|
May 2002
Hepatitis C virus
inhibition of T-lymphocyte response
Hepatitis C infection is a serious and growing public health problem,
with approximately 4 million cases in the United States alone. Hepatitis
C virus evades effective immune recognition and shows an extremely
high rate of viral persistence in the infected individual—more
than 90 percent, versus 10 percent for hepatitis B. The typical subclinical
phase may last 10 to 20 years, after which HCV infection may progress
to end-stage liver disease and is also highly correlated with the
development of hepatocellular carcinoma and autoimmune disease. An
intrinsically high rate of mutation in the RNA genome of HCV and variability
in the envelope protein likely contribute to the ineffective antibody
response against the virus. T-lymphocyte responses to HCV gene products
have been demonstrated, but the role of these responses in controlling
the infection are not well defined. HCV replication persists in hepatocytes
of patients with the infection, although lymphocytic infiltration
is detectable in the livers of these patients. Lack of an animal model
had been a major difficulty in addressing the mechanism of viral persistence
and viral replication with respect to host immune responses in HCV.
The authors developed a murine model to examine the influence of specific
HCV proteins on viral-antigen recognition and viral clearance. In
this way, they demonstrated that expression of HCV structural or nonstructural
proteins using recombinant vaccinia or Sindbis virus resulted in vigorous
T-lymphocyte responses and nonlethal infections with rapid viral clearance.
On the other hand, hepatitis C core protein suppresses protective
immune responses, such as the antiviral cytotoxic T-lymphocyte response.
This immunomodulatory role of core protein may play a critical role
in the pathogenesis of hepatitis C viral infection in conjunction
with identifying circulating naked core protein in the plasma of those
infected with HCV. The authors have screened a human leukocyte cDNA
library using a yeast two-hybrid system to identify host proteins
with which core can interact. One-quarter of the clones identified
encoded the p33gC1q receptor specific for the globular heads of the
complement C1q protein. In the current study, the authors described
the identification of the core binding to the gC1qR and have undertaken
a comprehensive analysis of the interaction as well as the effect
of the core on T-cell responsiveness. Like C1q, HCV core can inhibit
T-cell proliferative responses in vitro. This HCV core-induced anti-T-cell
proliferation is reversed by adding anti-gC1qR antibody in a T-cell
proliferation assay. Furthermore, the authors determined that HCV
core binds the region spanning amino acids 188 to 259 of gC1qR, which
is a site distinct from the binding region of C1q.
Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, et al. Interaction
between complement receptor gC1qR and hepatitis C virus core protein
inhibits T-lymphocyte proliferation. J Clin Invest. 2000;106:1239-1249.
Reprints: Young S. Hahn, Box 801386, University of Virginia Health
Sciences Center, Charlottesville, VA 22908; ysh5E@virginia.edu
Use of fractalkine
and its receptor in cardiac allograft rejection
Acute allograft rejection is characterized by a vigorous cellular
immune response with an influx of circulating leukocytes into the
transplant. Activated immune cells accumulate in the allograft, which
is essential to the pathogenesis of tissue injury. Recruiting leukocytes
into sites of inflammation involves a tightly regulated series of
molecular interactions that includes capture and rolling of cells
mediated by selectins followed by fixation on the endothelium, which
is a process mediated by the integrins. During these events, the leukocytes
become activated through stimulation of G protein-coupled chemokine
receptors, resulting in enhanced integrin adhesiveness and activation-dependent
stable arrest. The recruitment process culminates in diapedesis across
the endothelium and migration into the inflamed tissue. In rejection,
the expression of various adhesion molecules, such as ICAM-1 and E-selectin,
are up-regulated, but the functional importance of this has not been
well established. Although an expression of a variety of chemokines
has been demonstrated in rejecting transplants, their contribution
to the pathogenesis of rejection is not clear. The human chemokine
fractalkine (FKN) and its murine homologue neurotactin recently have
been identified as novel chemokines with unique transmembrane chemokine/mucin
hybrid structures. FKN promotes leukocyte activation and, unlike other
chemokines, can mediate each step of the leukocyte adhesion cascade.
