of the
cornea in C57BL/6 mice (Fig. 4). This difference in distribution was
also observed on day 3 postchallenge, with 96.8% of neutrophils
present in the peripheral cornea of µMT mice, and 52.6% in the
periphery of C57BL/6 mice (p = 0.0052). No
neutrophils were detected in any of the corneas on day 8.
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µMT mice develop similar Th2 cell responses and blood eosinophilia in response to helminth Ags
Previous studies showed that development of O.
volvulus-mediated keratitis is T cell- and IL-4-dependent
(4). To determine whether the absence of corneal
opacification and pathology in µMT mice reflects altered T cell
responses to O. volvulus Ags, splenocytes from immunized
C57BL/6 mice were removed 3 days after intrastromal injection and
incubated in vitro with parasite Ags. No differences in T cell
responses were noted from spleens removed 1, 3, or 8 days after
intrastromal injection (data not shown). As shown in Fig. 5, there was no significant difference in
O. volvulus-induced T cell proliferation between C57BL/6 and
µMT mice, although there was a difference in proliferation in the
absence of exogenous Ag (7.6 ± 1.0 x
103 vs 3.6 ± 1.8 x
103 cpm, respectively, p =
0.002). There were also no differences in Ag-induced IL-4 production
between C57BL/6 and µMT mice. Furthermore, although µMT mice
produced significantly less IL-5 than C57BL/6 mice in response to
parasite Ags (0.882 ± 0.39 vs 1.8 ± 0.29 ng/ml,
p < 0.05), this did not result in diminished blood
eosinophilia (Fig. 5). IFN- production was not elevated in the
absence of B cells (data not shown). Taken together, these observations
indicate that impaired corneal pathology in µMT mice is not due to a
deficiency in either T cell responsiveness or eosinophil
production.
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Given the similarity in T cell responses between µMT and
immunocompetent mice, it is unlikely that the defect in B
cell-deficient mice is at the level of Ag presentation/T cell
activation. Therefore, it is probable that Abs are necessary for
inflammatory cell recruitment to the cornea. We have demonstrated
previously that mice immunized with O. volvulus Ags produce
elevated serum IgE (4). To determine the IgG isotype
responses to parasite Ags, sera were collected from C57BL/6 mice after
s.c. immunization, and Ab responses were quantified. As shown in Fig. 6, O. volvulus-sensitized mice
had elevated parasite-specific responses of all IgG isotypes compared
with naive mice. However, IgG1, IgG2b, and IgG3 levels were elevated
compared with IgG2a, consistent with the development of a Th2 response.
B cell-deficient (µMT) mice immunized under identical conditions had
no detectable IgG (data not shown).
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To determine whether O. volvulus-specific Ab
contributes directly to the development of keratitis, parasite Ags were
incubated with normal or immune sera from C57BL/6 or µMT mice before
injection into the corneas of immunized µMT mice. As shown in Fig. 7, µMT mice injected with O.
volvulus Ag plus sera from naive C57BL/6 mice remained clear
throughout the study. In contrast, immunized µMT mice injected with
Ag plus immune sera from C57BL/6 mice developed pronounced corneal
opacification (Fig. 7). As a further control for the role of Ab in the
sera, µMT mice were injected with parasite Ag that had been incubated
with immune or naive sera from µMT mice, which have no Ab. These
animals did not develop corneal opacification (Fig. 7), indicating that
opacification is dependent upon the presence of specific Ab and is
likely a result of the formation of immune complexes. Consistent with
the presence of corneal opacification in µMT mice in the presence of
immune C57BL/6 sera, we found elevated numbers of neutrophils and
eosinophils in the central cornea (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our observations on the role of Ab differ from other models of T
cell-dependent immunopathology, in which the absence of B cells and Ab
either had no effect on the development of pathology
(13, 14, 15, 16) or resulted in exacerbated immunopathology
(17). Furthermore, in other models of Th2-mediated
pathogenesis in which eosinophils are prominent, B cell deficiency did
not alter eosinophil recruitment. There was no effect on eosinophil
migration either to the lungs in a mouse model of allergic asthma
(15, 18) or to the liver in a murine model of
schistosomiasis (17). Despite the differences in
pathological outcome between our studies and those cited, our data were
in agreement with these observations in noting that the absence of B
cells had no effect on T cell proliferation or IL-4 or IFN-
responses (14, 17). Although we found reduced IL-5
production in µMT mice, there was no effect on the development of
blood eosinophilia.
