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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3721-3729
Possible Role of Interleukin-10 (IL-10) and CD40 Ligand Expression in
the Pathogenesis of Hypergammaglobulinemia in Human Immunodeficiency
Virus Infection: Modulation of IL-10 and Ig Production After
Intravenous Ig Infusion
By
Fredrik Müller,
Pål Aukrust,
Ingvild Nordøy, and
Stig S. Frøland
From the Section of Clinical Immunology and Infectious Diseases,
Medical Department A and Research Institute for Internal Medicine,
University of Oslo, The National Hospital, Rikshospitalet, Oslo,
Norway.
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ABSTRACT |
The mechanisms leading to polyclonal hypergammaglobulinemia in
patients with human immunodeficiency virus (HIV) infection are not well
understood. In light of the important role of interleukin-10 (IL-10)
and the interaction between CD40 and CD40 ligand in the normal
regulation of B-lymphocyte function and Ig production, we examined
these parameters in 24 HIV-infected patients. Both plasma IL-10 levels
and the percentage of CD4+ and CD8+
lymphocytes expressing CD40 ligand were significantly higher in the
patients than in the 10 blood donor controls. Serum IgG correlated
positively with circulating IL-10 levels and the percentage of
CD4+ lymphocytes expressing CD40 ligand. Furthermore, a
single bolus infusion of intravenous Ig (0.4 g/kg) in 8 HIV-infected
patients caused a further increase in IL-10 levels in plasma and an
increase in both IL-10 and IgG production in peripheral blood
mononuclear cell cultures. In another patient group (Wegener's
granulomatosis) receiving a single bolus infusion of intravenous Ig, a
similar increase in plasma IL-10 levels was found, suggesting that this may be a general effect of intravenous Ig. In patients with HIV infection, our data suggest that a vicious cycle may be operative where
high endogenous Ig levels may enhance IL-10 production that, in turn,
leads to higher Ig production.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
MOST PATIENTS WITH human immunodeficiency
virus (HIV) infection have elevated serum Ig levels.1-3 The
hypergammaglobulinemia is usually polyclonal and comprises
several Ig isotypes.2-5 Although several studies over the
years have addressed the issue,6-12 the mechanisms leading
to hypergammaglobulinemia in HIV infection are still not well
understood. Central to the normal B-lymphocyte activation and Ig
production is a regulated interaction between CD40 ligand (CD40L; also
named glycoprotein 39 or CD154) on activated T lymphocytes and CD40 on
B lymphocytes.13 Also, interleukin-10 (IL-10) is important
for the regulation of Ig production as a switch factor for IgG during
B-lymphocyte maturation promoting plasma cell differentiation and
secretion of IgG, IgM, and IgA.14-18 So far, these aspects
have not been thoroughly investigated in patients with HIV infection.
In contrast to the hypergammaglobulinemia, in vitro B-lymphocyte
responses to mitogens and antigens in vitro as well as in vivo
responses to immunization are impaired in HIV-infected
patients.1,19-21 To try to compensate for this B-lymphocyte
deficiency, intravenous Ig (IVIg) preparations have been administered
to HIV-infected patients in several studies. IVIg has been shown to
benefit HIV-infected children with recurrent bacterial
infections.22-24 In adults, data are discrepant regarding
the effects of IVIg on infectious complications and
mortality24-26 (and references therein). Any beneficial
effects of IVIg therapy in HIV infection may be due both to
antimicrobial effects of the passively transferred polyclonal Igs and
to immunomodulatory effects of IVIg preparations on pathophysiological
processes27-29 leading to enhanced antimicrobial immunity.
The aims of the study were to examine CD40L expression and IL-10
production in relation to Ig production in patients with HIV infection
and to study the immunomodulatory effects of a single infusion of IVIg
on the B-lymphocyte system in patients with HIV infection,
with special emphasis on Ig secretion, CD40L expression, and IL-10
production.
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MATERIALS AND METHODS |
Patients.
Twenty-four HIV-seropositive patients were included in the study (21 men and 3 women; median age, 41 years; age range, 22 to 58 years).
