Update Immunopathophysiology of Measles

wp-1466680670546.jpgMeasles, also known as rubeola, is one of the most contagious infectious diseases, with at least a 90% secondary infection rate in susceptible domestic contacts. It can affect people of all ages, despite being considered primarily a childhood illness. Measles is marked by prodromal fever, cough, coryza, conjunctivitis, and pathognomonic enanthem (ie, Koplik spots), followed by an erythematous maculopapular rash on the third to seventh day. Infection confers life-long immunity.

Pathophysiology

In temperate areas, the peak incidence of infection occurs during late winter and spring. Infection is transmitted via respiratory droplets, which can remain active and contagious, either airborne or on surfaces, for up to 2 hours. Initial infection and viral replication occur locally in tracheal and bronchial epithelial cells.

After 2-4 days, measles virus infects local lymphatic tissues, perhaps carried by pulmonary macrophages. Following the amplification of measles virus in regional lymph nodes, a predominantly cell-associated viremia disseminates the virus to various organs prior to the appearance of rash.

Measles virus infection causes a generalized immunosuppression marked by decreases in delayed-type hypersensitivity, interleukin (IL)-12 production, and antigen-specific lymphoproliferative responses that persist for weeks to months after the acute infection. Immunosuppression may predispose individuals to secondary opportunistic infections, particularly bronchopneumonia, a major cause of measles-related mortality among younger children.

In individuals with deficiencies in cellular immunity, measles virus causes a progressive and often fatal giant cell pneumonia. In immunocompetent individuals, wild-type measles virus infection induces an effective immune response, which clears the virus and results in lifelong immunity.

Immunopathogenesis

Measles virus (MV)3 infection is responsible for an acute childhood disease which remains the fourth cause of infant mortality in the world. Paradoxically, the development of the MV-specific response, which establishes efficient long-term immunity, is associated with a transient but profound immunosuppression. The latter persists several weeks after infection and contributes to the high frequency of opportunistic infections. MV infection has been involved in decrease of tuberculin skin reactivity, inhibition of Ab response to Salmonella typhi vaccine, reduced proliferation capacity of T and B lymphocytes in response to mitogens, and dysregulation of cytokine responses with a Th2 polarization (1). Moreover, in vitro studies have suggested that both lymphocytes and APCs might be involved in MV-induced immunosuppression (2, 3). MV-infected DCs become unable to induce both allogeneic and syngeneic T cell proliferation. MV infection of monocytes and dendritic cells (DCs) inhibits their ability to secrete IL-12. Infected T cells, monocytes, and DCs die by apoptosis .

DCs belong to a family of professional APCs responsible for the generation of effector CD4+ and CD8+ T cells. They originate from CD34+ bone marrow progenitors. Immature DCs form a network within all epithelia, as Langerhans cells (LCs) in the skin or DCs in the respiratory mucosa. These immature DCs are able to capture particular Ags via phagocytosis and soluble Ags via macropinocytosis or receptor-mediated endocytosis . They express low levels of MHC class II (MHC-II) molecules at their cell surface. To become a potent APC, the immature DCs need to be activated by stimuli that promote their maturation and migration to the T cell areas of lymphoid tissues. Living bacteria, microbial products (LPS), or various cytokines (TNF-α, GM-CSF, IL-1β) stimulate DC maturation. Upon maturation, MHC-II molecules are delivered to the plasma membrane (12) and the expression of costimulatory membrane molecules is increased, thus favoring T cell activation.

When the mature DCs reach secondary lymphoid organs, they interact with T cells, receiving signals which induce their terminal differentiation into mature effector DCs. CD40-CD40 ligand (CD40L) interaction between DCs and T cells is essential for an optimal cytokine production. The best-known consequence of CD40 ligation is the IL-12 production by DCs. In human, the X-linked immunodeficiency hyper-IgM syndrome has been attributed to mutations in the CD40L gene. Over the past year, it was recognized that the function of CD40 accounts not only for the regulation of T-dependent humoral immune responses, but also for cellular immune responses. Several immune dysfunctions observed in CD40L-deficient mice and patients could be explained by a failure properly to activate APCs. Recent in vivo studies in mouse demonstrated that CD40 ligation on the DCs can replace CD4+ T cells to prime CD8+ cytotoxic responses.

The mechanisms by which MV infection interferes with the functions of DCs remained unknown. MV replication induces normal maturation of immature monocyte-derived DCs and LCs. But, we show that MV replication leads to an abnormal terminal differentiation of CD40L-activated human DCs. Impairment of CD40/CD40L signaling following MV infection was demonstrated by inhibition of tyrosine-phosphorylation level in MV-infected DCs after CD40 activation. This could explain why DCs display impaired APC functions and may consequently promote MV-induced immunosuppression.

Measles virus causes a severe systemic illness. The rash occurs simultaneously with the onset of the effector phase of the antiviral immune response and substantial evidence of immune activation. This immune response is effective in clearing virus and in establishing long-term resistance to reinfection but is associated with immune suppression, autoimmune encephalomyelitis, and increased susceptibility to secondary infections. This apparent paradox may be explained in part by preferential long-term activation of type 2 CD4+ T cells by measles virus infection. Preferential stimulation of type 1 CD4+ T cells by inactivated virus vaccines is hypothesized to play a role in subsequent development of atypical measles.