FKN interacts with its unique receptor, CX3CR1, to affect
firm adhesion of resting monocytes, resting and activated CD8+ T lymphocytes,
and activated NK cells. The authors postulated that FKN may play a
functional role in allograft rejection and tested this hypothesis
using mouse models. They demonstrated that FKN expression is enhanced
in rejecting mouse cardiac allografts and that enhanced FKN expression
on activated mouse endothelial cells promotes increased leukocyte
adhesion. They also found that inhibition of FKN-CX3CR1
signaling with an anti-CX3CR1 Ab significantly prolongs
survival of the cardiac allografts in mice. At early time points,
the FKN expression was particularly prominent on the endothelium and
vascular tissues. As rejection progressed, FKN expression was increased,
with prominent anti-FKN staining seen around vessels and on cardiac
myocytes. To determine the capacity of FKN on endothelial cells to
promote leukocyte adhesion, the authors performed adhesion assays
with PBMC and monolayers of TNF-a activated murine endothelial cells
under low shear conditions. They found the treatment with anti-FKN
or anti-CX3CR1-blocking Ab significantly inhibited PBMC binding, indicating
that a large proportion of leukocyte binding to murine endothelium
occurs via these receptors. Treatment of murine cardiac allograft
recipients with daily injections of anti-CX3CR1 Ab significantly
prolonged allograft survival from 7±1 to 49±30 days, which was highly
significant. These studies identify a critical role for FKN in the
pathogenesis of acute rejection and suggest that FKN may be a useful
therapeutic target in rejection.
Robinson LA, Nataraj C, Thomas
DW, et al. A role for fractalkine and its receptor (CX3CR1)
in cardiac allograft rejection. J Immunol. 2000; 165:6067-6072.
Reprints: Dr. Lisa A. Robinson, Box 3959, Duke University Medical
Center, Durham, NC 27710; robin025@mc.duke.edu
Biofilms in the
urinary tract
A biofilm is a surface accumulation of microorganisms in which large
amounts of organic polymers of microbial origin bind the cells and
other material together and to the substratum. The bacteria growing
in biofilms differ from planktonic cells in the same environment and
from cells grown in pure laboratory cultures. The formation of a biofilm
may be a stress response of bacteria to promote survival in a hostile
environment. Killing doses of antibiotics determined in the laboratory
may be ineffective in treating biofilms. The author reviewed the role
of exopolysaccharides in producing a variety of extracellular polymers
differing by organism and site. He asserted that fluoroquinolone at
high concentrations—20 times the minimal inhibitory concentration—shows
considerable killing effect against biofilms, but no commercially
available drugs are sufficiently active against the cells in a mature
biofilm. The author recommended treating urinary biofilm infection
by managing the local urinary condition and removing the local underlying
disease, as well as instituting a combination therapy of fluoroquinolone
and macrolide or fluoroquinolone and fosfomycin.
Kumon H. Management of biofilm infections in the urinary tract.
World J Surg. 2000;24:1193-1196.
Reprints: Dr. H. Kumon, Dept. of Urology, Okayama University Medical
School, 2-5-1 Shikata, Okayama 700-8558, Japan; kumon@med.koayama-u.ac.jp
Hepatitis B vaccination
and positive tests for hepatitis B surface antigen
Several reports have indicated that otherwise healthy individuals
who have received hepatitis B vaccines may test positive for the HBV
surface antigen for a short time after vaccination. The authors investigated
HBsAg reactivity in eight healthy volunteers after they received their
first dose of HBV vaccine. Blood samples were collected on days 0,
3, 5, 7, and 10 post-vaccination. Several different screening assays
were used. The highest reactivities were found on samples taken on
day 3, but two of the eight volunteers were reactive on day 5. All
samples from days 7 and 10 were nonreactive. This study demonstrated
that HBsAg assays detect individuals who have recently received the
HBV vaccine up to five days after vaccination. Blood donors who have
received the HBV vaccine probably should be deferred from blood donation
for seven days after being vaccinated.
Dow BC, Yates P, Galea G, et al. Hepatitis B vaccines may be mistaken
for confirmed hepatitis B surface antigen-positive blood donors. Vox
Sang. 2002;82:15-17.
Correspondence: Dr. Brian C. Dow, SNBTS Microbiology Reference Unit, West
of Scotland Transfusion Centre, 25 Shelley Rd., Glasgow G12 OXB, United Kingdom;
brian.dow@snbts.csa.scot.nhs.uk
C. pneumoniae
infection and mortality from ischemic
heart disease
Several small retrospective studies have linked ischemic heart disease
with various chronic infections, in particular those caused by Helicobacter
pylori and Chlamydia pneumoniae. The susceptibility of
these studies to bias and confounding have led to interest in designing
and conducting large, prospective studies of socially homogeneous
cohorts of subjects. (Socioeconomically disadvantaged individuals
may be more likely to develop infection and coronary artery disease
independently of one another.) Previous studies have generated mixed
results, regardless of whether IgG or IgA was measured. The authors
undertook a study to determine the concentration of IgG and IgA antibodies
to C. pneumoniae in a cohort of 21,520 healthy British professional
men aged 35 to 64 years who went to the BUPA center in London for
routine medical examinations between 1975 and 1982. The distributions
of concentrations of IgG and IgA antibodies to C. pneumoniae
were similar in the 647 men who subsequently died of ischemic heart
disease and the 1,294 age-matched controls who did not die. There
was no association with heart disease at any cut-off point chosen
to define seropositivity.
