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NEOPLASIA
From the Immunocompromised Host Section, Pediatric
Oncology Branch, National Cancer Institute (NCI), National Institutes
of Health (NIH); Laboratory of Immunoregulation, National Institute of
Allergy and Infectious Diseases, NIH; HIV and AIDS Malignancy Branch,
NCI, NIH; Biostatistics and Data Management, NCI, NIH; Critical Care
Medicine Department, Clinical Center, NIH; and the Dermatology Branch,
NCI, NIH, Bethesda, MD.
Kaposi sarcoma (KS) is an angioproliferative inflammatory condition
that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the
development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the
association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1 Kaposi sarcoma (KS) is an invasive
angioproliferative inflammatory condition that occurs commonly in men
infected with human immunodeficiency virus (HIV). In the early stages
of KS, lesions appear reactive and are stimulated to grow by the action
of inflammatory cytokines and growth factors.1-3 In the
late stages of KS, a malignant phenotype that appears to be monoclonal
can develop.4 Infection with human herpesvirus 8 (HHV-8),
also known as KS-associated herpesvirus, is necessary but not
sufficient for development of KS.1,5 Coinfection with HIV
markedly increases the likelihood of development of KS, and
epidemiologic evidence suggests that additional environmental,
hormonal, and genetic cofactors contribute to its
pathogenesis.6,7
Perturbations in the levels and activity of inflammatory cytokines have
been described during HIV infection and contribute to the profound
disruption of immune regulation. In early-stage KS, large numbers of
inflammatory cells, including lymphocytes and macrophages, are
recruited into KS lesions.8 These cells produce high
levels of proinflammatory cytokines, including interleukin (IL)-6,
tumor necrosis factor (TNF) Host genetic factors have been shown to modify the risk of acquiring
HIV as well as the rate of HIV disease progression. In particular,
variants of chemokines were informative in genetic association studies
and led to important insights into the pathogenesis of HIV
infection.15-17 In addition, chemokine and
chemokine-receptor gene variants were reported to influence the risk of
development of non-Hodgkin lymphoma in patients infected with
HIV-1.18 We previously reported that variant genotypes of
the Fc- To study whether polymorphisms altering the function or expression of
proinflammatory cytokine genes contribute to the pathogenesis of KS, we
selected the following 6 candidate genes for analysis: IL6,20,21 TNF,22
LTA (which encodes TNF- The study population primarily consisted of deceased
HIV-infected white men who had been enrolled in either National Cancer Institute or National Institute of Allergy and Infectious Diseases (NIAID) protocols at the National Institutes of Health (NIH) and who
had acquired HIV through sex with other men. Approval for research
involving human subjects was obtained from the Office of Human Subjects
Research at the NIH. Also included were 4 living patients with KS who
provided informed consent to analysis under the auspices of the NIAID
institutional review board. In this cohort, 115 patients with KS were
analyzed and compared with 126 patients without KS. The 2 groups,
patients with KS and patients with no history of KS, did not differ in
age or CD4 count at the time of death. None of the deceased patients
had received highly active antiretroviral therapy (HAART), and nearly
all died before 1996. The frequency of antibodies against lytically
expressed HHV-8 antigens was previously determined in this population;
88 of 103 KS patients (85%) and 42 of 118 patients without KS (36%) were seropositive for HHV-8.19
Genomic DNA was extracted from cryopreserved lymphocyte pellets by
using a salt precipitation extraction method (Puregene DNA isolation
kit; Gentra Systems, Minneapolis, MN). Polymorphism analysis for each
of 6 cytokine genes The distribution of genotypes for each candidate gene in patients with
and without KS was compared by using a The association between cytokine polymorphisms and the overall
lifetime risk of development of KS was determined in HIV-infected men
with and without KS (Table 2). A strong
association between genotype and the risk of development of KS was
observed at the IL6 locus. Among the 115 patients with KS,
the distribution of the IL6-174 genotypes was as follows: CC
in 10 patients (8.7%), CG in 44 patients (38.3%), and GG in 61 patients (53.0%). At the IL6 locus, the distribution of
genotypes in the KS patients differed significantly from that in both