Clinically, 11 patients were classified as asymptomatic (Centers for
Disease Control and Prevention [CDC] group A) and 1 patient as
symptomatic (CDC group B), whereas 12 patients were classified
as CDC group C (acquired immunodeficiency syndrome [AIDS]).30 Because of the immunological similarities
between patients in groups CDC A and B, they are analyzed together in the following. At the time of blood sampling, 2 patients were treated
for Mycobacterium avium infection, 3 patients were treated for
cytomegalovirus retinitis, and 1 patient was treated for visceral leishmaniasis. Three patients had Kaposi's sarcoma. Eleven patients received antiretroviral therapy (5 zidovudine [ZDV], 1 didanosine, 1 ZDV + lamivudine [3TC], 1 ZDV + 3TC + ritonavir, 1 ZDV + 3TC + saquinavir, 1 ZDV + 3TC + indinavir, and 1 ZDV + stavudine + indinavir). However, they had not initiated therapy or changed dosage
regimen during the last 3 months.
Controls were 10 healthy, volunteer, HIV-seronegative blood donors (7 men and 3 women; median age, 39 years; age range, 23 to 59 years).
Eight of the HIV-seropositive patients (6 men and 2 women; median age,
32 years; age range, 25 to 52 years; all in CDC group A) participated
in an Octagam (Octapharma, Vienna, Austria) IVIg study as detailed
below. Patients with CD4+ lymphocyte counts in peripheral
blood between 150 and 400 × 106/L during the last
year were included in the IVIg study. No patients had shown any signs
of overt infection during the last 2 months before the study. At the
time of the study, 2 patients received ZDV, whereas none was receiving
immunosuppressive drugs. At the time of the study, the serum level of
alanine aminotransferase was less than 40 U/L and the serum creatinine
level was less than 70 µmol/L in all patients.
Also, 7 patients with Wegener's granulomatosis (median age, 35 years;
age range, 23 to 66 years) who all had received a single bolus infusion
of IVIg (Octagam; 0.4 g/kg) were examined. Blood samples were taken
preinfusion and postinfusion at 20 and 44 hours.
IVIg study design.
The IVIg study was part of an Octagam tolerance study performed in our
department as previously reported.31 All patients received
a single infusion of Octagam (0.4 g/kg). Blood samples were taken
preinfusion and postinfusion at 1, 20, 44, and 144 hours (6 days). The
study was approved by the Regional Ethical Comitee and by the Norwegian
Medicines Control Authority. Signed informed consent was obtained from
all participants.
Ig preparation.
Octagam is a liquid virus-inactivated IVIg preparation (pH 4) produced
from fresh frozen plasma collected in Norwegian blood banks. The final
product is dispensed in sterile water containing 10% maltose (final
IgG concentration, 50 g/L; final IgA and IgM concentrations, <0.1
g/L). Each portion has been tested and found negative for
antibodies to HIV-1 and HIV-2 and hepatitis B and C virus. The
endotoxin level in the IVIg preparation was less than 10 pg/mL
(Quantitative chromogenic limulus amebocyte lysate test; BioWhittaker,
Inc, Walkersville, MD). The IL-10 concentration in Octagam was 5.8 pg/mL, as determined by the high-sensitivity enzyme-linked
immunosorbent assay (ELISA; see below).
Blood sampling protocol.
Blood was drawn into sterile pyrogen-free vacuum blood collection tubes
(Becton Dickinson, San Jose, CA) using EDTA as anticoagulant. Blood was
immediately immersed in melting ice and the tubes were centrifuged
within 10 minutes (600g and 4°C for 10 minutes). Plasma was
then transferred to sterile Eppendorf tubes (Treff AG, Degersheim, Switzerland) and further centrifuged at 10,000g and 4°C to
obtain platelet-free plasma. Plasma was stored at  80°C in
multiple aliquots until analysis. Samples were frozen and thawed only
once.
Isolation and stimulation of cells.
Peripheral blood mononuclear cells (PBMCs) were obtained from
heparinized blood by Isopaque-Ficoll (Lymphoprep; Nycomed Pharma AS,
Oslo, Norway) gradient centrifugation within 45 minutes after blood
sampling, as previously described.32 The fractions of monocytes (CD14+) and lymphocyte subsets (CD4+,
CD8+, CD19+) in the isolated PBMCs were
determined by immunomagnetic quantification.33 The
endotoxin level in the culture medium was less than 10 pg/mL (Quantitative limulus amebocyte lysate test; BioWhittaker).