Wald NJ, Law MR, Morris JK, et al. Chlamydia pneumoniae infection
and mortality from ischaemic heart disease: large prospective study.
Brit Med J. 2000;321:204-207.
Reprints: N.J. Wald, BUPA Epidemiological Research Group, Wolfson
Institute of Preventive Medicine, St. Bartholomew’s and The Royal
London School of Medicine and Dentistry, London, EC1M 6BQ, England;
n.j.wald@mds.qmw.ac.uk
The ABCA1 gene
and Tangier disease
Low high-density lipoprotein cholesterol level is an independent risk
factor for coronary artery disease. Inherited forms of this condition
include Tangier disease and familial hypoalphalipoproteinemia associated
with reduced cholesterol efflux. The authors and others have shown
that FHA is allelic to Tangier disease and due to heterozygosity for
mutations of the ABCA1 gene. They reported having identified 13 ABCA1
mutations in 11 families and have examined the phenotypes of 77 individuals
heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes
have significantly reduced HDL cholesterol and significantly elevated
triglycerides. Age is an important effect modifier of the carrier
state, with a greater proportion of individuals 30 to 70 years of
age having HDL-C greater than the fifth percentile for age and gender,
compared with carriers younger than 30 years old. These ABCA1 heterozygotes
have a greater than three-fold increased risk of CAD and earlier onset
than unaffected family members. CAD correlates with the level of cholesterol
efflux, which correlates directly with HDL-C levels. This provides
direct evidence that impaired cholesterol efflux and, consequently,
reverse cholesterol transport are associated with reduced plasma HDL-C
levels and increased risk of CAD.
Clee SM, Kastelein JJ, vanDam M, et al. Age and residual cholesterol
efflux affect HDL cholesterol levels and coronary artery disease in
ABCA1 heterozygotes. J Clin Invest. 2000;106(10):1263-1270.
Reprints: Michael R. Hayden, Centre for Molecular Medicine and
Therapeutics, 980 W. 29th Ave., Vancouver, BC, Canada, V5H 4Z4;
mrh@cmmt.ubc.ca
Lack of diurnal
variation in C-reactive protein
Baseline high-sensitivity C-reactive protein has been shown to be
a powerful independent predictor of cardiovascular risk. CRP is produced
in the liver in response to stimulation by interleukin-6 and other
cytokines. The plasma concentration of IL-6 has been shown to follow
a marked diurnal variation—low in the morning and high in the
evening. This variation may reflect feedback inhibition of cytokine
concentration by endogenous cortisol. The authors conducted a study
to assess whether such diurnal variation in CRP levels in healthy
subjects could be detected using a new high-sensitivity assay. They
sampled blood from 20 healthy male and three healthy female subjects
aged 21 to 35 years. The samples were taken hourly during a baseline
day in a controlled environment (eight hours of nighttime sleep).
Only three of the subjects had CRP concentrations greater than 2 mg/L.
The raw measurements were stable throughout the 24 hours. When interpreted
by comparison with population-based quintiles, no subject was reclassified
as a result of diurnal variation. Nonparametric ANOVA and cosine curve
fitting of the data were negative for diurnal variation.
Meier-Ewert HK, Ridker PM, Rifai N, et al. Absence of diurnal
variation of C-reactive protein concentrations in healthy human subjects.
Clin Chem. 2001;47:426-430.
Reprints: Hans K. Meier-Ewert, Dept. of Cardiology, Lahey Clinic
Medical Center, 41 Mall Rd., Burlington, MA 01805; hans.k.meierewert@lahey.org
Diagnosis of Lyme
disease in children
Overdiagnosis and overtreatment are potential problems of Lyme disease,
the most common vector-borne disease in the United States. In 1995,
the Centers for Disease Control and Prevention provided criteria for
diagnosing Lyme disease. The authors examined the incidence of overdiagnosis
of Lyme disease in an endemic area using the diagnostic criteria developed
by the CDC. The CDC criteria require the presence of erythema migrans
or characteristic symptoms of active Lyme disease (articular, neurologic,
or cardiac manifestations) with serologic confirmation. Serologic
confirmation involved a two-test approach and included an enzyme immunoassay
or an immunofluorescent assay and a Western immunoblot for IgG and
IgM antibody. The authors studied 216 patients with presumptive Lyme
disease who were referred to a pediatric infectious disease clinic.