the 126 HIV-positive subjects without KS (CC in 27 [21.4%], CG in 55 [43.7%], and GG in 44 [34.9%]; P = .0035;
The pathogenesis of KS in HIV-infected men has been closely linked to
infection with HHV-8. In an effort to isolate the contribution of
IL6 genotype to HHV-8 seropositivity, we performed a
preliminary analysis in our pilot study. We compared genotype
frequencies in HIV-infected men with probable HHV-8 infection (ie,
documented HHV-8 serologic result plus all other KS patients Similar calculations were performed using only the subgroup of men who had documented seropositivity for HHV-8 lytic antibody (GG in 60, GC in 51, and CC in 16). When this population was compared with the documented HHV-8-negative population (without KS and negative for HHV-8), there was a trend at the locus (P = .077) that, on closer analysis, suggested underrepresentation of the CC genotype (13% versus 23%; P = .055) and overrepresentation of the GG genotype (47% versus 34%; P = .065). The association between IL6 genotype and HHV-8 seropositivity was not observed (P = .90) in the small cohorts of those with documented HHV-8 serologic results: HHV-8-negative men (GG in 27, GC in 34, and CC in 18) and HHV-8-positive men with no history of KS (GG in 15, GC in 16, and CC in 8). The risk of development of KS was estimated in HIV-infected men with probable HHV-8 infection (ie, those with serologic documentation plus those with KS). The distribution of IL-6 genotypes in the group with KS (GG in 61, GC in 44, and CC in 10) was compared with the distribution in men without KS who were seropositive for HHV-8 (GG in 15, GC in 16, and CC in 8). It was not significant at the locus (P = .091) or with respect to 3 genotypes, including the IL-6 CC genotype (patients without KS with antibody to HHV-8 compared with those with KS, 21% versus 9%; P = .079 by F). Analysis of the risk of progression to KS was also performed in a subgroup restricted to those with documented seropositivity for HHV-8 lytic antibody. Of the patients with available serum samples, 88 men had both lytic antibody to HHV-8 and a history of KS. The distribution of IL-6 genotypes in this group (GG in 45, CC in 35, and CC in 8) was compared with the distribution in HHV-8-positive men with no history of KS (GG in 15, GC in 16, and CC in 8). Although the CC genotype was increased in the group without KS (21% versus 9%; P = .087 by F), the findings were not significant at either the level of individual genotypes or the locus (P = .16). When both KS status and HHV-8 status were evaluated in a subanalysis, the distribution of IL-6 genotypes was found to differ significantly between the KS group and the HHV-8-seronegative subjects without KS (P = .0056). The GG genotype was present in 34.2% (27 of 79) of the HHV-8-negative subjects without KS but in 53% (61 of 115) of the KS patients (P = .0095). Similarly, the CC genotype was found in 22.8% (18 of 79) of the HHV-8-negative patients without KS but in 9% (10 of 115) of the KS patients (P = .0061). Similar results were obtained when this analysis was used to compare the population of men with both lytic antibody to HHV-8 and a history of KS with those who were seronegative for HHV-8 and did not have KS (P = .019). The GG genotype was present in 51% (45 of 88) of the KS patients (P = .027) and the CC genotype in 9% (8 of 88; P = .015). For the genes TNF, LTA, IL1A, and ILIB, no significant associations with KS were observed for either the gene locus or the individual genotypes. Although strong overall associations between genotype and KS were not observed at the IL1RN locus (P = .67), there could possibly be an increased risk of development of KS in individuals who have either 2 different rare alleles or alleles 2 and 3 or who are homozygous for allele 3 (P = .011 by F; OR, 15.2 [95% CI, 0.8-273.1]). KS developed in all 5 patients with a 2/3 genotype (P = .023 by F; OR, 12.7 [95% CI, 0.7 to 233.2]) and in one patient homozygous for the 3/3 genotype. Studies enrolling more subjects with these particular IL1RN alleles are needed to definitively link these genotypes to KS. Polymorphisms in SDF1 (P = .21), the principal
ligand for chemokine receptor 4, CXCR4, and CCR5
(P = .14), although reported to modify the severity and
rate of progression of HIV infection, were not independently associated
with KS in our population (Table 3). Even
when present together, informative genotypes for CCR5
In a preliminary analysis, we looked at the distribution of HHV-8 seropositivity in the population without KS. No significant associations with HHV-8 seropositivity were identified for any of the 6 cytokine genes evaluated in this study or for CCR5 or SDF1 at either the locus or genotype level (data not shown).