For positive selection of B lymphocytes, monodisperse immunomagnetic
beads coated with anti-CD19 antibody (Dynal, Oslo, Norway) were added
to PBMCs in a cell-to-bead ratio of 1:5 and incubated on a
Rock-N-Roller (Labenco, Breda, The Netherlands) platform at 4°C for
30 minutes and rosetted cells were isolated by application of a
samarium cobalt magnet (Dynal). To enable detachment of beads from B
lymphocytes, sheep antimouse Fab (Detach-a-bead-CD19; Dynal) was added
and the cells were incubated for 1 hour at room temperature on a sample
mixer (Dynal).
The purity of the B lymphocytes was greater than 98% as assessed by
staining of cytospins of positively selected cells by a panel of
monoclonal antibodies as previously described.34 To examine
the effect of non-B-lymphocyte factors on a constant number of B
lymphocytes, we used a constant number of B cells in purified and mixed
(PBMC) cultures. Thus, 125,000 B lymphocytes/mL or PBMCs containing
125,000 B lymphocytes/mL were cultured in RPMI 1640 with 2 mmol/L
L-glutamine and 25 mmol/L HEPES buffer (GIBCO BRL, Paisley, UK)
supplemented with 10% fetal calf serum (Myoclone; GIBCO) in
triplicates (0.2 mL/well) in 96-well plates (Costar, Cambridge, MA) and
stimulated by anti-CD40 antibody (clone EA-5; 2 µg/mL; Ancell Corp,
Bayport, MN) or left unstimulated. After 7 days, supernatants were
harvested and frozen at 20°C in aliquots until Ig analysis.
Quantification of IL-10.
IL-10 in plasma was quantified by ELISA (IL-10 high-sensitivity ELISA;
R&D Systems, Minneapolis, MN). IL-10 in cell culture supernatants was
assayed by ELISA (reagents were kindly provided by Dr S. Narula,
Schering-Plough Research Institute, Kenilworth, NJ) as described
elsewhere.35 The limit of detection was 0.7 pg/mL and 5 pg/mL for the high-sensitivity IL-10 (R&D) and IL-10 immunoassays,
respectively. Intra-assay and interassay coefficients of variation were
less than 10% for both assays.
Quantification of Igs in cell culture supernatants.
Igs in cell culture supernatants from 8 HIV-infected patients (those
who participated in the Octagam study; all in CDC stage A), 10 blood
donor controls, and 2 patients with Wegener's granulomatosis were
quantified by ELISA as described previously for IgA and
IgM,36 with some modifications. Briefly, polystyrene
microplates (Costar) were coated overnight with rabbit antihuman IgG,
IgA, or IgM (Dako, Glostrup, Denmark; catalogue no. A423, A262, and
A425, respectively, all at 1 µg/mL in phosphate-buffered saline
[PBS; GIBCO]). This and all subsequent incubations were performed at
room temperature on a shaker. Plates were blocked with bovine serum
albumin (BSA; Behringwerke, Marburg, Germany) at 5 g/L in 0.01 mol/L
PBS for 90 minutes. Between each of the remaining incubations, which
all included BSA (5 g/L) and Tween 20 (0.1%), plates were washed four times with isotonic saline containing 0.1% Tween 20. After application of standards (IgG, IgA, and IgM from plasma; Calbiochem, La Jolla, CA)
and appropriate dilutions of samples in triplicates, the following monoclonal antibodies (courtesy of T. Lea, Institute of Immunology and
Rheumatology, The National Hospital, Oslo, Norway) were added for 90 minutes (anti-IgG, ascites, 1/250,000, clone B7B2; anti-IgA, ascites,
1/100,000, clone DE2C1; and anti-IgM, ascites, 1/500,000, clone IIE2).
Plates were then incubated with alkaline-phosphatase-conjugated rabbit antimouse Igs (Dako; catalogue no. D314; 1/1,500) for 90 minutes
and subsequently with substrate (1 mg/mL p-nitrophenyl sodium
phosphate [Sigma, St Louis, MO] in diethanolamine buffer; pH
9.8). Optical density was measured at 405 nm (Labsystems
Multiskan RC; Labsystems, Helsinki, Finland).
IgG2 in cell culture supernatants was quantified by ELISA (The Binding
Site, Birmingham, UK) according to the manufacturer's guidelines.