Measles is a highly contagious childhood disease associated with an immunological paradox: although a strong virus-specific immune response results in virus clearance and the establishment of a life-long immunity, measles infection is followed by an acute and profound immunosuppression leading to an increased susceptibility to secondary infections and high infant mortality. In certain cases, measles is followed by fatal neurological complications. To elucidate measles immunopathology, we have analyzed the immune response to measles virus in mice transgenic for the measles virus receptor, human CD150. These animals are highly susceptible to intranasal infection with wild-type measles strains. Similarly to what has been observed in children with measles, infection of suckling transgenic mice leads to a robust activation of both T and B lymphocytes, generation of virus-specific cytotoxic T cells and antibody responses. Interestingly, Foxp3(+)CD25(+)CD4(+) regulatory T cells are highly enriched following infection, both in the periphery and in the brain, where the virus intensively replicates. Although specific anti-viral responses develop in spite of increased frequency of regulatory T cells, the capability of T lymphocytes to respond to virus-unrelated antigens was strongly suppressed. Infected adult CD150 transgenic mice crossed in an interferon receptor type I-deficient background develop generalized immunosuppression with an increased frequency of CD4(+)CD25(+)Foxp3(+) T cells and strong reduction of the hypersensitivity response. These results show that measles virus affects regulatory T-cell homeostasis and suggest that an interplay between virus-specific effector responses and regulatory T cells plays an important role in measles immunopathogenesis. A better understanding of the balance between measles-induced effector and regulatory T cells, both in the periphery and in the brain, may be of critical importance in the design of novel approaches for the prevention and treatment of measles pathology.

A generalized immunosuppression that follows acute measles frequently predisposes patients to bacterial otitis media and bronchopneumonia. In approximately 0.1% of cases, measles causes acute encephalitis. Subacute sclerosing panencephalitis (SSPE) is a rare chronic degenerative disease that occurs several years after measles infection.

After an effective measles vaccine was introduced in 1963, the incidence of measles decreased significantly. Nevertheless, measles remains a common disease in certain regions and continues to account for nearly 50% of the 1.6 million deaths caused each year by vaccine-preventable childhood diseases. The incidence of measles in the United States and worldwide is increasing, with outbreaks being reported particularly in populations with low vaccination rates.

Maternal antibodies play a significant role in protection against infection in infants younger than 1 year and may interfere with live-attenuated measles vaccination. A single dose of measles vaccine administered to a child older than 12 months induces protective immunity in 95% of recipients. Because measles virus is highly contagious, a 5% susceptible population is sufficient to sustain periodic outbreaks in otherwise highly vaccinated populations. A second dose of vaccine, now recommended for all school-aged children in the United States, induces immunity in about 95% of the 5% who do not respond to the first dose. Slight genotypic variation in recently circulating strains has not affected the protective efficacy of live-attenuated measles vaccines.

Unsubstantiated claims that suggest an association between the measles vaccine and autism have resulted in reduced vaccine use and contributed to a recent resurgence of measles in countries where immunization rates have fallen to below the level needed to maintain herd immunity.

Modulation of immune functions by measles virus.

Measles virus remains among the most potent global pathogens killing more than 1 million children annually. A profound suppression of general immune functions occurs during and for weeks after the acute disease, which favors secondary infections. In contrast, virus-specific immune responses are efficiently generated, mediate viral control and clearance and confer a long-lasting immunity. Because they sense pathogen-associated molecular patterns, and subsequently initiate and shape adaptive immune responses, professional antigen-presenting cells (APC) such as dendritic cells are likely to play a key role in the induction and quality of the virus-specific immune response. Key features of immune suppression associated with measles virus, however, are compatible with interference with APC maturation and function and subsequent qualitative and quantitative alterations of T cell activation.

