We report a significant relationship between two known promoter polymorphisms in MIF
, not studied previously in genome-wide association studies, and the incidence and clinical severity of SLE (19
). The presence of the high expression MIF
haplotype, 7C, was associated with a lower incidence of SLE in Caucasians and to a lesser extent in African-Americans. When compared with ethnically matched controls, African-Americans with SLE had lower frequencies of high expression −173*C containing MIF
genotypes. We further observed that high expression MIF
genotypes are associated with a reduced incidence of ANA, which is the hallmark serologic abnormality of SLE (35
). When the SLE and the control groups were stratified by MIF
haplotype, a significant association between plasma MIF levels and high or low expression MIF
haplotype also was evident. These results collectively suggest that a genetic predisposition to increased MIF production may confer protection against the development of an autoimmune response leading to SLE
MIF is a pro-inflammatory mediator and an upstream regulator of TNFα expression. That an increase in TNFα production may confer protection against SLE was suggested over twenty years ago by the studies of McDevitt and colleagues, who reported that monocytes with the HLA-DR3 or DR4 SLE susceptibility loci showed low levels of inducible TNFα production (36
). These authors also found that TNFα administration to lupus-prone mice delayed the onset of autoimmunity (37
). More recently, it has been noted that the administration of anti-TNFα therapies can lead to the development of an ANA (38
), further pointing to the potentially protective role of TNFα in SLE.
Our data also indicate that patients with established SLE who have low expression, −794 CATT5
genotypes may be protected from the development of the inflammatory clinical manifestations of serositis, nephritis, and CNS involvement. These conclusions mirror the associations that have been reported previously between high expression MIF
alleles and disease severity in such inflammatory disorders as rheumatoid arthritis (10
), systemic sclerosis (14
), and asthma (15
). Thus, once autoimmunity develops, a genetic propensity for increased MIF
expression likely contributes to specific disease manifestations and end-organ damage.
What is less evident however, is how a genetic predisposition to increased MIF
expression and a downstream response that includes TNFα production (6
) may protect against the development of autoimmunity or clinical progression to SLE. High expression MIF
alleles have been shown to be associated with improved survival from certain infections, in part by augmenting innate immune responses (28
). It has been hypothesized that antecedent infections play a role in SLE by mechanisms that may involve antigenic mimicry, oligoclonal B or T cell activation, and loss of tolerance (39
) Thus, a more robust, MIF-dependent anti-microbial response may promote the clearance and the timely resolution of infection, thereby protecting against the development of autoimmunity. Our in vitro
data provide some support of this notion since monocytes with a high expression, 7C MIF
haplotype produce more MIF upon the stimulation of TLR7. Finally, recent data support a role for excessive apoptosis or defective clearance of apoptotic cells in the immunopathogenesis of SLE. Apoptotic nuclei may overwhelm the reticulo-endothelial system, break immune tolerance, and induce autoantibody production against nuclear components (40
). Higher level of MIF expression may reduce the apoptotic response during inflammation and decrease the likelihood of an autoimmune response progressing to SLE (30
Our ELISA analyses did not reveal a significant difference in circulating MIF levels among SLE patients with different disease manifestations. Although higher MIF levels in plasma may be anticipated in patients with active end-organ disease, the measurement of MIF in the blood may be confounded by several factors. Plasma may not accurately reflect elevated levels of MIF expression in sites of tissue inflammation, and baseline MIF levels are known to vary in a circadian rhythm (41
). While high-dose, exogenous glucocorticoids suppress MIF secretion, low doses may actually induce MIF release in vivo
. Thus, any conclusions based on the measurement of plasma MIF must be tempered by the heterogeneity of disease activity and the different treatment protocols in patients, which include glucocorticoids. Finally, lymphopenia is a feature of SLE and may reduce circulating, immune cell sources of MIF production.
Recent genome-wide association scans have identified several gene polymorphisms that are associated with susceptibility to SLE (4
). These analyses have been limited to the study of selected SNPs and have not examined microsatellite repeats such as the MIF
−794 CATT site. Moreover, these studies have focused on disease susceptibility and not clinical manifestations, and they have so far been limited to Caucasian populations.
The main limitation of the present study is in its cross-sectional design. Thus, the clinical phenotype was determined up to the point in time that the study was performed. Internationally established SLE activity and damage indices also were not available for many patients; therefore, the inclusion of end-organ involvement served as our assessment of disease severity. Finally, our findings do not replicate the report of Sanchez et al
. who found that, in a smaller Spanish population, there was an increased incidence of SLE in those individuals with the homozygous −173 C/C MIF
). It is possible that our conclusions differ because of sample size or unknown genetic variations between populations.
In summary, our genetic association analyses of prevalent and functional MIF polymorphisms suggest that MIF plays a dual role in SLE. In Caucasians and African-Americans, high expression MIF polymorphisms are associated with a lower incidence of SLE. In patients with established SLE however, low-expression MIF polymorphisms are associated with a lower incidence of end-organ injury. The possibility that some SLE patients demonstrate a propensity for end-organ disease based on their MIF allele may support a pharmacogenomic approach to MIF-directed that are entering clinical evaluation.