The limits of detection were 3 ng/mL for IgG and IgM and 4 ng/mL for
IgA and IgG2, respectively. The intra-assay and interassay coefficients of variation were less than 8% for the IgG, IgA, and IgM
assays and less than 12% for the IgG2 ELISA. All samples from each
patient were measured in the same ELISA plate.
Quantification of serum Ig.
IgA, IgG, and IgM in serum were determined by a nephelometric assay in
relation to a commercial standard (Behringwerke).
Cryopreservation of PBMCs.
Immediately after isolation, aliquots of PBMCs were cryopreserved and
stored in liquid nitrogen for up to 8 months as described in detail
elsewhere.37 The cell viability of thawed cells exceeded 98% as determined by acridine orange (Sigma) and ethidium bromide (Sigma) staining.32
Immunofluorescence staining and flow cytometry.
After thawing of cryopreserved PBMCs, 5 × 105 cells
were washed once in PBS with 2% BSA and 0.1% sodium azide (washing
buffer) and preincubated in PBS with human IgG (Octagam; 5 g/L), 5%
mouse serum (Sigma), 2% BSA (Calbiochem), and 0.1% sodium azide
(Sigma) for 15 minutes at room temperature. Cells were washed twice in washing buffer and incubated for 30 minutes at +4°C with monoclonal antibody conjugates. The following antibodies were used for staining: anti-CD3 (clone SK7) phycoerythrin (PE), anti-CD4 (clone SK3) peridinin
chlorophyll protein (PerCP), anti-CD19 (clone 4G7) fluorescein isothiocyanate (FITC), anti-CD8 (clone SK1) PerCP (all from Becton Dickinson); anti-CD40 (clone EA-5) PE, and anti-CD40L (clone 24-31) FITC (both from Ancell). Isotype matched FITC- , PE- (Pharmingen, San
Diego, CA), and PerCP- (Becton Dickinson) conjugated mouse IgGs were
used as negative controls. Calibrated setup of the FACScan flow
cytometer (Becton Dickinson) was performed using CaliBRITE beads (FITC,
PE, and PerCP-conjugated; Becton Dickinson) and AutoCOMP software
(Becton Dickinson). Ten thousand cells were acquired and analyzed by
CellQuest software (Becton Dickinson). B-lymphocyte, CD4+
lymphocyte, and CD8+ lymphocyte gates were set on
two-parameter plots of side scatter versus CD19 (FL1), CD3 (FL2) versus
CD4 (FL3), and CD3 (FL2) versus CD8 (FL3), respectively, and the
percentages of CD40+ B lymphocytes and CD40L+
CD4+ and CD8+ lymphocytes were determined.
Statistical analysis.
For each parameter, patients and controls were compared by the
Mann-Whitney U test, whereas preinfusion and postinfusion values in the
patients were compared by the Wilcoxon matched pairs test. Coefficients
of correlation (r) were calculated by the Spearman rank test.
The calculations were performed using the STATISTICA (StatSoft, Tulsa,
OK) software package. Data are given as medians and 25th to 75th
percentiles, if not otherwise stated. P values are two-sided
and considered significant when P < .05.
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RESULTS |
Serum Ig levels.
Both patients in CDC group A/B and group C had significantly increased
serum levels of both IgG and IgA compared with controls, whereas
elevated IgM levels were restricted to patients in CDC group A/B
(Table 1).
Ig production in cell culture.
Ig production in vitro was assessed in cell cultures from 8 HIV-infected patients (those who participated in the IVIg infusion study; all in CDC stage A) and 10 controls. Unstimulated PBMC cultures
from HIV-infected patients had a significantly higher production of
both IgG (~200% increase) and IgA (~480% increase) compared with
PBMC cultures from healthy controls (Table
2). Also, the IgM production tended to be higher in PBMC cultures from
HIV-infected patients compared with control cultures (~90% increase;
P = .06) as shown in Table 2. Enhanced Ig production was seen
both in patient and control cultures after stimulation with anti-CD40
antibody, except for IgM synthesis in control cultures (Table 2). When
the ratios between anti-CD40 stimulated and unstimulated production of
IgG, IgA, and IgM were calculated, no significant differences were
noted when patient and control cultures were compared, as shown in
Table 2.
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Table 2.