Because key proinflammatory cytokines function as autocrine or
paracrine growth factors for HIV-associated KS, we compared the
frequency of variant alleles of 6 proinflammatory cytokines in patients
with acquired immunodeficiency syndrome (AIDS) with or without a
lifetime history of KS. Each of the polymorphisms maps to a putative
regulatory region in the selected candidate genes
TNF,22 LTA,23
IL1A,24 IL1B,26
IL1RN,33 and IL6.20 Our
results indicate that KS is strongly associated with the The IL6-174 promoter polymorphism appears to be both biologically and clinically important. Compared with the G allele, the C allele has been associated with both decreased transcription and lower plasma levels of IL-6. Clinically, the frequency of homozygotes for the IL6-174C allele was reported to be reduced in, and appears to be protective against, systemic-onset juvenile chronic arthritis.20 In addition, the C allele of the IL-6 gene was reported to delay the onset and reduce the risk of development of Alzheimer's disease.21 It is also plausible that the informative IL6 locus could be in linkage dysequilibrium with one or more other informative sites that contribute to the pathogenesis of KS. Nonetheless, our results provide preliminary in vivo evidence that genetic differences in IL-6 levels may contribute to the pathogenesis of KS, although this information alone is not sufficient to determine whether the interaction influences the risk of HHV-8 infection, the risk of progression to KS in HHV-8-positive men, or both. The association between IL6 genotype and KS is interesting for several reasons. IL-6 is both a proinflammatory and a Th2-type cytokine that is capable of stimulating T-cell-dependent humoral immune responses. In HIV infection, progression to AIDS is correlated with immune dysregulation and an imbalance in Th1- and Th2-type cytokines.35 It is possible that in AIDS patients with a genetic predisposition favoring a Th2-type immune response, HHV-8 might escape cell-mediated immunity and promote development of KS. In vitro studies demonstrated that AIDS-KS cell growth is stimulated in response to endogenously produced cytokines, including IL-6.10 In addition, IL-6 levels could be a useful marker for severe immune suppression in HIV-infected patients. Some investigators have suggested that increased IL-6 levels are a risk factor for development of KS,36 but this idea was not supported by a nested case-control study.37 This apparent contradiction could reflect variability in circulating IL-6 levels during the course of HIV infection and inadequate measurement of IL-6 in the microenvironment. One possible advantage of studying cytokine polymorphisms, as we did here, is that when the genotype is physiologically relevant, it may provide a more accurate reflection of cytokine response in the microenvironment. The potential importance of IL-6 in the pathogenesis of KS is further suggested by the observation that HHV-8 encodes a viral homologue of the human IL6 gene.38 Seroprevalance studies have suggested that exposure to HHV-8
commonly occurs during childhood in African populations, but in North
American and European HIV-infected populations, transmission usually
occurs later in life through sexual contact.1 It is of
interest that the Current theories suggest that the risk of development of KS is influenced not only by the risk of becoming infected with HHV-8 but also by the subsequent risk of progression to KS. Although all patients with KS are presumed to be infected with HHV-8 (nearly 90% of our KS patients had evidence of circulating lytic antibody to HHV-8), only 36% of our population without KS had lytic antibodies. If HHV-8 infection is a necessary cofactor for development of KS, then many of our controls without KS may not have been at risk for development of KS. In a subanalysis, we examined whether IL-6 genotype influenced the risk of progression to KS in the subgroup of men with evidence of HHV-8 infection. The results were not statistically significant, reflecting the limited power of the subanalysis. The results were similar when the population exposed to HHV-8 was restricted to only those with serologic evidence of HHV-8 infection. Although chemokines and chemokine receptors have been reported to modify the risk of development of HIV-associated lymphomas,18 we did not observe a strong association between either CCR5 or SDF1 and the risk of KS. Our results suggest that genetic modifiers of immunologically important pathways may contribute to the specific complications that occur in an immunocompromised population.32 If our findings are confirmed in follow-up studies, polymorphisms in
genes encoding immunologically important molecules, such as
IL6 and Fc
We thank Sandra Cohen, John O'Mara, Renée Chen, Edward Garmey, and Elizabeth Hart for technical assistance.
Submitted February 2, 2000; accepted June 8, 2000.
Supported by a Mildred Scheel Stipendium, Deutsche Krebshilfe eV (T.L.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Stephen J. Chanock, Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Advanced Technology Center, 8717 Grovemont Circle, Gaithersburg, MD 20877; e-mail: sc83a{at}nih.gov.
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 A. J. Stratigos, D. Malanos, G. Touloumi, A. Antoniou, I. Potouridou, D. Polydorou, A. D. Katsambas, D. Whitby, N. Mueller, J. D. Stratigos, et al. Association of Clinical Progression in Classic Kaposi's Sarcoma With Reduction of Peripheral B Lymphocytes and Partial Increase in Serum Immune Activation Markers Arch Dermatol, November 1, 2005; 141(11): 1421 - 1426. [Abstract] [Full Text] [PDF]
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 C. A. Fielding, R. M. McLoughlin, C. S. Colmont, M. Kovaleva, D. A. Harris, S. Rose-John, N. Topley, and S. A. Jones Viral IL-6 Blocks Neutrophil Infiltration during Acute Inflammation J. Immunol., September 15, 2005; 175(6): 4024 - 4029. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
,
IL-1
, tumor necrosis factor (TNF) 
32) polymorphisms to KS development. The population consisted of
115 HIV-infected men with KS and 126 deceased HIV-infected men without
KS. The only strong association was observed between an IL6
promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected
men (P = .0035). Homozygotes for IL6 allele
G, associated with increased IL6 production, were
overrepresented among patients with KS (P = .0046),
whereas allele C homozygotes were underrepresented
(P = .0062). Substantial in vitro evidence indicates that
IL-6 contributes to the pathogenesis of KS. Our results show that
IL6 promoter genotypes associated with altered gene
expression are risk factors for development of KS. Identification of a
genetic risk factor for development of KS has important clinical implications for prevention and therapy.
(Blood. 2000;96:2562-2567)
, IL-1
IL6 (G-174C),
2 test or the
Mehta and Patel
174 polymorphism in the promoter region of the human IL6 gene
(P = .0035). The 
TH2 switch is a critical step in the etiology of HIV infection.
Immunol Today.
1993;14:107-111