Mechanism of Suppression of Cell-Mediated Immunity by Measles Virus

Karp, Christopher L.; Wysocka, Maria; Wahl, Larry M.; Ahearn, Joseph M.; Cuomo, Peter; Sherry, Barbara; Trinchieri, Giorgio; Griffin, Diane E.

doi:10.1126/science.273.5272.228

Cited by 522 publications

(352 citation statements)

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“…A role of CD46 in IL-12p40 and p70 expression have been previously reported (Karp et al, 1996;KuritaTaniguchi et al, 2000;Schnorr et al, 1997;Smith et al, 2003). Hence, we analyzed the role of CD46 in both IL-12 and IL-23 inductions.…”

Section: Cd46 Modulates Lps-mediated Maturation Of Mdcsmentioning

confidence: 78%

“…Production of IL-12p70 by APC can be modulated by cross-linking of CD46 at their surface, either increasing or decreasing IL-12 depending on the cell type and stimulus used. An inhibition of IL-12 production by monocytes is observed after CD46 ligation by antibodies or C3b binding (Karp et al, 1996), and a posttranscriptional inhibition of IL-12p70 was also observed when CD46 was triggered by HHV6 (Smith et al, 2003). On the other hand, IL-12p40 was increased by CD46 ligation on GM-CSF treated monocytes (KuritaTaniguchi et al, 2000), and infection of dendritic cells by measles virus led to an increase in IL-12p40 (Schnorr et al, 1997).…”

mentioning

confidence: 99%

“…The engagement of CD46 at the surface of APC has been shown to modulate the production of IL-12 (p70) and/or p40 subunit, either increasing or decreasing their expression depending on the cell type and stimulus used (Karp et al, 1996;Kurita-Taniguchi et al, 2000;Schnorr et al, 1997;Smith et al, 2003). CD46 is a widely expressed transmembrane protein initially identified as a complement regulatory protein (Seya et al, 1986).…”

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confidence: 99%

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Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

Vaknin‐Dembinsky¹,

Murugaiyan²,

Hafler³

et al. 2008

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In MS, myeloid dendritic cells (mDCs) secrete elevated amounts of IL-23, a potent pro-inflammatory cytokine, compared to healthy donors. Here, we examined the role of CD46, a complement binding factor, in mDCs by analyzing cytokine and chemokine production in healthy donors and patients with MS. There were striking differences between these groups with increased IL-23p19, CCL2 and CCL5 production, but decreased CCL2 levels in patients. This demonstrates major differences of DC activation upon CD46 activation, with a potential role in the pathogenesis of MS. KeywordsMultiple sclerosis; human dendritic cells; chemokines; IL-23; CD46 1-IntroductionMultiple sclerosis is a chronic inflammatory demyelinating disease of the CNS (Hafler et al., 2005;Weiner, 2004b) in which both the release of inflammatory mediators and chemotaxis are important (Adorini, 2004;Elhofy et al., 2002). DCs are professional antigen-presenting cells (APC) which secrete cytokines and chemokines upon maturation and play a key role in the induction of immune responses by activating naïve T cells. We previously demonstrated that mDCs from patients with MS secrete elevated amounts of IL-23 compared to healthy controls (Vaknin-Dembinsky et al., 2006). IL-23 is a proinflammatory cytokine that consists of a specific p19 subunit associated with the shared IL-12p40 subunit (also called IL-12 beta1 subunit which associates with IL-12p35 to form IL-12 (p70)) (Frucht, 2002;Oppmann et al., 2000;Trinchieri et al., 2003). IL-23 promotes the expansion of a specific subset of T cells secreting IL-17, a potent inflammatory cytokine (Bettelli et al., 2007) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Comabella et al., 1998;Soldan et al., 2004). Therefore, production of both IL-12 and IL-23 are dysregulated in patients with MS (Gran et al., 2004). NIH Public AccessThe engagement of CD46 at the surface of APC has been shown to modulate the production of IL-12 (p70) and/or p40 subunit, either increasing or decreasing their expression depending on the cell type and stimulus used (Karp et al., 1996;Kurita-Taniguchi et al., 2000;Schnorr et al., 1997;Smith et al., 2003). CD46 is a widely expressed transmembrane protein initially identified as a complement regulatory protein (Seya et al., 1986). It has then been described as a 'magnet for pathogens ' (Cattaneo, 2004), acting as a receptor for several virus and bacteria. More recently, it was identified as a co-stimulatory molecule for T cell activation (Astier et al., 2000;Ma...