Therefore, the absence of disease in µMT mice was not a consequence of impaired development of Ag-specific T cell responses. Instead, the effect was found to be at the level of inflammatory cell recruitment, as eosinophil and neutrophil infiltration of the cornea is abrogated in B cell-deficient mice. Our findings demonstrated that the failure of µMT mice to develop corneal opacification in response to intrastromal challenge is due to impaired recruitment of neutrophils and eosinophils to the central cornea. As the cornea is normally avascular, inflammatory cells are recruited from the limbal vessels in the periphery and migrate toward the site of corneal injury. In µMT mice, eosinophils are recruited from the limbal vessels into the peripheral cornea, but do not migrate to the central cornea. This finding indicates that at least two sets of signals regulate eosinophil migration in the cornea: one that mediates exocytosis from the blood and is not dependent upon Ab, and a second Ab-dependent mechanism that regulates migration from the periphery to the central cornea.
In contrast to eosinophils, there were significantly fewer neutrophils in the peripheral corneas of µMT mice, indicating that Ab-dependent signals are required for exocytosis of neutrophils from the limbal vessels to the corneal stroma. In addition, migration of neutrophils from the periphery to the central cornea is also dependent upon the presence of Ab, as >90% of total neutrophils in µMT mice remain in the periphery.
IgG and IgM are present in normal corneas at concentrations that
reflect serum levels (19, 20); therefore, the
parasite-specific IgG isotype response in the sera likely reflects the
isotype profile in the cornea. We predict that these Abs react with
parasite Ags in the cornea (after intrastromal injection), and that the
resulting immune complexes stimulate granulocyte recruitment either by
cross-linking Fc receptors (FcRs) and stimulating the release of
chemokines, or by activation of the complement cascade and subsequent
release of the chemotactic peptides C3a and C5a. These conclusions are
supported by our observation that injection of parasite Ags and immune
sera under conditions that are likely to form immune complexes leads to
the development of keratitis in µMT mice (Fig. 7).
We have demonstrated that several eosinophil chemokines, including
macrophage inflammatory protein-1
(MIP-1), RANTES, and eotaxin
are up-regulated in mice with severe keratitis (7).
Furthermore, eotaxin gene knockout mice have significantly fewer
eosinophils in the corneas (21), indicating an important
role for this chemokine. Although the source of eotaxin in the cornea
has yet to be determined, eosinophils express eotaxin mRNA
(22), and cross-linking Ig receptors on the eosinophil
surface causes the release of several cytokines (23).
Further studies will examine the possibility that immune complexes
trigger Fc-mediated release of these chemokines. In addition, Lausch
and colleagues showed that MIP-1 and MIP-2 are essential for
neutrophil recruitment to the cornea in a murine model of herpes
simplex keratitis (24, 25). These authors speculate that
stromal fibroblasts are the source of these chemokines initially, but
neutrophils may themselves produce chemokines upon subsequent
activation, possibly by Fc-mediated mechanisms. Of interest is our
observation that the eosinophils often migrate close to the epithelium
(Fig. 2), implicating epithelial cells as a possible source of
chemotactic molecules. Alternatively, this distribution of eosinophils
might reflect deposition of O. volvulus Ags after
intrastromal injection. Further studies will examine more directly the
fate of Ags in the cornea.
