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RI+ Cells Through Interaction with the VH3 Region of IgE1
University of Naples Federico II, Division of Clinical Immunology and Allergy, Naples, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain of high-affinity receptor for IgE (Fc
RI)
was unaffected by this treatment. Three human
VH3+ monoclonal IgM inhibited gp120-induced
secretion of IL-4 from basophils. In contrast,
VH6+ monoclonal IgM did not inhibit the release
of IL-4 induced by gp120. Synthetic peptides distant from the
NH2 and COOH termini of gp120MN inhibited the
activating property of gp120MN. These results indicate that
gp120, which acts as a viral superantigen, interacts with the
VH3 region of IgE to induce the release of IL-4 and IL-13
from human FcRI+ cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-2, whereas TH2 cells produce IL-4,
IL-5, and IL-13. A type 2 cytokine profile secreted by
CD4+ T cells stimulates IgE levels (2, 3). Serum IgE levels are increased in adults and in children
with HIV-1 infection (4, 5, 6, 7, 8). Elevated IgE levels in
HIV-1-infected children and adults have been associated with the
progression of HIV-1 disease (9, 10, 11). Thus, IgE levels
could be a marker of poor prognosis in some patients in the early or
late stages of HIV-1 infection (9, 10, 11). These observations generated great interest and some controversy. Clerici et al. (12, 13) suggested that, during the early stages of HIV-1 infection, there is a switch from "TH1-like" toward a "TH2-like" pattern of cytokine production. This hypothesis was indirectly supported by the observation that IL-4 gene-targeted mice lacking TH2 responses do not develop murine AIDS (14). However, the association with another gene product is a prerequisite for nondevelopment of murine AIDS (15). Graziosi et al. (16) did not detect an overall shift in the cytokines pattern toward the TH2 subset in lymph nodes of HIV-1-infected individuals . In another study, Maggi et al. (17) did not find a bias toward TH2-like cytokine patterns in T cell clones from HIV-1-infected individuals during the progression to AIDS . They demonstrated a preferential depletion of CD4+ TH2-type cells in the advanced phases of HIV-1 infection and found that HIV-1 replicates preferentially in TH2 rather than in TH1 clones (17). Subsequent reports have added to the controversy (18, 19, 20, 21). The apparently conflicting results could be due to 1) technical reasons, 2) the production of TH2-like cytokines by cell types other than lymphocytes, 3) stimulation by specific superantigens, or 4) cytokines other than IL-4. In fact, most studies have focused on IL-4 and IL-10, whereas recent data show that other cytokines such as IL-13 are critical for TH2 cell polarization (22, 23, 24).
Basophils and mast cells are the only cells that synthesize histamine
and express high-affinity receptors for IgE
(FcRI)3 (25, 26). Immunologic activation of human basophils generate and
secrete a restricted profile of cytokines (IL-4 and IL-13)
(27, 28, 29, 30) that are critical for TH2
cell polarization (1, 2, 3, 22, 23, 24). Also, immunologically
activated human mast cells synthesize IL-4 and IL-13
(31, 32, 33). Moreover, HIV Ags induce histamine release from
basophils (34).
HIV-1 and HIV-2 destroy CD4+ lymphocytes, which
leads to AIDS (35, 36). The entry of HIV into host cells
is mediated by sequential interaction of the viral envelope
glycoprotein (gp) gp120, with the CD4 gp (36, 37) and
chemokine receptors on the cell surface (38, 39, 40). HIV-1
gp120 is a new member of the Ig superantigen family
(41, 42, 43). Ig VH3 gene products are
the ligand for gp120 (44), and this interaction might
explain the superantigen activation of human B lymphocytes in patients
with AIDS (45). Protein Fv, an endogenous superantigen
stimulated by viral infections in humans (46), interacts
with the VH3 domain of IgE to induce the release
of IL-4 and IL-13 from human FcRI+ cells
(47, 48). In this study, we demonstrate that HIV-1 gp120
interacts with the VH3 domain of IgE to induce
the release of IL-4 and IL-13 from human FcRI+
cells, thus acting as a viral superantigen.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following were purchased: 60% HClO4
(Baker, Deventer, The Netherlands); BSA, PIPES, hyaluronidase,
collagenase, chymopapain, elastase type I, human serum albumin (Sigma,
St. Louis, MO); HBSS, IMDM, and FCS (Life Technologies, Grand Island,
NY); deoxyribonuclease I (Calbiochem, La Jolla, CA); RPMI 1640 with 25
mM HEPES buffer, Eagle’s MEM (Flow Laboratories, Irvine, Scotland);
and Dextran 70, Percoll, and protein A-Sepharose (Pharmacia Biotech,
Uppsala, Sweden). Rabbit anti-human-Fc Ab was a generous gift
from Drs. Teruko and Kimishige Ishizaka (La Jolla Institute for Allergy
and Immunology, La Jolla, CA). The mAb against the -chain of FcRI
was a generous gift from Dr. John Hakimi (Roche Research Center,
Hoffman-LaRoche, Nutley, NJ).
