Medicine in focus
Measles: immune suppression and immune responses

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Abstract

Measles is a highly contagious viral disease that remains the leading vaccine-preventable cause of child mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. Several abnormalities of the immune system have been described, including changes in lymphocyte number and function, shifts in cytokine responses, immunomodulatory effects of interleukin-10, down regulation of interleukin-12, impaired antigen presentation, and altered interferon α/β signaling pathways. Although the current vaccine is very effective, knowledge of the molecular basis of the immune responses to measles virus could contribute to the development of a safer, more immunogenic measles vaccine. However, the safety of new measles vaccines must be carefully investigated, as two measles vaccines have resulted in unintended immunologic consequences: atypical measles following administration of the formalin-inactivated measles vaccine and increased mortality in girls following administration of high-titer measles vaccines.

Introduction

Measles is a highly contagious viral disease characterized by a prodromal illness of fever, coryza, cough, and conjunctivitis followed by the appearance of a diffuse maculopapular rash. Despite the availability of a protective, attenuated measles virus vaccine, measles remains the leading vaccine-preventable cause of childhood mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections. This period of increased susceptibility lasts for several weeks to months after the onset of rash, extending far beyond the resolution of clinical illness and elimination of detectable infectious measles virus.

Increased susceptibility to secondary infections following measles is attributed to immune suppression. Following early clinical observations that measles could exacerbate disease due to Mycobacterium tuberculosis, von Pirquet reported in the early 20th century that delayed-type hypersensitivity (DTH) responses to tuberculin were suppressed after measles. In the 1940s, clinicians investigated the use of measles virus-induced immunosuppression to treat autoimmune diseases, such as nephrotic syndrome. In addition to depressed immune responses to recall antigens (such as tuberculin), subsequent studies determined that antibody production and cellular immune responses to new antigens are impaired during the acute and convalescent stages of measles.

Research on the immune responses to measles virus, conducted in a variety of animal models (cotton rat, rhesus and cynomolgus macaques) and in vitro systems, has begun to characterize the mechanisms underlying measles virus-induced immune suppression. These systems provide important insights into the multiple pathways by which measles virus can modulate immune responses to other antigens. However, the mechanisms identified in these systems may not be operative in the complex immunologic network of humans. Proposed mechanisms of immune suppression must account for the fact that measles virus is cleared and a long-term protective immune response is established. Because immunologic abnormalities persist long after clearance of measles virus, and only a small proportion of peripheral blood cells are infected, mechanisms of immunosuppression that do not involve direct viral infection of lymphoid cells must be involved.

Section snippets

Pathogenesis

Several abnormalities of the immune system have been described, suggesting that multiple mechanisms are likely responsible for the immune suppression following measles virus infection (Schneider-Schaulies, Bieback, Avota, Klagge, & ter Meulen, 2002) (Fig. 1). Measles is accompanied by a transient lymphopenia, with a reduction in the number of CD4+ and CD8+ T-lymphocytes (Ryon, Moss, Monze, & Griffin, 2002). Increased surface expression of Fas (CD95) and annexin V staining on both CD4+ and CD8+

Therapy and prevention

Knowledge of the molecular mechanisms underlying measles virus-induced immune suppression could lead to improved therapies or to an understanding of how vitamin A reduces measles mortality. Several trials have demonstrated a reduction in morbidity and mortality in children with measles treated with vitamin A. vitamin A has profound and diverse effects on the immune system and the integrity of epithelial barriers, and its beneficial effect on measles is almost certainly mediated in part by

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