Unstimulated and Anti-CD40-Stimulated IgG, IgA, and IgM
Levels in PBMCs and Purified B-Lymphocyte Culture Supernatants From 8 Patients With HIV Infection (All in Clinical Stage CDC A) and From 10 HIV-Seronegative Blood Donors
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In purified B-lymphocyte cultures from HIV-infected patients,
anti-CD40-stimulated production of IgG was significantly higher (~50% increase) compared with the control cultures (Table 2). In
contrast, IgA and IgM production remained low after anti-CD40 stimulation in both patient and control cultures (Table 2). Low levels
of all three Ig isotypes were found in unstimulated B-lymphocyte cultures from both patients and controls (Table 2).
T-lymphocyte membrane expression of CD40L.
A significantly higher percentage of both CD4+ and
CD8+ lymphocytes from HIV-seropositive patients expressed
CD40L compared with CD4+ and CD8+ lymphocytes
from controls (Table 3). When analyzed
separately, both CDC group A/B and group C patients had increased
percentages of CD40L+ CD4+ lymphocytes compared
with controls, with the highest percentage in CDC group C patients
(Table 3). Elevated percentages of CD40L+ CD8+
lymphocytes were restricted to the CDC group C patients, whereas the
CDC group A/B patients and controls had similar percentages of
CD40L+ CD8+ lymphocytes (Table 3). When
comparing patients in CDC group C with and without opportunistic
infections, no significant differences in the percentage of T
lymphocytes expressing CD40L were noted (data not shown).
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Table 3.
Plasma Levels of IL-10 and Expression of CD40L on
CD4+ and CD8+ T Lymphocytes From
HIV-Infected Patients and Controls
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B-lymphocyte membrane expression of CD40.
CD40 membrane expression was measured on B lymphocytes from 8 patients
(those participating in the IVIg study) and 10 controls. Almost all B
lymphocytes from patients and controls (>95%) expressed CD40.
However, as seen in Table 4, the mean
fluorescence intensity (MFI) of CD40 was approximately 20% higher on B
lymphocytes from patients compared with controls (P = .01).
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Table 4.
MFI of CD40 on B Lymphocytes From Controls
(n = 10) and HIV Patients Before and 1, 20, 44, and 144 Hours
After IVIG Infusion (n = 8)
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IL-10 in plasma.
Circulating IL-10 was significantly higher in the HIV-infected patients
compared with controls, as shown in Table 3. Although patients in CDC
group C tended to have higher IL-10 levels than patients in CDC group
A/B, this difference was not significant (P = .12). Patients in
CDC group C with opportunistic infections did not have higher IL-10
levels than those without ongoing infections (data not shown).
In patients with Wegener's granulomatosis, the median plasma IL-10
concentration was 4.7 pg/mL (range, 2.0 to 4.9 pg/mL), which was
significantly higher than in the controls (P < .001).
Association between serum Igs, IL-10, and T lymphocyte CD40L
expression.
Because both IL-10 and the interaction between CD40 on B lymphocytes
and CD40L on T lymphocytes have been associated with enhanced Ig
production in vitro, we examined the relationship between these
parameters among the HIV-seropositive patients. Significant, positive
correlations were found between serum IgG on one hand and circulating
IL-10 and CD40L expression on CD4+ lymphocytes on the other
hand, as shown in Fig 1. No significant correlation was found between serum IgG and CD40L expression on CD8+ lymphocytes (r = .27; P = .24). The
correlation coefficients between serum IgA and CD40L expression on
CD4+ and CD8+ lymphocytes were .41 (P = .08) and .56 (P = .01), respectively. No significant
correlations were found between serum IgA and IL-10 (r = .04),
between serum IgM and IL-10 (r = .14), or between IgM and CD40L
expression on CD4+ or CD8+ lymphocytes
(r = .12 and r = .19, respectively).
Effect of IVIg infusion on plasma IL-10 concentrations.
A significant increase in circulating IL-10 levels after IVIg infusion
was observed in patients with HIV infection, as shown in
Fig 2.
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| Fig 2.
Effect of a single bolus infusion (0.4 g/kg) of IVIg on
plasma IL-10 levels in 8 patients with HIV infection. IL-10 was assayed
by ELISA. Data are given as medians and 25th and 75th percentiles.
*P < .05 versus levels before infusion (0 hours).