Buffers
The PIPES buffer used in these experiments was made up of 25 mM PIPES (pH 7.37), 110 mM NaCl, and 5 mM KCl. The mixture is referred to as P. PCG contained, in addition to P, 5 mM CaCl2 and 1 g/L dextrose (47); pH was titrated to 7.4 with sodium bicarbonate. PBS contained 8.0 g/L NaCl, 2.89 g/L Na2HPO4 · 7H2O, 0.2 g/L KH2PO4, 0.2 g/L KCl, (pH 7.3); TCF contained 8.0 g/L NaCl, 0.2 g/L KCl, 0.05 g/L NaH2PO4, 0.28 g/L NaHCO3, and 1.0 D-glucose (pH 7.3); TGMD contained 0.25 g/L MgCl2 · 6H2O, 10 mg/l DNase, and 1 g/L gelatin in addition to TCF (pH 7.3) (46).
Purification of human monoclonal IgM
Monoclonal IgM were purified from the sera of patients with Waldenstrom’s macroglobulinemia by gel permeation, as described (46). Variable regions of these monoclonal IgM were determined using a well-characterized panel of primary sequence-dependent VH and VK family-specific reagents that identify framework regions previously described (46).
Purification of peripheral blood basophils
Basophils were purified from peripheral blood cells of normal subjects, aged 19–47 years (mean age, 36.1 ± 5.2 years), undergoing hemapheresis. Buffy coat cell packs from healthy volunteers provided by the Immunohematology Service at the University of Naples Federico II were reconstituted in PBS containing 0.5 g/l human serum albumin and 3.42 g/L sodium citrate and loaded onto a countercurrent elutriator (model J2-21; Beckman Instruments, Fullerton, CA). Several fractions were collected, and fractions containing basophils in large numbers (>20 x 106 basophils) and of improved purity (>15%) were further enriched by discontinuous Percoll gradients (49). Yields by this technique ranged from 3 to 10 x 106 basophils, with a purity from 74 to 98%, as assessed by basophil staining with Alcian blue and counting in a Spiers-Levy eosinophil counter (49).
Isolation and purification of human lung mast cells
Macroscopically normal lung tissue obtained from patients undergoing thoracotomy and lung resection, mostly for lung cancer, was dissected free from pleura, bronchi, and blood vessels, minced into 3- to 8-mm fragments, and dispersed into single-cell suspensions as described (46). Yields with this technique ranged between 3 x 106 and 20 x 106 mast cell, with a purity between 1 and 8%. The cells were resuspended and incubated overnight in RPMI 1640 containing 25 mM HEPES, 2 mM L-glutamine, 1% gentamicin, and 10% FCS as described previously (46). Mast cells isolated from lung parenchyma were fractionated in a Beckman elutriator (Beckman Instruments). Elutriation fractions with the greatest percentage of mast cells were pooled, and further purified by flotation in Percoll density gradients as described (46). The fractions rich in mast cells were then counted by Alcian blue stain.
Histamine and cytokine release assay
Basophils (
6 x 104 basophils/tube) or
mast cells (3x 104 cells/tube) resuspended in
PCG (histamine release) or IMDM (cytokine release) and 0.1 ml of the
cell suspension were placed in 12- x 75-mm polyethylene tubes and
warmed to 37°C; 0.1 ml of each preformed stimulus for release was
added, and incubation was continued at 37°C for 45 min (histamine
release), 4 h (IL-4 secretion), or 18 h (IL-13 secretion)
(47, 48). At the end of this step, the reaction was
stopped by centrifugation (1000 x g, 22°C, 2 min),
and the cell-free supernatants were stored at -20°C for subsequent
assay of histamine and cytokine content. The cell-free supernatants
were assayed for histamine with an automated fluorometric technique
(50). Total histamine content was assessed by lysis
induced by incubation of cells with 2% perchloric acid before
centrifugation. To calculate histamine release as a percentage of total
cellular histamine, the spontaneous release of histamine from basophils
(0–8% of the total cellular histamine) and mast cells (4–18% of the
total cellular histamine) was subtracted from both the numerator and
denominator (49). All values are based on means of
duplicate or triplicate determinations. Replicates differed from each
other in histamine content by <10%.
