Macrophage Migration Inhibitory Factor (MIF) and Thyroid Hormone Alterations in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to be released from lymphocytes, macrophages and endothelial cells and also in animal models shown to be inducible with glucocorticoids (GC). In contrast, thyroxine seems to antagonize MIF activity. To investigate whether MIF is increased in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and possible correlations with GC dosing and thyroid hormone levels, 27 consecutive patients with active AAV were studied and followed prospectively. Disease activity was assessed using Birmingham Vasculitis Activity Score 2003 (BVAS) at baseline and at follow-up at 3 and 6 months, along with MIF, thyroid hormones free triiodothyronine (fT3) and free thyroxine (fT4), C-reactive protein (CRP) and creatinine. MIF was elevated significantly at baseline compared with follow-up at 3 and 6 months (8,618 pg/mL versus 5,696 and 6,212 respectively; P < 0.002) but did not correlate to CRP GC dose, creatinine or organ involvement. fT3 was depressed significantly at baseline compared with follow-up (1.99 pg/mL versus 2.31 and 2.67 respectively; P = 0.01) and correlated inversely to the BVAS score at baseline. We found a significant correlation between the MIF/fT4 ratio at baseline versus MIF/fT4 ratio at 6 months (p = 0.52, P < 0.005) and a trend between the baseline MIF/fT3 ratio versus MIF/fT3 ratio at 6 months (ρ = 0.39, P = 0.05). These results suggest a possible role for MIF and thyroid status in AAV. Further studies could reveal whether the association between AAV and thyroid hormone levels in the context of elevated MIF may present a link as well as a target of treatment.

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

“…These findings mirror the associations that have been reported previously between MIF polymorphisms and disease susceptibility or clinical severity in several autoimmune diseases, including systemic lupus erythematosus (13, 41), scleroderma (14), rheumatoid arthritis (15, 42), autoimmune liver disease (43), and celiac disease (44), as well as in granulomatous conditions such as sarcoidosis (6) and tuberculosis (25, 45). Furthermore, higher MIF plasma levels were noted in patients with GPA when compared to healthy controls, a finding previously reported in ANCA-associated vasculitis and other granulomatous diseases (8, 46, 47). Recent genome-wide association studies have identified several gene polymorphisms that are associated with susceptibility to GPA.…”

“…Furthermore, higher MIF plasma levels were noted in patients with GPA compared to healthy controls, a finding previously reported in AAV and other granulomatous diseases . Recent genome‐wide association studies have identified several gene polymorphisms that are associated with susceptibility to GPA.…”

Macrophage Migration Inhibitory Factor in Clinical Kidney Disease

“…In patients with severe sepsis, low plasma T4 concentrations were inversely correlated with plasma MIF concentrations ( 65 ). In our human study, there was a strong correlation over time between the baseline MIF/T4 ratio and the MIF/T4 ratio at 6 months in AAV patients in remission ( 61 ). Both the preclinical and clinical data therefore suggest that blocking the inflammatory active site of MIF may both reduce inflammatory responses and improve the availability of T4.…”

“…We studied MIF in a prospective study of incident AAV patients at induction treatment, and at follow-up at 3 and 6 months and found elevated plasma levels at baseline. MIF decreased significantly during follow-up when most patients were in remission, but remained still elevated as compared with controls at all time points ( 61 ). MIF levels did not correlate with CRP, creatinine, or organ involvement.…”

Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics

“…T4 is considered as a potential antagonist of MIF as the binding of T4 suppresses the catalytic activity of the hydrophobic pocket that is associated with the pro-inflammatory activities of MIF. In patients with active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), an increase in MIF was detected with a decreased fT3 level [46]. It is noteworthy that MIF binds to its natural receptor CD74, a type II transmembrane protein, to initiate downstream inflammatory signals.…”