The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community‐acquired pneumonia

Abstract

The cytokine, macrophage migration inhibitory factor (MIF), is encoded in a functionally polymorphic locus and subjects with high-expression MIF alleles are at an increased risk of inflammatory disease. Severe sepsis is the leading cause of death in intensive care units, and the prevailing hypothesis is that an excessive innate response contributes to its pathogenesis. To assess if MIF alleles influence the clinical course of infection, we conducted a case-control study to assess susceptibility and a parallel inception cohort study of community-acquired pneumonia (CAP) to assess risk of severe sepsis and 90-d mortality. Two distinct polymorphisms in the MIF promoter were analyzed: a G/C transition at -173 and a CATT repeat at -794. The frequency of both polymorphisms was similar in the CAP cohort (n=1739) and controls (n=639); however, the 90-d mortality was lower for the high-expression C allele (P=0.003). This association remained significant after adjusting for demographics, comorbid conditions, and disease severity score [hazard ratio=0.64 (0.44-0.91), P=0.01]. The hazard ratio was similar in different geographic subcohorts, and the association remained significant after adjusting for false discovery. These data indicate that polymorphisms associated with higher MIF expression may have a beneficial effect in community-acquired pneumonia.

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

“…with severe sepsis (31), and with survival in patients with community-acquired pneumonia (32). Carriage of the low-expression MIF allele (CATT 5 ) protected children from meningococcemia (33), but it predisposed older adults to Gram-negative bacteremia (34).…”

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis

“…Control sera were obtained from 143 disease-free subjects with similar demographics enrolled in the Genetic and Inflammatory Markers of Sepsis Study (30). Serum MIF levels were measured by sandwich ELISA using specific antibodies (27).…”

“…In infectious diseases, there are reported associations between high-expression MIF alleles and improved outcomes in outpatient pneumonia and meningococcal meningitis, but more severe malaria (29)(30)(31). Analogous to the role of MIF defined in mouse models, it seems that the influence of MIF on the severity of infectious diseases (exacerbation or protection) depends on the particular pathogen or disease pathology.…”

Role of macrophage migration inhibitory factor in age-related lung disease

“…Genetic variations consistent with low MIF expression are associated with increased risk for community-acquired pneumonia and recent studies have demonstrated that Mif-knockout mice have increased Streptococcus pneumoniae nasal carriage and decreased clearance of these bacteria (34,158). MIF is critical for the transcription of the pattern recognition receptor dectin-1, which is important for mediating clearance of Mycobacterium tuberculosis (33).…”