Immune complexes activate complement via the classical pathway, resulting in the production of inflammatory mediators, including the peptides C3a and C5a, which have potent granulocyte chemotactic activity (26, 27, 28, 29). Components of the classical pathway of complement are present in normal corneas (30), and stromal fibroblasts can synthesize complement factors (30, 31). Hazlett et al. demonstrated that complement-depleted mice have significantly fewer neutrophils in the cornea in a murine model of Pseudomonas keratitis (32), although it was not determined whether complement was activated via the classical or alternate pathways. In addition, in vitro experiments with live O. volvulus microfilariae showed that human peripheral blood granulocytes migrated in response to microfilariae only in the presence of both immune serum and fresh serum, indicating a requirement for parasite-specific Abs and a source of complement (33). Future studies will determine the role of specific isotypes and complement in neutrophil and eosinophil recruitment and in the development of corneal pathology.
In addition to the role of Ab in the recruitment of neutrophils and eosinophils, Ab may also be important in Fc-mediated degranulation. Neutrophils and eosinophils express FcRs (34, 35, 36), and eosinophil degranulation is mediated by Ab and FcR interactions (37, 38, 39). Therefore, it is likely that once present at the site of inflammation, Abs induce the release of cytotoxic mediators that contribute to corneal injury. Damage to corneal endothelial cells, which regulate corneal hydration, would result in stromal edema and corneal opacification (40). Similarly, a cytotoxic effect on keratocytes, which produce and maintain the collagen matrix of the cornea, would also result in loss of corneal clarity. MBP is a highly cationic protein that forms the crystalline core of the eosinophil granule. As MBP has been shown to have a direct cytotoxic effect on resident corneal cells (41) and to inhibit corneal wound healing (42), it seems reasonable to assume that MBP and other cationic proteins would have a cytotoxic effect on resident corneal cells in vivo, and result in corneal opacification. Neutrophil degranulation also results in the release of cytotoxic components such as oxygen radicals, proteases, and peroxidases (43). Future studies will determine the role of FcRs in the degranulation of these cells and in the development of keratitis.
In conclusion, our findings from the current series of experiments support a novel role for Ab in T cell-dependent corneal pathology, and may have further implications for the role of Ab in other diseases in which neutrophils and eosinophils are prominent.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Eric Pearlman, Division of Geographic Medicine, Case Western Reserve University School of Medicine, W137, 2109 Adelbert Road, Cleveland, OH 44106. E-mail address:
3 Abbreviations used in this paper: MBP, major basic protein; FcR, Fc receptor; MIP, macrophage inflammatory protein.
Received for publication May 21, 1999. Accepted for publication August 10, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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prevents the development of blinding herpes stromal keratitis. J. Virol. 72:3705.
receptors on murine eosinophils: implications for the functional significance of elevated IgE and eosinophils in parasitic infections. Blood 89:3826.This article has been cited by other articles:
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  K. Gentil and E. Pearlman Gamma Interferon and Interleukin-1 Receptor 1 Regulate Neutrophil Recruitment to the Corneal Stroma in a Murine Model of Onchocerca volvulus Keratitis Infect. Immun., April 1, 2009; 77(4): 1606 - 1612. [Abstract] [Full Text] [PDF]
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 M. M. M. Ali, G. ElGhazali, S. M. Montgomery, S. E. Farouk, A. Nasr, S. I. A. Noori, M. M. Shamad, O. E. Fadlelseed, and K. Berzins Fc{gamma}RIIa (CD32) Polymorphism and Onchocercal Skin Disease: Implications for the Development of Severe Reactive Onchodermatitis (ROD) Am J Trop Med Hyg, December 1, 2007; 77(6): 1074 - 1078. [Abstract] [Full Text] [PDF]