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In patients with Wegener's granulomatosis, a similar effect was
observed as plasma IL-10 levels increased from 4.7 pg/mL (2.0 to 4.9 pg/mL) preinfusion to 7.5 pg/mL (4.1 to 7.8 pg/mL) 20 hours after
infusion (P = .02 v preinfusion) and to 7.0 pg/mL (3.5 to 8.3 pg/mL) 44 hours after infusion (P = .03 v
preinfusion).
Effect of IVIg infusion on IL-10 production in mononuclear cells from
HIV patients.
When PBMCs from the patients before and after IVIg infusion were
cultured for 7 days and left unstimulated or stimulated with anti-CD40
antibody during culture, the IL-10 concentration in PBMC supernatants
was significantly higher after IVIg infusion with a maximum after 44 hours (~9-fold increase compared with preinfusion levels), as shown
in Fig 3A and B. However, the profile of
IL-10 production after IVIg infusion was similar in unstimulated and
anti-CD40 stimulated cultures.
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| Fig 3.
Effect of a single bolus infusion (0.4 g/kg) of IVIg on
IL-10 production in PBMCs from 8 patients with HIV infection. PBMCs
were prepared from blood samples taken at the indicated time points
before and after IVIg infusion and cultured without stimulation (A) or
with anti-CD40 monoclonal antibody (B). Supernatants were harvested
after 7 days and assayed for IL-10 by ELISA. Data are given as medians
and 25th and 75th percentiles. *P < .05 versus levels before
infusion (0 hours).
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In preliminary experiments, PBMC IL-10 production did not differ
significantly after 1, 2, and 7 days of culture (data not shown).
Effect of IVIg infusion on in vitro Ig production in mononuclear
cells.
Anti-CD40 stimulated IgG production in PBMCs from HIV-infected patients
increased to a maximum of 20 hours postinfusion (~1.5-fold increase
compared with preinfusion concentration; P < .05), whereas concentrations comparable to preinfusion levels were found in cultures
44 hours and 6 days postinfusion (Fig 4).
No significant differences were noted for preinfusion versus
postinfusion levels of anti-CD40-stimulated IgA or IgM or from
unstimulated IgG, IgA, or IgM (Fig 4). No significant changes were
noted for IgG2 production in PBMC cultures before and after IVIg
infusion (Fig 4).
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| Fig 4.
Effect of a single bolus infusion (0.4 g/kg) of IVIg on
IgG, IgG2, IgA, and IgM production in PBMC cultures from 8 patients
with HIV infection. PBMCs were prepared from blood samples taken at the
indicated time points before and after IVIg infusion and cultured
without stimulation (left panels) or stimulated with anti-CD40
monoclonal antibody (right panels). Supernatants were harvested after 7 days and assayed for Igs by ELISA. Data are given as medians
and 25th and 75th percentiles. *P < .05 versus levels
before infusion (0 hours).
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In unstimulated PBMC cultures from 2 patients with Wegener's
granulomatosis, IgG levels were 2,200 and 1,500 ng/mL (preinfusion) and
2,500 and 2,100 ng/mL (20 hours postinfusion). In anti-CD40-stimulated cultures, IgG levels were 4,300 and 3,300 ng/mL (preinfusion) and 4,600 and 2,900 ng/mL (20 hours postinfusion).
Effect of IVIg infusion on in vitro Ig production in B lymphocytes
from HIV patients.
Ig production in unstimulated B lymphocytes increased from preinfusion
levels to a maximum at 44 hours postinfusion; from 2 ng/mL (0 to 7 ng/mL) to 156 ng/mL (32 to 187 ng/mL) for IgG, from 6 ng/mL (0 to 18 ng/mL) to 56 ng/mL (44 to 146 ng/mL) for IgA, and from 0 ng/mL (0 to 4 ng/mL) to 13 ng/mL (8 to 21 ng/mL) for IgM
(Fig 5). No significant alterations in
anti-CD40 stimulated Ig production were noted (Fig 5).
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| Fig 5.
Effect of a single bolus infusion (0.4 g/kg) of IVIg on
IgG, IgA, and IgM production in purified B-lymphocyte cultures from 8 patients with HIV infection. B lymphocytes were prepared from blood
samples taken at the indicated time points before and after IVIg
infusion and cultured without stimulation (left panels) or stimulated
with anti-CD40 monoclonal antibody (right panels). Supernatants were
harvested after 7 days and assayed for Igs by ELISA. Data are given as
medians and 25th and 75th percentiles. *P < .05 versus levels
before infusion (0 hours).