Measles virus induced immunosuppression: targets and effector mechanisms.
A profound, transient suppression of immune functions during and after the acute infection is the major cause of more than one million cases of infant deaths associated with measles worldwide. Concommittant with the generation of an efficient measles virus (MV) specific immunity, immune responses towards other pathogens are strongly impaired and provide the basis for the establishment and severe course of opportunistic infections.
The molecular basis for MV-induced immunosuppression has not been resolved as yet. Similar to other immunosuppressive viruses, MV is lymphotropic and viral nucleic acid and proteins are detectable in peripheral blood mononuclear cells (PBMC). It is considered central to MV-induced immunosuppression that PBMC isolated from patients largely fail to proliferate in response to antigen specific and polyclonal stimulation. The low abundancy of MV-infected PBMC suggests that MV-induced immunosuppression is not directly caused by infection-mediated cell loss or fusion, but rather by indirect mechanisms such as deregulation of cytokines or surface contact-mediated signaling which may lead to apoptosis or impair the proliferative response of uninfected PBMC. Evidence for a role of any of these mechanisms was obtained in vitro, however, much has still to be learned about the tropism of MV and its interactions with particular host cells such as dendritic cells in vivo.
Measles virus (MV) infection induces both an efficient MV-specific immune response and a transient but profound immunosuppression characterised by a panlymphopenia that occasionally results in opportunistic infections responsible for a high rate of mortality in children. On the basis of in vitro studies, the putative roles of dendritic cells (DCs) in MV infection are discussed. (1) DCs could participate in anti-MV innate immunity because MV turns on TNF-related apoptosis-inducing ligand (TRAIL)-mediated DC cytotoxicity. (2) Cross-priming by non-infected DCs might be the route of MV adaptive immune response. (3) After CD40-ligand activation in secondary lymphoid organs, MV-infected DCs could initiate the formation of Warthin-Finkeldey multinucleated giant cells, replicating MV and responsible for in vivo spreading of MV. There is integrated viral attack of the host immune system also targets DCs: Progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression observed in vivo is presented and their potential role in lymphopenia is underlined.
Measles virus (MV) infection induces both an efficient MV-specific immune response and a transient but profound immunosuppression characterised by a panlymphopenia that occasionally results in opportunistic infections responsible for a high rate of mortality in children. On the basis of in vitro studies, the putative roles of dendritic cells (DCs) in MV infection are discussed. (1) DCs could participate in anti-MV innate immunity because MV turns on TNF-related apoptosis-inducing ligand (TRAIL)-mediated DC cytotoxicity. (2) Cross-priming by non-infected DCs might be the route of MV adaptive immune response. (3) After CD40-ligand activation in secondary lymphoid organs, MV-infected DCs could initiate the formation of Warthin-Finkeldey multinucleated giant cells, replicating MV and responsible for in vivo spreading of MV. (4) We review how integrated viral attack of the host immune system also targets DCs: Progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression observed in vivo is presented and their potential role in lymphopenia is underlined.
Measle virus (MV) infection induces a transient but profound immunosuppression characterized by a panlymphopenia which occasionally results in opportunistic infections responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DC) in the respiratory mucosa or in the secondary lymphoid organs. After a brief presentation of DCs, we review progress in understanding the immunobiology of MV-infected DCs that could account for MV-induced immunosuppression. In addition, we develop the newly described TRAIL-mediated cytotoxic function of DCs that is turned on by MV infection, but also by interferons or double-stranded RNA (poly (I:C)). The model where the measles-associated lymphopenia could be mediated by TRAIL and the measles-induced immunosuppression could be transiently prolonged by Fas-mediated destruction of DCs.
Measles virus (MV) infection induces a profound immunosuppression responsible for a high rate of mortality in malnourished children. MV can encounter human dendritic cells (DCs) in the respiratory mucosa or in the secondary lymphoid organs. The purpose of this study was to investigate the consequences of DC infection by MV, particularly concerning their maturation and their ability to generate CD8+ T cell proliferation. We first show that MV-infected Langerhans cells or monocyte-derived DCs undergo a maturation process similarly to the one induced by TNF-alpha or LPS, respectively. CD40 ligand (CD40L) expressed on activated T cells is shown to induce terminal differentiation of DCs into mature effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression down-regulation. Moreover, the CD40L-induced cytokine pattern in DCs is modified by MV infection with inhibition of IL-12 and IL-1alpha/beta and induction of IL-10 mRNAs synthesis. Using peripheral blood lymphocytes from CD40L-deficient patients, we demonstrate that MV infection of DCs prevents the CD40L-dependent CD8+ T cell proliferation. In such DC-PBL cocultures, inhibition of CD80 and CD86 expression on DCs was shown to require both MV replication and CD40 triggering. Finally, for the first time, MV was shown to inhibit tyrosine-phosphorylation level induced by CD40 activation in DCs. MV replication modifies CD40 signaling in DCs, thus leading to impaired maturation. This phenomenon could play a pivotal role in MV-induced immunosuppression.

References

  • Sellin CI1, Jégou JF, Renneson J, Druelle J, Wild TF, Marie JC, Interplay between virus-specific effector response and Foxp3 regulatory T cells in measles virus immunopathogenesis. Horvat B. PLoS One. 2009;4(3):e4948.
  • Griffin DE1, Ward BJ, Esolen LM. Pathogenesis of measles virus infection: an hypothesis for altered immune responses. J Infect Dis. 1994 Nov;170 Suppl 1:S24-31.
  • Schneider-Schaulies S1, ter Meulen V.Modulation of immune functions by measles virus. Springer Semin Immunopathol. 2002;24(2):127-48.
  • Schneider-Schaulies S1, Niewiesk S, Schneider-Schaulies J, ter Meulen V. Measles virus induced immunosuppression: targets and effector mechanisms. Curr Mol Med. 2001 May;1(2):163-81.
  • Servet-Delprat C1, Vidalain PO, Valentin H, Rabourdin-Combe C. Measles virus and dendritic cell functions: how specific response cohabits with immunosuppression. Curr Top Microbiol Immunol. 2003;276:103-23.
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