Functional and Phenotypic Changes in Circulating Lymphocytes from Hospitalized Zambian Children with Measles

Abstract

Measles is associated with immunosuppression and increased susceptibility to secondary infections and is a particular problem in developing countries. Lymphocyte changes accompanying immune activation and regulation of the immune response may contribute to immunosuppression. To evaluate lymphocyte changes during measles, children (n ‫؍‬ 274) hospitalized with measles in Lusaka, Zambia, were evaluated at entry, discharge, and 1-month follow-up and compared to healthy Zambian children (n ‫؍‬ 98). Lymphopenia was present on hospital admission and reflected decreased CD4 and CD8 T cells but resolved quickly. Lymphopenia was most marked in girls, in those with temperatures of >38.5°C, and in malnourished children. CD4/CD8 ratios were decreased at all time points and were lower in boys than in girls at discharge and follow-up. Spontaneous death occurred in cultured lymphocytes, and the proportions of freshly isolated cells undergoing apoptosis, based on annexin V and propidium iodide staining, were increased. Surface Fas was increased on both CD4 and CD8 T cells compared to controls, and expression was greater on CD4 T cells and was inversely correlated with lymphocyte viability in culture at study entry. Mitogen stimulation of lymphocytes improved viability, but inhibitors of Fas, tumor necrosis factor (TNF)-related apoptosis-inducing ligand, and TNF did not. Plasma levels of ␤ 2 microglobulin and soluble Fas, Fas ligand, CD8, CD4, and TNF receptor were increased, and soluble CD8 was higher in boys than in girls. The multiple effects of measles on lymphocytes from Zambian children include decreased numbers in circulation, increased activation, and increased susceptibility to cell death, with substantive differences in the magnitude of these changes between boys and girls.Measles causes nearly 1 million deaths per year worldwide, with the heaviest burden occurring in sub-Saharan Africa (9). The high morbidity and mortality associated with measles virus (MV) infection is due primarily to secondary infections, particularly of the respiratory and gastrointestinal tracts (12,53,55). Increased susceptibility to other infectious diseases has been linked to the immune suppression associated with this infection. Cell-mediated immunity, manifested by decreased delayed-type hypersensitivity responses to skin test antigens and decreased proliferation of lymphocytes after stimulation in vitro, is suppressed, and this suppression may persist for several months after recovery (74,80,86,87).The mechanism of MV-induced immune suppression is incompletely understood, and few studies of children in developing countries, where mortality rates are highest, have been done. Lymphocyte activation is a consistent feature of acute measles (34, 38) in North and South American children, and we have proposed that the observed cytokine "shift" from type 1 cytokines early during infection to type 2 cytokines during and after recovery (35) inhibits development of effective type 1 cytokine-mediated cell-mediated immunity responses upon subsequent exp...

Measles Virus Infection: Mechanisms of Immune Suppression

“…All subjects produced IFN-γ, and in subjects who produced both IFN-γ and IL-4, maximal IFN-γ production in vitro always greatly exceeded that of IL-4 (Dhiman et al, 2005b). In Zambian children plasma IL-5 levels were lower in patients compared with controls (Ryon et al, 2002). In contrast, a significant upregulation of IL-5 mRNA has been reported among seropositive adult donors after vaccination .…”

“…An increase in IFN-γ in MV-infected children compared with healthy controls has been observed in other studies and it may serve to inhibit viral growth and limit the spread of infection (Griffin et al, 1990a). Children with measles display a transient increase in both IL-2 and IFN-γ, lasting for a few days following rash Ryon et al, 2002), followed by sustained IL-4 production (Ryon et al, 2002). A similar response was observed when a clinical isolate of MV was used to infect PBMCs (Dhiman et al, 2005b).…”

“…Sustained high levels of IL-10 during convalescence suggest a role for this immunoregulatory cytokine in MV-induced immune-suppression. Plasma levels of IL-10 remain elevated for weeks in children with MV infection (Ryon et al, 2002). The increased IL-10 levels may also be implicated in the decrease in IL-5 expression, because IL-10 is known to inhibit IL-5 production by T cells and in mouse models of allergic disease (Staples et al, 2000).…”

“…It is reported that MV infection results in remarkable lymphopenia in all measles cases with reduction in cell numbers of CD4+ T cells, CD8+ T cells, B cells, neutrophils, and monocytes in circulation, increased lymphocyte activation, and increased susceptibility to cell death of lymphocytes in children (Ryon et al, 2002), in young adults (Okada et al, 2000;Vinante et al, 1999), in cultured peripheral blood mononuclear cells (PBMC) (Salonen et al, 1989), and in animal models (Hahm et al, 2003). Interestingly, in Chinese adult measles patients with no vaccination history, a general decrease in CD4+ and CD8+ T cells was not observed, although there was a trend toward lower levels compared with healthy donors (Yu et al, 2008).…”

MAVS-dependent IRF3/7 bypass of interferon β-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells

“…The plasma level of the anti-inflammatory cytokine IL-10 is increased in patients with measles (Atabani et al, 2001;Yu et al, 2008). This elevated level of plasma IL-10 probably contributes to the impaired cellular immunity and depressed hypersensitivity response following MV infection (Ryon et al, 2002). However, the primary DC response and source of IL-10 in MV-infected patients is at present not clear.…”