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I. Gillette-Ferguson, A. G. Hise, Y. Sun, E. Diaconu, H. F. McGarry, M. J. Taylor, and E. Pearlman Wolbachia- and Onchocerca volvulus-Induced Keratitis (River Blindness) Is Dependent on Myeloid Differentiation Factor 88 Infect. Immun., April 1, 2006; 74(4): 2442 - 2445. [Abstract] [Full Text] [PDF]
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 A. G. Hise, I. Gillette-Ferguson, and E. Pearlman Immunopathogenesis of Onchocerca volvulus keratitis (river blindness): a novel role for TLR4 and endosymbiotic Wolbachia bacteria Innate Immunity, December 1, 2003; 9(6): 390 - 394. [Abstract] [PDF]
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T. Ramalingam, B. Rajan, J. Lee, and T. V. Rajan Kinetics of Cellular Responses to Intraperitoneal Brugia pahangi Infections in Normal and Immunodeficient Mice Infect. Immun., August 1, 2003; 71(8): 4361 - 4367. [Abstract] [Full Text] [PDF]
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 R. B. Berger, N. M. Blackwell, J. H. Lass, E. Diaconu, and E. Pearlman IL-4 and IL-13 Regulation of ICAM-1 Expression and Eosinophil Recruitment in Onchocerca volvulus Keratitis Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 2992 - 2997. [Abstract] [Full Text] [PDF]
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 A. v. S. Andre, N. M. Blackwell, L. R. Hall, A. Hoerauf, N. W. Brattig, L. Volkmann, M. J. Taylor, L. Ford, A. G. Hise, J. H. Lass, et al. The Role of Endosymbiotic Wolbachia Bacteria in the Pathogenesis of River Blindness Science, March 8, 2002; 295(5561): 1892 - 1895. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, M. I. Araujo, and E. J. Pearce Immunology of Parasitic Helminth Infections Infect. Immun., February 1, 2002; 70(2): 427 - 433. [Full Text] [PDF]
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 L. R. Hall, E. Diaconu, and E. Pearlman A Dominant Role for Fc{{gamma}} Receptors in Antibody-Dependent Corneal Inflammation J. Immunol., July 15, 2001; 167(2): 919 - 925. [Abstract] [Full Text] [PDF]
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J. T. Kaifi, E. Diaconu, and E. Pearlman Distinct Roles for PECAM-1, ICAM-1, and VCAM-1 in Recruitment of Neutrophils and Eosinophils to the Cornea in Ocular Onchocerciasis (River Blindness) J. Immunol., June 1, 2001; 166(11): 6795 - 6801. [Abstract] [Full Text] [PDF]
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L. R. Hall, E. Diaconu, R. Patel, and E. Pearlman CXC Chemokine Receptor 2 But Not C-C Chemokine Receptor 1 Expression Is Essential for Neutrophil Recruitment to the Cornea in Helminth-Mediated Keratitis (River Blindness) J. Immunol., March 15, 2001; 166(6): 4035 - 4041. [Abstract] [Full Text] [PDF]
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J. T. Kaifi, L. R. Hall, C. Diaz, J. Sypek, E. Diaconu, J. H. Lass, and E. Pearlman Impaired Eosinophil Recruitment to the Cornea in P-Selectin-Deficient Mice in Onchocerca volvulus Keratitis (River Blindness) Invest. Ophthalmol. Vis. Sci., November 1, 2000; 41(12): 3856 - 3861. [Abstract] [Full Text]
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L. R. Hall, J. T. Kaifi, E. Diaconu, and E. Pearlman CD4+ Depletion Selectively Inhibits Eosinophil Recruitment to the Cornea and Abrogates Onchocerca volvulus Keratitis (River Blindness) Infect. Immun., September 1, 2000; 68(9): 5459 - 5461. [Abstract] [Full Text] [PDF]
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 V. Moulin, F. Andris, K. Thielemans, C. Maliszewski, J. Urbain, and M. Moser B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo: Increased Interleukin 12 Production by DCs from B Cell-Deficient Mice Results in T Helper Cell Type 1 Deviation J. Exp. Med., August 21, 2000; 192(4): 475 - 482. [Abstract] [Full Text] [PDF]
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