IL-4 and IL-13 ELISA
The harvested supernatants were assayed for IL-4 or IL-13 by using the IL-4 or IL-13 Quantikine high sensitivity kit (R&D Systems, Minneapolis, MN). The standard curve for these kits was run in the same medium used for the release experiments (47, 48).
Isolation of cellular mRNA
RNA was isolated by harvesting the basophils from culture wells and centrifuging for 30 s at 10,000 x g. After removal of the supernatants, the cell pellet was extracted with RNAzol B (Tel-Test, Friendswood, TX), which is a modified guanidinium thiocyanate single-step procedure, as described (47).
RT-PCR and quantitative PCR
An aliquot of total cellular mRNA was reversed transcribed to
cDNA and PCR expanded using the GeneAmp RNA PCR Core kit (Perkin-Elmer
International, Nieuwerkerk, The Netherlands), as described
(47). In this protocol, RT was performed on 2 µl of the
RNA extract (10–20% of the total RNA extracted). The RT mix (5 mM
MgCl2) was incubated for 20 min in a
Perkin-Elmer/Cetus thermocycler (Perkin-Elmer/Cetus, Norwalk, CT)
followed by 2 min at 95°C to inactivate the RT. Buffers, dNTPs (final
concentration, 0.4 mM each), Amplitaq polymerase (1 U/50 µl
reaction), and paired primers (0.5 µM each) were added to RT tubes
(bringing MgCl2 to 2 mM), and the PCR reaction
was cycled according to the following protocol: denaturation at 95°C
for 15 s, annealing at 60°C for 15 s and at 72°C for
30 s. IL-4 was cycled 56 times before a 15-min incubation at
72°C for a final extension. The primers for IL-4 and IFN- was
performed and synthesized with commercial source (Life Technologies)
based on the known cDNA sequences for the cytokines.
An aliquot (10 µl) of the reaction product was visualized on 2% agarose in buffer containing 0.5 µg/ml of ethidium bromide. As a negative control, an aliquot of each RNA sample was subjected to PCR amplification without the RT step.
In some experiments, an aliquot of total cellular mRNA was reversed-transcribed to cDNA and PCR expanded for quantitative PCR using a Cytopress Detection kit (BioSource International, Camarillo, CA). This technique is a competitive PCR in which a known copy number of an exogenous synthesized DNA, known as the internal calibration standard (ICS). The ICS was constructed to contain PCR primer binding sites identical to the IL-4 cDNA and a unique capture binding site that allows the resulting ICS amplicon to be distinguished from the IL-4 amplicon. The Cytopress kit contains IL-4 primers, one of, which is biotinylated, to be included in the PCR mix. During amplification, biotin-labeled primer is incorporated into both ICS and IL-4 amplicons. After PCR, the amplicons are denatured and hybridized to either ICS or IL-4 sequence-specific capture oligonucleotides. Capture oligonucleotides are prebound to microtiter wells. The captured biotinylated sequences are detected and quantified by the addition of an enzyme-streptavidin conjugate HRP, followed by the addition of the substrate. The signal generated in the reaction is proportional to the amount of amplicon present. Because the ICS is amplified at an efficiency identical to the IL-4 cDNA, it can serve as a standard for IL-4 cDNA quantitation. The number of copies of IL-4 in each PCR reaction is calculated from the ratio of the total OD for the IL-4-specific well to the total OD for the ICS well and the input copy number of the ICS. The following formula is used to calculate the starting copies of IL-4 cDNA in the PCR reaction: (total IL-4/total ICS OD) x 2 x input copy number of ICS = starting copy number of IL-4 cDNA. Factor 2 is used to correct for double-stranded DNA ICS. The copy number is adjusted for any dilution done on cDNA before amplification according the manufacturer’s protocol.