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Section: Cd46 Modulates Lps-mediated Maturation Of Mdcsmentioning

confidence: 78%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

Vaknin‐Dembinsky¹,

Murugaiyan²,

Hafler³

et al. 2008

Journal of Neuroimmunology

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“…Earlier studies have shown that IL-12 is important to the development of cell-mediated immunity and is a necessary cytokine for acquisition of a Th1 type immune response [17,35]. It was demonstrated that measles virus binding to the CD46 receptor leads to down-regulation of IL-12 secretion in measles-infected monocytes after in vitro measles stimulation [16,21]. The decrease in IL-12 production by monocytes was shown to be greater when the p40 monomer was measured rather than the bioactive p70 heterodimer [16,41].…”

Section: Discussionmentioning

confidence: 99%

“…Two main T helper subsets have been recognized: Th1 cells producing cytokines favoring cell-mediated immunity (IFN-γ, IL-2, TNF-α and IL-12), and Th2 cells producing cytokines necessary for humoral immune responses (IL-4, IL-5, IL-6, IL-10, and IL-13) [13,14]. Measles virus infection induces a Th2 type response and it is likely that cytokine imbalances play a role in immunosuppression [15][16][17][18]. In contrast, vaccination with measles virus preferentially induces Th1 type immune responses [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: Is there evidence of the HLA effect?

et al. 2006

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HLA class I and class II associations were examined in relation to measles virus-specific cytokine responses in 339 healthy children who had received two doses of live attenuated measles vaccine. Multivariate linear regression modeling analysis revealed suggestions of associations between the expression of DPA1*0201 (p=0.03) and DPA1*0202 (p=0.09) alleles and interleukin-2 (IL-2) cytokine production (global p-value 0.06). Importantly, cytokine production and DQB1 allele associations (global p-value 0.04) revealed that the alleles with the strongest association with IL-10 secretion were DQB1*0302 (p=0.02), DQB1*0303 (p=0.07) and DQB1*0502 (p=0.06). Measlesspecific IL-10 secretion associations approached significance with DRB1 and DQA1 loci (both global p-values 0.08). Specifically, suggestive associations were found between DRB1*0701 (p=0.07), DRB1*1103 (p=0.06), DRB1*1302 (p=0.08), DRB1*1303 (p=0.06), DQA1*0101 (p=0.08), and DQA1*0201 (p=0.04) alleles and measles-induced IL-10 secretion. Further, suggestive association was observed between specific DQA1*0505 (p=0.002) alleles and measles-specific IL-12p40 secretion (global p-value 0.09) indicating that cytokine responses to measles antigens are predominantly influenced by HLA class II genes. We found no associations between any of the alleles of HLA A, B, and Cw loci and cytokine secretion. These novel findings suggest that HLA class II genes may influence the level of cytokine production in the adaptive immune responses to measles vaccine.

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Deficiency of the Humoral Immune Response to Measles Vaccine in Infants Immunized at Age 6 Months

Gans¹

1998

JAMA

247

166

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Context.-Measles causes serious morbidity in infants, with the highest risk among those who are 6 to 12 months of age. In the United States, measles vaccine has been given at age 12 to 15 months to minimize interference by passive antibodies and to achieve the high seroprevalence required for herd immunity. Infants of mothers with vaccine-induced immunity may lose passively acquired antibodies before 12 months, leaving them susceptible to measles infection. Objective.-To assess the immunogenicity of measles vaccine in infants younger than 12 months. Design.-Cohort study conducted before and after measles immunization. Setting.-Pediatric clinic in Palo Alto, Calif. Participants.-Infants 6 (n = 27), 9 (n = 26), and 12 (n = 34) months of age were enrolled; 72 provided both initial and follow-up samples. Main Outcome Measures.-Evaluation of immunogenicity before and 12 weeks after measles vaccination, including measles neutralizing antibody titers, measlesspecific T-cell proliferation, and cytokine profiles. Results.-Measles neutralizing antibodies were present before vaccination in 52% (12/23), 35% (7/20), and 0% (0/22) of 6-, 9-, and 12-month-old infants, respectively. In the absence of detectable passive antibodies, geometric mean titers after vaccination were significantly lower in 6-month-old infants compared with 9-month-old infants (27 vs 578, P = .01) and 12-month-old infants (27 vs 972, P = .001). The seroconversion rate, defined as a 4-fold rise in antibody titer, in these 6-month-old infants was only 67%, and only 36% of these infants achieved seroprotective neutralizing antibody titers of 120 or higher after vaccination compared with 100% of 9-and 12-month-old infants lacking detectable passive antibody prior to vaccination. T-cell proliferation and cytokine responses to measles did not differ with age. Conclusions.-Humoral immunity was deficient in 6-month-old infants given measles vaccine, even in the absence of detectable passively acquired neutralizing antibodies. Comparison of their responses with those of 9-and 12-month-old infants indicates that a developmental maturation of the immune response to measles may occur during the first year of life, which affects the immunogenicity of measles vaccine.

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Mechanism of Suppression of Cell-Mediated Immunity by Measles Virus

Cited by 522 publications

References 49 publications

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: Is there evidence of the HLA effect?

Deficiency of the Humoral Immune Response to Measles Vaccine in Infants Immunized at Age 6 Months

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