Macrophage migration inhibitory factor (MIF): Genetic evidence for participation in early onset and early stage rheumatoid arthritis
Highlights
► MIF polymorphisms are involved in rheumatoid arthritis susceptibility. ► −794 CATT7 allele is associated with early onset RA. ► MIF and TNFα soluble levels correlate positively in RA. ► MIF levels correlated negatively with years of disease duration.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population worldwide. It is characterized by chronic and symmetric inflammation of synovial joints; leading to joint destruction, loss of function and disability. The immunopathogenesis of RA is recognized to be multifactorial, with a significant contribution of genetic factors; approximately 60% of disease susceptibility has been estimated to be due to genetics [1].
Immune cytokines are central regulators of the inflammatory process and their role in the pathogenesis of RA has been well established in the past decade. Macrophage migration inhibitory factor (MIF) was first postulated to be an important contributor to RA pathophysiology based on murine and clinical investigations [2], [3]. Discovered over 50 years ago by its ability to inhibit the random migration of macrophages [4], the molecular identify of MIF remained unknown until its unambiguous cloning in 1993 [5]. MIF now is recognized to be a key regulator of the innate and adaptive immune responses [6]; it promotes the expression and secretion of downstream pro-inflammatory mediators such as: TNFα, IL-1β, IL-2, IL-6, IL-8, IL-12, adhesion molecules, chemokines and matrix metalloproteinases [7], [8], [9], [10], [11], [12], [13]. Moreover, MIF inhibits p53 dependent apoptosis [14], and favors T cell activation and proliferation [11]. Of note, MIF also is an endogenous counter-regulator of the immunosuppressive action of glucocorticoids. Once secreted; it overrides the anti-inflammatory effects of glucocorticoids, creating a regulatory loop whereby MIF and glucocorticoids regulate both the setpoint and the expression of inflammation and immunity [8], [15].
The serum and synovial fluid of RA patients exhibit high levels of MIF that correlate with disease evolution, which suggest a role of MIF in disease progression [3], [16], [17]. Moreover, in animal models of arthritis, the role of MIF on disease pathogenesis is well established. Treatment with anti-MIF antibodies or a DNA vaccine delays the onset of disease and leads to a marked decline in incidence and severity [18], [19], [20].
Two promoter polymorphisms have been identified on MIF gene: a CATT5–8 tetranucleotide repeat at −794 and a G > C transversion at −173 [21]. The presence of the C allele on −173 may facilitate the binding of the AP4 transcription factor and in vitro and in vivo studies suggest that this allele is associated with increased MIF gene expression and protein levels [21], [22]. With respect to the −794 CATT5–8 polymorphism, gene reporter assays have demonstrated that the CATT5 allele has the lowest transcriptional activity [23] while carriers of higher repeats (CATT6, CATT7, CATT8) alleles show higher circulating MIF levels than non-carriers [22], [24], [25].
An association between these MIF promoter polymorphisms with susceptibility [26], [27] or severity [22], [23] of RA and other autoimmune and inflammatory diseases has been reported in several populations, as well as strong linkage disequilibrium between the −794 CATT7 and −173*C allelic variants. Consistent with the proposed role of MIF on early stages of RA, Martinez et al. recently showed an association of the −173*C allele with RA susceptibility, mainly on early onset Spanish patients [27].
The aim of this study was to investigate the potential association of these MIF genetic variants with RA susceptibility and activity as well as with MIF serum levels in a western Mexican population. Mexican mestizo population is composed of an admixture of Amerindian, European and African genes, and shows significant heterogeneity and shows an asymmetric genetic distribution throughout the country [28], the genetic contribution of the MIF gene to autoimmune diseases has not been previously analyzed in this population. Furthermore, the association of serum MIF levels with clinical biomarkers of disease was also determined.
Section snippets
Subjects
The study group was composed of 226 RA patients recruited from two centers in Jalisco, Mexico (Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Guadalajara and Hospital Valentín Gómez Farías, Zapopan) and classified according to the 1987 American College of Rheumatology (ACR) criteria [29]. As a control group, 210 unrelated, healthy subjects (HS) as identified by self-report and recruited from western Mexico general population were included. To prevent results from deviation and include
Patients
The clinical characteristics of the 226 RA patients in this study are shown in Table 1. The median age of RA patients was 47 years and 94% were female. In general, the RA patients had longstanding disease with a median disease duration of 8 years as well as moderate disease activity scores as evaluated by DAS28 [30], and mild disability as assessed through the Spanish HAQ-DI index [38]. In terms of ACPA and RF levels, 87% and 86% of RA patients were positive respectively, while only 8% of HS were
Discussion
Autoimmune disorders are complex pathologies that involve both genetic and environmental factors. The investigation of gene polymorphisms involved in the pathogenesis of this sort of diseases has been increasing over the last years. With respect to RA several genetic loci have been described to be associated with disease susceptibility and severity in Caucasian populations, with the best established association to be at the HLA-DR locus (OR > 30) [41]. Other associated genes comprise PTPN22
Acknowledgements
This study was supported by Grant No. 180663 to JFMV from the National Council of Science and Technology (CONACYT Ciencia Básica-Universidad de Guadalajara). The funding source had no involvement on any steps of the study.
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