Statistical analysis
The results are means ± SEM. The data subjected to linear regression were calculated by the least-squares method (y = a + bx) in which a was the y-axis intercept and b the slope of the line (51).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For our experiments we purified (>98%) human peripheral blood
basophils from healthy individuals who were seronegative for Abs to
HIV-1 and HIV-2. We then cultured basophils with recombinant human IL-3
(10 ng/ml for 16 h), washed the cells, and challenged them with
recombinant gp120 from HIV-1 (10 nM) or anti-IgE (1 µg/ml). Fig. 1
shows a representative result of four
experiments in which we examined the effects of gp120 and anti-IgE
on the levels of extracellular IL-4 protein, specific IL-4 mRNA, and
secretion of histamine. These experiments demonstrated that gp120 and
anti-IgE increased specific IL-4 mRNA copies. gp120 and
anti-IgE stimulated the release of IL-4 parallel to the secretion
of histamine from basophils. In contrast, IFN- mRNA was not detected
in any of the basophil preparations stimulated with gp120, suggesting
that gp120-mediated stimulation of FcRI+ cells
induced only cytokines of the TH2 profile (data
not shown).
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To verify that HIV-1 envelope glycoprotein gp120 has the capacity
to induce basophil activation, we compared four recombinant gp120
(gp120MN, gp120SF2,
gp120LAV, and gp120CM)
derived from divergent HIV-1 isolates from different viral clades (B
and E) of various geographical origins (United States, France, and
Thailand). These highly divergent samples of gp120 induced IL-4 release
from basophils. This implies that the capacity to induce cytokine
release from basophils is a general feature of gp120, which has been
maintained throughout the evolution of the virus (Fig. 2). Two unrelated gps, BSA and human
serum albumin (1–100 nM), did not activate any of the basophil
preparations tested (data not shown).
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Fig. 3A compares the
kinetics of histamine, IL-4, and IL-13 release from basophils
challenged with gp120. Histamine release was complete within 5 min,
IL-4 release was complete in 3–4 h, whereas IL-13 release plateaued at
18 h. Lower concentrations of gp120 consistently exerted a more
potent effect on the secretion of IL-13 than on IL-4 and histamine
release (Fig. 3B). Similar results were obtained with the
four gp120 derived from different clades (data not shown). These data
demonstrate that nanomolar concentrations of gp120 induce the secretion
of IL-13, an important cytokine for the polarization of
TH2 cells (22, 23, 24), from
basophils.
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Two immunophilin-binding drugs, CsA and tacrolimus (FK-506), are
potent inhibitors of the IgE-dependent release of proinflammatory
mediators from human basophils and mast cells (52, 53, 54). We
compared the effects of preincubation of low concentrations of CsA
(24–800 nM) and tacrolimus (1–30 nM) on the release of histamine and
the secretion of IL-4 from purified basophils activated by gp120. CsA
concentration-dependently inhibited the gp120-induced release of
histamine and IL-4 from basophils at concentrations as low as 24 nM
(Fig. 4A). The inhibition of
IL-4 release ranged from 
30% at 24 nM to 90–95% at 240 nM, with
an IC50 of 31.6 ± 6.4 nM, similar to that
calculated from the inhibition of histamine release (46.0 ± 9.3
nM). The effects of tacrolimus on the release of histamine and the
secretion of IL-4 from human basophils were similar to those observed
with CsA (Fig. 4B). However, tacrolimus was more potent than
CsA with an IC50 for IL-4 release of 2.3 ±
0.2 nM, similar to that calculated from the inhibition of histamine
release (2.0 ± 0.4 nM).
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Brief exposure to low pH removes most of the IgE bound on
FcRI+ cells, thus greatly reducing the
activating properties of IgE-mediated stimuli (46). Fig. 5 shows that brief exposure to lactic
acid completely blocks the effect exerted by gp120 and by anti-IgE
on IL-4 secretion from basophils. In contrast, the response to the mAb
cross-linking the -chain of FcRI (47) was not
affected by this treatment. These data are compatible with the
hypothesis that gp120 activates FcRI+ cells
through the interaction with IgE bound on basophils.
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To evaluate the mechanism whereby gp120 activates basophils from
healthy individuals, we incubated gp120 with monoclonal IgM of
different VH families according to a recently
described procedure (47). In these experiments, gp120 (10
nM) was preincubated (15 min, 37°C) with increasing concentrations
(0.1–10 µg/ml) of three different preparations of monoclonal IgM
VH3+ (IgM M3, IgM M11, and
IgM LAN) or monoclonal IgM
VH6+ (M14). Basophils
isolated from HIV-1- and HIV-2-negative subjects were then added, and
the incubation was continued for an additional 4 h at 37°C. At
the end of this incubation, IL-4 in the supernatants was assayed. Fig. 6 shows that preincubation of three
preparations of monoclonal IgM (M3, M11, and LAN), which possess the
VH3 domain, concentration-dependently inhibited
the effect of gp120 on IL-4 secretion. In contrast, a monoclonal IgM
(M14), which possesses a VH6 domain, had no
effect.