Thirty-nine children had previously been diagnosed with and treated
for Lyme disease, and 17 had symptoms of another illness but were
thought to have an acute recurrence of Lyme disease by the referring
physician or family member. One hundred and nine of the subjects did
not meet the diagnostic criteria for Lyme disease. Of the 216 children,
68 met the criteria for active Lyme disease (36 had arthritis, 15
had erythema migrans, and 17 had central nervous system disease—two
had Lyme meningitis and 15 had facial nerve palsy). One hundred and
forty-seven of the 216 children had a history of tick bite but never
had symptoms, and all had received antibiotic therapy. The authors
concluded that overdiagnosis and overtreatment of Lyme disease in
children is common and is significantly related to lack of education
about diagnostic guidelines and misinterpretation of Western immunoblot
results.
Qureshi MZ, New D, Zulqarni NJ, et al. Overdiagnosis and overtreatment
of Lyme disease in children. Pediatr Infect Dis J. 2002;21:12-14.
Correspondence: Department of Pediatrics, Division of Infectious
Diseases, State University of New York at Stony Brook, Stony Brook,
NY 11794 (reprints not available)
Prenatal CMV diagnosis
Cytomegalovirus infection occurs intrauterinely in 0.3 to 2.0 percent
of all live births, making it the most common intrauterine infection.
Only 10 to 15 percent of infected fetuses show symptoms at birth,
but severe central nervous system and multi-organ involvement may
lead to a 20 to 30 percent perinatal mortality rate in this group
and major neurologic sequelae in more than 90 percent of survivors.
The authors assessed whether amniotic CMV viral load determinations
correlate with outcome. They studied 138 pregnant women with primary
infection, defined as IgG seroconversion or presence of IgM with low
avidity IgG. Of these subjects, 68 accepted amniocentesis. Amniotic
fluid samples were tested by polymerase chain-reaction and quantitative
PCR. CMV infection in neonates was determined by urinary viral isolation
during the first postnatal week or histologically in aborted fetuses.
CMV infection was found in 16 fetuses and neonates (23 percent)—five
of whom were symptomatic. Quantitative PCR showed that 103
genome equivalents or greater predicted mother-child infection with
100 percent probability and 105 genome equivalents or greater
predicted development of a symptomatic infection. The authors concluded
that fewer CMV-infected fetuses are at risk for CMV disease than expected.
Guerra B, Lazzarotto T, Quarta S, et al. Prenatal diagnosis of
symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol.
2000;183(2):476-482.
Reprints: Dr. Brunella Guerra, Clinica Obstetrica e Ginecologica II, Policlinico
S. Orsola, Via Massarenti 13, 40138 Bologna, Italy.
Incidence of tuberculosis
in U.S. immigrants
Infection with Mycobacterium tuberculosis is extremely widespread
internationally, affecting as much as one-third of the worlds population.
In developed countries, substantial immigration rates have contributed
to the incidence of TB and sustained TB occurrence rates. The number
of cases of TB in the United States has decreased since its peak in
1992, but the decline has occurred among those born in the United
States. The authors performed a descriptive analysis of U.S. TB surveillance
data between 1993 and 1998 and found that TB among the U.S. foreign-born
population increased 2.6 percent, totalling 7,402 in 1993 and 7,591
in 1998, and the proportion of all U.S. TB cases represented by foreign-born
persons rose from 29.8 percent to 41.6 percent. The 1993 to 1998 TB
case rate was 32.9 per 100,000 foreign-born persons and 5.8 per 100,000
U.S.-born persons. Of cases involving foreign-born subjects, 73.4
percent were reported in the states of California, New York, Texas,
Florida, New Jersey, and Illinois, and two-thirds of the infected
subjects originally were from Mexico, Philippines, Vietnam, India,
China, Haiti, or South Korea. Most subjects with TB were males aged
25 to 44 years—51.5 percent had been in the United States less
than five years before diagnosis. The authors concluded that TB control
strategies for the foreign-born community are essential to eliminating
the disease in the United States.
Talbot EA, Moore M, McCray E, et al. Tuberculosis among foreign-born
persons in the United States, 1993-1998. JAMA. 2000;284:2894-2900.
Reprints: Dr. Marisa Moore, Surveillance and Epidemiology Branch,
Division of TB Elimination, Centers for Disease Control and Prevention,
Mail Stop E-10, Atlanta, GA 30333; mmoore@cdc.gov
|
|
|