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Igs in serum from HIV patients after IVIg infusion.
The serum IgG level increased from 17.3 g/L (14.8 to 20.0 g/L)
preinfusion to a maximum of 23.8 g/L (21.7 to 25.7 g/L) 1 hour after
IVIg infusion; thereafter, a gradual decrease was seen, with a serum
IgG level of 19.7 g/L (17.2 to 22.7 g/L) after 6 days. No changes in
serum IgA or IgM concentrations were seen after IVIg infusion (data not
shown).
Expression of CD40L and CD40 on lymphocytes from HIV patients after
IVIg infusion.
No significant changes in CD40L expression on CD4+ or
CD8+ lymphocytes was observed after IVIg infusion (data not
shown). CD40 expression on B lymphocytes was always greater than 95%.
The CD40 MFI on B lymphocytes did not change from preinfusion till 44 hours postinfusion, whereas the MFI was significantly reduced at
6 days postinfusion compared with the preinfusion levels
(Table 4).
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DISCUSSION |
One of the first immunological abnormalities observed in patients with
HIV infection was the elevation of circulating Ig levels, often
comprising several isotypes.1-5 Previous in vitro studies have suggested various mechanisms contributing to the
hypergammaglobulinemia and B-lymphocyte activation in HIV infection,
such as stimulation by HIV, HIV viral proteins, IL-6, or membrane-bound
tumor necrosis factor- (TNF-) on CD4+
lymphocytes.6,9-12,38 However, the mechanisms leading to
hypergammaglobulinemia in HIV infection are still not well
understood.6-12 In the present study, we found a
significant correlation between serum Ig levels and both the percentage
of CD4+ lymphocytes expressing CD40L and plasma IL-10
levels.
Although our data do not, of course, prove that there is a causal
relationship between the increased Ig production and dysregulation in
T-lymphocyte CD40L expression or IL-10 metabolism in HIV infection, our
findings are of particular interest in relation to present concepts of
B-lymphocyte regulation and Ig secretion. Furthermore, the data suggest
that an increased percentage of CD4+ lymphocytes expressing
CD40L and enhanced IL-10 activity are involved in the
hypergammaglobulinemia during HIV infection.
The present study is, to our knowledge, the first report of increased
percentages of CD40L expression on T lymphocytes from patients with HIV
infection. Among the receptor-ligand pairs that are important for
contact-dependent T-B-lymphocyte collaboration, the CD40-CD40L
interaction plays a central role.13 CD40L is a member of
the TNF gene superfamily,13 and its importance in vivo for
normal Ig secretion was shown by studies of patients with hyper-IgM
syndrome having high serum levels of IgM but severely reduced levels of
other isotypes due to mutations in the gene coding for
CD40L.39 Mice infected with a murine retrovirus causing murine AIDS develop hypergammaglobulinema and treatment with anti-CD40L reduced their elevated Ig levels.40 Brugnoni et
al41 have previously shown that, after optimal in vitro
stimulation, CD40L expression of T lymphocytes was not impaired in
patients with HIV infection. However, they did not study CD40L
expression in unstimulated cells.41 On the other hand,
Macchia et al38 did not find CD40L expression on
T-lymphocyte clones that had been HIV-infected in vitro. However, this
experimental in vitro system does not permit the important interplay
between various cell types leading to in vivo immune activation that is
probably central to the immunopathogenesis of HIV
infection.42,43 Our findings of an elevated percentage of T
lymphocytes expressing CD40L may well be a manifestation of this immune
activation. However, when patients in CDC group C with and without
ongoing opportunistic infections were compared, no difference in the
percentage of T lymphocytes expressing CD40L was noted.