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). Thus, binding to the
VH3 domain inhibits the interaction of gp120 with
IgE bound to FcRI on basophils and lung mast cells.
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To map the IgE binding sites on gp120, we tested the inhibitory
capacity of a panel of synthetic peptides encompassing the
gp120MN sequence (55). The synthetic
peptides of the gp120MN core motif (peptides
1959, 1960, 1985, 1988, and 1989), concentration-dependently inhibited
the effect of gp120MN on basophils. In contrast,
peptides 1922 and 2015, which span the gp120MN
amino- and COOH-terminal region, respectively, failed to induce
inhibition. Each of these peptides alone neither induced nor inhibited
anti-IgE-induced cytokine or histamine release from human
FcRI+ cells (data not shown). Our results are
consistent with the hypothesis that the superantigen-binding site(s) on
gp120 is formed by protein sequences of at least two regions, which
span in a discontinuous fashion the constant and variable domains of
the molecule (41).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI+ cells. The activity of gp120 is mediated
by interaction with the VH3 region of IgE present
on human basophils and mast cells. This is the first demonstration that
gp120 triggers the release of two cytokines critical for
TH2 polarization from human
FcRI+ cells.
The relevance of this finding is 3-fold. It suggests that during the
early phase of HIV infection, which is associated with high levels of
viremia and spreading of the virus (35, 36), basophils
exposed to virus-bound or shed gp120 (56) might represent
an initial source of IL-4 and IL-13, thereby favoring a shift from a
TH0 toward a TH2 phenotype.
In advanced HIV-1 infection when CD4+ T cells are
decreased, FcRI+ cells might also represent a
significant source of TH2-like cytokines.
Therefore, during both early and advanced HIV-1 infection, basophils
and mast cells might be a source of cytokines that contribute to the
polarization of CD4+ cells toward
TH2 cells. Finally, our findings might be
significant also from a quantitative viewpoint.
TH2 cells represent 0.2–2% of
CD4+ cells (57), whereas basophils
represent 1% of peripheral blood leukocytes (25). Viral
Ags interact with individual TH clones; viral
superantigen gp120 can produce a rapid and massive activation of
basophils via VH3+ IgE.
Because the VH3 family is the largest in the
human repertoire (50%; see Refs. 42, 43, 44), it is likely
that shed or virus-bound gp120 interacts with a high frequency with
VH3+ IgE bound to basophils
of normal or early-infected individuals. Finally, the levels of IL-4
produced by human lymphocytes are about 10–20% of those generated by
immunologically challenged basophils (58).
IL-4 and IL-13 released from human FcRI+ cells
might also indirectly (i.e., through chemokine receptors) play a role
in the entry of HIV-1 into CD4+ cells. The
chemokine receptors CXCR4 and CCR5 are major coreceptors for HIV-1
entry into CD4+ T cells (38, 39, 40).
Up-regulation of CXCR4 by IL-4 (59) facilitates HIV-1
infection of T cells and might even be sufficient to trigger
CD4+ T cell depletion (60). IL-4 and
IL-13 trigger monocytes to produce the T cell chemoattractant protein-1
STCP-1 (or macrophage-derived chemokine), a chemokine selectively
active on CCR4 receptor expressed on TH2 cells
(61). These results evoke an amplification loop of
polarized TH2 responses based on induction of
chemokine receptors by gp120-stimulated IL-4 and IL-13 from basophils.
The latter observation is important because HIV-1 replicates
preferentially in TH2 rather than in
TH1 cells (17). In this context,
basophils may play a role since they can rapidly produce IL-4 and IL-13
in a restricted manner without synthesizing
TH1-type cytokines (e.g., IFN-).
We found that the FcRI+ cell-activating
property is well conserved in gp120 from divergent HIV isolates from
clades of different geographic locations. Consequently, conservation of
these VH3 binding sites of gp120 between viral
clades could be an important mechanism by which the virus can elude the
specific immune surveillance of the host.
