Response to Fatal Meningococcal Infection Based on Genetic Control of Cytokine P
Response to Fatal Meningococcal Infection Based on Genetic Control of Cytokine Production
ABSTRACT & COMMENTARY
Synopsis: TNF and IL-10 production may be genetically determined; low TNF and high IL-10 productions are each associated with poor outcome of meningococcal infection in relatives.
Source: Westendorp RGJ, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349:170-173.
Few illnesses are as devastating as acute invasive meningococcal infection. Why some patients progress quickly to death while others have much less volatile courses remains unknown. Dutch investigators reasoned that the production of tumor necrosis factor (TNF) and interlukin-10 on Gram-negative bacterial sepsis may be regulated by the human host’s genetic background. Westendorp et al had already shown that survivors of fulminant meningococcal infection had low TNF levels that were sustained long after their infections.
During 1988-1994, Westendorp and colleagues studied 80 patients with meningococcal disease. More than 90% of serogroups isolated were group B, and the remainder were group C. Sixteen patients died. Previously, 50 of the survivors were studied. In the current study, the authors extended their observations to first-degree relatives of survivors and non-survivors; 61 families participated. Cytokine production was measured, and the sequence of the TNF gene promoter was determined.
TNF and IL-10 production were examined for their correlation among the first-degree relative. In relatives of non-survivors, production of TNF in response to endotoxin stimulation was only half that of relatives of survivors P < 0.001). Conversely, IL-10 production was higher in relatives of patients who died. Using a method called the dichotomy around the median, the authors found that families with low TNF production had a 10-fold risk for dying with meningococcemia. Moreover, families with high IL-10 production had a 20-fold chance of dying. The analysis of allelic polymorphism showed no difference between the groups of families.
COMMENT BY JOSEPH F. JOHN, MD
This study indicates, at least for the two cytokines studied, that there is a strong genetic predisposition to a fatal outcome with invasive meningococcal infection. The basis for the underproduction of TNF was not because of differences in the part of the TNF gene that initiates transcription (i.e., the promoter). One site of promoter polymorphism around position 308 has been associated with altering the outcome of cerebral malaria but not, based on the current study, in meningococcemia.
The authors recognize that they and others have found that poor outcome in meningococcal infection may relate to high levels of TNF. They now refute that data, emphasizing the present findings of low TNF production in relatives of non-survivors. The opposite is true for IL-10 (i.e., high IL-10 production is a risk factor for fatal outcomes).
This study reminds us of the complex cytokine response initiated by Gram-negative infection in which production of certain cytokines, like TNF in specific diseases like meningococcemia, are protective and necessary for survival. High production of others like IL-10 have an adverse effect.
It will be interesting to see how each of these systems can be further perturbed to reduce the risk of death with meningococcemia. It is unlikely that use of a single "magic bullet" like antiendotoxin antibody for the therapy of Gram-negative sepsis will prove to be sufficient to modify clinical infection. It is more likely, at least for meningococcemia, that a cocktail of procytokine (like TNF agonists) and anticytokine (IL-10 antagonists) products will be necessary to alter an otherwise fatal outcome.
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