IL-10 is important for the regulation of Ig production, because it is a
switch factor for IgG during B-lymphocyte maturation and promotes
plasma cell differentiation and secretion of IgG, IgM, and
IgA.14-18 With regard to IgG, IL-10 promotes a selective secretion of IgG1 and IgG3, but not of IgG2 or IgG4.14
Interestingly, the IgG subclass pattern seen in patients with HIV
infection is characterized by the same IgG subclass dysbalance both in
serum4,44,45 and lymphoid tissue.44 We suggest
that the elevated IL-10 levels found in HIV-infected patients may be of
importance for their elevated Ig secretion. Elevated IL-10 levels or
enhanced cellular production of IL-10 in HIV infection have been
reported previously.46-52 In vitro, both HIV
infection53-55 and stimulation with HIV viral proteins48,56 or mycobacterial proteins35,57
lead to enhanced IL-10 production. However, in our study, patients in
CDC group C with opportunistic infections did not have higher IL-10
levels than those without ongoing infections.
IVIg treatment has been used in HIV-infected patients to strengthen the
antibody defense against bacterial pathogens.22-24,26 The
present study demonstrates that a single IVIg infusion in vivo not only
results in elevated serum level of IgG, but also induces a further
enhancement of the patients own IgG production as studied in vitro.
However, the enhanced IgG production did not comprise IgG2, which may
be of importance for the immunity to bacterial infections in
HIV-infected patients.58
Also, a marked increase in IL-10 levels, both in plasma and
anti-CD40-stimulated PBMC supernatants, was observed after IVIg infusion. Previously, IVIg has been suggested to have immunosuppressive effects by increasing the level of IL-1 receptor
antagonist27,59 and downregulating the TNF
system.31,60,61 In particular, we have shown elsewhere that
IVIg infusion in HIV-infected patients with abnormally increased
TNF- activity leads to a downregulation of the TNF
system.31 However, this is the first report of increased levels of IL-10 after IVIg infusion. In addition to the effect in HIV
infection, we show a similar effect of IVIg on IL-10 levels in patients
with Wegener's granulomatosis. This may suggest that the ability to
increase IL-10 levels is a general IVIg effect. Thus, it may be a
contributory factor to the beneficial effects of IVIg in various
inflammatory and autoimmune disorders.62,63
The IVIg preparation contained a low amount of IL-10 that may have
contributed to the elevation of plasma IL-10 briefly after infusion.
However, administration of IL-10 has shown that this molecule has a
short half-life of 2 to 4 hours.64,65 Thus, the
persistently high IL-10 levels over several days cannot be due to
passive transfer of IL-10. Also, the upregulated IL-10 production in
PBMC culture after IVIg infusion in HIV-infected patients suggests that
IVIg induces IL-10 production.
In the present study, the enhanced IL-10 production in PBMC
supernatants after IVIg infusion probably contributed to the elevated Ig levels in the same cultures.
This raises the possibility of a vicious circle in HIV infection in
which high IL-10 levels lead to enhanced IgG production that, in turn,
further upregulates IL-10 production. However, IL-10 production was not
dependent on CD40 stimulation. Several cell types may contribute to the
IL-10 production in the PBMC cultures, because both T lymphocytes, B
lymphocytes, and monocytes have been shown to produce
IL-10.66-68
In conclusion, our findings of increased percentages of T lymphocytes
expressing CD40L and elevated circulating IL-10 levels may well be of
importance for the enhanced Ig production and hypergammaglobulinemia seen in HIV-infected patients. In line with these findings, a single
bolus of IVIg administered to HIV-infected patients leads to elevated
levels of IL-10 in vivo and in vitro, with a concomitant elevation of
Ig production in cell cultures.
We suggest that the enhanced production of IL-10 as well as increased
expression of CD40L on T lymphocytes may be important factors for the
development of hypergammaglobulinemia in patients with HIV infection.
| |
ACKNOWLEDGMENT |
The authors thank Bodil Lunden and Lisbeth Wikeby for excellent
technical assistance and Tor Lea (Institute of Immunology and
Rheumatology, The National Hospital) for the monoclonal antibodies to
IgA, IgG, and IgM. Recombinant IL-10 and IL-10 antibodies were kindly
provided by S. Narula (Schering-Plough Research Institute).
| |
FOOTNOTES |
Submitted January 27, 1998;
accepted June 30, 1998.
Supported by Octapharma, Hurdal, Norway; the Norwegian Research
Council; the Norwegian Cancer Society; Medinnova Foundation; Anders
Jahre's Foundation; and Odd Kåre Rabben's Memorial Fund for AIDS
research.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Fredrik Müller, MD, PhD, Section of
Clinical Immunology and Infectious Diseases, Medical Department A and
Research Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo,
Norway.
| |
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Abstract
Introduction