Our previous in vitro (47, 52, 53) and in vivo
(54) studies demonstrated that immunophilin-binding drugs
(i.e., CsA and tacrolimus) exert anti-inflammatory effects by
inhibiting the IgE-dependent release of proinflammatory mediators from
human FcRI+ cells. In this study, we
demonstrate that CsA and tacrolimus concentration-dependently
inhibit also the gp120-induced release of cytokines from human
basophils. These findings imply that some of the effects exerted by
this class of anti-inflammatory/immunosuppressive drugs on HIV-1
replication (62, 63) reflect their actions on IL-4
secretion from FcRI+ cells. T cells with a
TH2-oriented cytokine profile are more
susceptible to HIV-1 infection than are
TH1-oriented cells (17). This is due
to up-regulation of CXCR4 receptors induced by IL-4 on T cells
(59). The inhibitory effect of CsA and tacrolimus on IL-4
secretion from FcRI+ cells might be an
additional mechanism whereby this class of compounds exerts antiviral
activity (62, 63).
In conclusion, we provide the first evidence that gp120 from different
viral clades induces the release of IL-4 and IL-13 from human
FcRI+ cells. Because HIV-1 enters the body
predominantly through mucosal surfaces and because the early phases of
infection are associated with high levels of viremia, mast cells and
basophils can be exposed to shed or virus-bound gp120. This suggests
that FcRI+ cells might be a novel source of
TH2 cytokines, thus contributing to the
dysregulation of the immune system in HIV-1 infection. The latter
observation might reconcile the apparently conflicting results of
several investigators (12, 13, 16, 17, 18, 19, 20, 21). In fact, it
highlights the importance of a specific viral superantigen, gp120,
acting on cell types other than lymphocytes in the production of
TH2-like cytokines. This novel observation might
be relevant in the design of drugs selectively acting on
FcRI+ cells in the treatment of HIV-1-infected
subjects.
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Acknowledgments |
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RI+ cells in
HIV-1 infection. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Gianni Marone, Division of Clinical Immunology and Allergy, University of Naples Federico II, Via S. Pansini 5, 80131 Napoli, Italy. E-mail address:
3 Abbreviations used in this paper: anti-FcRI, monoclonal Ab anti--chain of high-affinity receptor for IgE; gp, glycoprotein; CsA, cyclosporin A; ICS, internal calibration standard.
Received for publication August 27, 1999. Accepted for publication October 25, 1999.
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RI+ cells through interaction with the VH3 Region of IgE. J. Immunol. 161:5647.RI+ cells. J. Immunol. 146:2374.[Abstract]
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A. de Paulis, G. Florio, N. Prevete, M. Triggiani, I. Fiorentino, A. Genovese, and G. Marone HIV-1 Envelope gp41 Peptides Promote Migration of Human Fc{epsilon}RI+ Cells and Inhibit IL-13 Synthesis Through Interaction with Formyl Peptide Receptors J. Immunol., October 15, 2002; 169(8): 4559 - 4567. [Abstract] [Full Text] [PDF]
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Y. Yang, L. Li, G. W. Wong, S. A. Krilis, M. S. Madhusudhan, A. Sali, and R. L. Stevens RasGRP4, a New Mast Cell-restricted Ras Guanine Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding Motifs. IDENTIFICATION OF DEFECTIVE VARIANTS OF THIS SIGNALING PROTEIN IN ASTHMA, MASTOCYTOSIS, AND MAST CELL LEUKEMIA PATIENTS AND DEMONSTRATION OF THE IMPORTANCE OF RasGRP4 IN MAST CELL DEVELOPMENT AND FUNCTION J. Biol. Chem., July 5, 2002; 277(28): 25756 - 25774. [Abstract] [Full Text] [PDF]
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 T. H. Mogensen and S. R. Paludan Molecular Pathways in Virus-Induced Cytokine Production Microbiol. Mol. Biol. Rev., March 1, 2001; 65(1): 131 - 150. [Abstract] [Full Text] [PDF]
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A. de Paulis, R. De Palma, L. Di Gioia, M. Carfora, N. Prevete, G. Tosi, R. S. Accolla, and G. Marone Tat Protein Is an HIV-1-Encoded {beta}-Chemokine Homolog That Promotes Migration and Up-Regulates CCR3 Expression on Human Fc{epsilon}RI+ Cells J. Immunol., December 15, 2000; 165(12): 7171 - 7179. [Abstract] [Full Text] [PDF]
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F. H. Falcone, H. Haas, and B. F. Gibbs The human basophil: a new appreciation of its role in immune responses Blood, December 15, 2000; 96(13): 4028 - 4038. [Full Text] [PDF]
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