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Increased Macrophage Migration Inhibitory Factor (MIF) in the Sera of Patients with Extensive Alopecia Areata

2002; Elsevier BV; Volume: 118; Issue: 3 Linguagem: Inglês

10.1046/j.0022-202x.2001.01669.x

1523-1747

Tadamichi Shimizu, Riichiro Abe, Hirokazu Watanabe, Hiroshi Shimizu, Jun Nishihira, Yuka Mizue,

Nuclear Receptors and Signaling

To the Editor: The pathogenesis of alopecia areata is still uncertain. The immune system has been implicated in the pathogenesis of alopecia areata and certain immunomodulatory cytokines play an important role in this disease. The contribution of cytokines thought to be involved in the pathogenesis of extensive alopecia areata has been studied. Several lines of clinical and experimental data point towards cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, which may be crucial inducers of hair loss in alopecia areata. For example, IL-1 has been shown to inhibit hair growth in vitro and may be one of the factors triggering the arrest of hair growth in vivo (Harmon and Nevins, 1993Harmon C.S. Nevins T.D. IL-1α inhibits human hair follicle growth and hair fiber production in whole-organ cultures.Lymphokines Cytokines Res. 1993; 12: 197-203PubMed Google Scholar). TNF-α also inhibits hair follicle growth in vitro (Philpott et al., 1996Philpott M.P. Sanders D.A. Bowen J. Kealey T. Effects of interleukins, colony- stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata.Br J Dermatol. 1996; 135: 942-948Crossref PubMed Scopus (141) Google Scholar). Thus, IL-1 and TNF-α may play a role in the pathophysiology of inflammatory hair loss in alopecia areata. MIF is the first lymphokine reported to prevent the random migration of macrophages (Bloom and Bennett, 1966Bloom B.R. Bennett B. Mechanism of reaction in vivo associated with delayed-type hypersensitivity.Science. 1966; 153: 80-82Crossref PubMed Scopus (1225) Google Scholar). A recent finding demonstrated that MIF functions as an initiator of inflammation and the immune response by the regulation of a number of proinflammatory cytokines, including TNF-α and IL-1 (Calandra et al., 1994Calandra T. Bernhagen J. Mitchell R.A. Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor.J Exp Med. 1994; 179: 1895-1902Crossref PubMed Scopus (864) Google Scholar). In human inflammatory diseases, MIF has a regulatory role in acute respiratory distress syndrome, asthma, and rheumatoid arthritis. In skin diseases, we have reported that MIF production by peripheral blood mononuclear cells was markedly upregulated in patients with atopic dermatitis and that increased serum MIF levels were observed (Shimizu et al., 1999Shimizu T. Abe R. Ohkawara A. Nishihira J. Increased production of macrophage migration inhibitory factor by PBMCs of atopic dermatitis.J Allergy Clin Immunol. 1999; 104: 659-664Abstract Full Text Full Text PDF PubMed Google Scholar). We postulated that MIF might play a key role in the pathogenesis of extensive alopecia areata. In this study, we analyzed the serum MIF concentration in patients with alopecia areata and normal healthy individuals. The study group composed of 27 patients with extensive alopecia areata (with >50% bald area of the scalp; aged from 13 to 32 y, mean age 21.3 ± 1.3 y; nine males and 18 females; the duration of their alopecia areata was between 6 mo and 11 y, mean 3.8 y), 11 patients with mild alopecia areata (1–3 patchy hair loss lesions with < 10% bald area of the scalp and with an inactive condition; aged from 11 to 36 y, mean age 24.9 ± 1.6 y; two males and nine females; the duration of their alopecia areata was between 2 mo and 3 y, mean 1.2 y), and 12 normal healthy individuals (aged from 18 to 45 y, mean age 29.3 ± 1.8 y; four males and eight females). None of the patients was having topical immunotherapy, systemic, or topical steroids therapy at the time of the study. Eight patients with extensive alopecia areata showed successful hair regrowth (100% hair regrowth) when treated with topical sensitizer (squaric acid dibutylester or diphencyprone) and the serum was obtained at least 1 mo after the final topical therapy. The serum level of MIF was measured by enzyme-linked immunosorbent assay (ELISA) as described previously (Shimizu et al., 1999Shimizu T. Abe R. Ohkawara A. Nishihira J. Increased production of macrophage migration inhibitory factor by PBMCs of atopic dermatitis.J Allergy Clin Immunol. 1999; 104: 659-664Abstract Full Text Full Text PDF PubMed Google Scholar). MIF levels were compared using the Student's t test (p < 0.05). Five patients' scalp biopsy specimens with an extensive alopecia areata were immunohistochemically examined for MIF immunoreactivity. Sections were stained using an avidin-biotin-peroxidase complex procedure using a Vector ABC kit according to the manufacturer's protocol (Shimizu et al., 1996Shimizu T. Ohkawara A. Nishihira J. Sakamoto W. Identification of macrophage migration inhibitory factor (MIF) in human skin and its immunohistochemical localization.FEBS Lett. 1996; 381: 199-202Abstract Full Text PDF PubMed Scopus (133) Google Scholar). The mean serum MIF concentration in extensive alopecia areata patients (n = 27) was 50.6 ± 5.7 ng per ml (mean ± SE), whereas that of mild alopecia areata (n = 11) or healthy individuals (n = 12) was 15.1 ± 2.1 ng per ml or 8.9 ± 1.3 ng per ml, respectively (p < 0.001) (Figure 1a). In eight extensive alopecia areata patients serum MIF was also examined before (>50% bald area of the scalp) and after hair regrowth (100% hair regrowth of the scalp). The mean serum MIF concentration before treatment was 55.8 ± 14.9 ng per ml, whereas that after the treatment was 15.7 ± 2.8 ng per ml (p < 0.01) (Figure 1b). Immunohistochemical studies with an anti-MIF antibody were positive in perifollicular-infiltrated lymphocytes of telogen hair follicles in patients with extensive alopecia areata (Figure 2).Figure 2Immunohistochemical analysis of MIF expression in an extensive alopecia areata scalp biopsy. Tissue specimens were stained with a Vector ABC staining kit using polyclonal antihuman MIF antibody. (A) Intense MIF staining was observed in the perifollicular-infiltrated lymphocytes of telogen hair follicles. Hair follicle MIF staining was also apparent. (B) No specific positive staining was observed using the tissue sample stained with preimmune rabbit IgG. Scale bar: 50 µm.View Large Image Figure ViewerDownload (PPT) The results presented here demonstrate that the mean levels of MIF in the sera were significantly elevated in patients with extensive alopecia areata. Alopecia areata is considered to be a T cell-mediated autoimmune disease involving the hair follicle, which is characterized by peribulbar infiltration by activated T cells (Bodemer et al., 2000Bodemer C. Peuchmaur M. Fraitaig S. et al.Role of cytotoxic T cells in chronic alopecia areata.J Invest Dermatol. 2000; 114: 112-116Crossref PubMed Scopus (106) Google Scholar). Although the function of these T cells in the pathogenesis is still unknown, cytokines released from T cells are important mediators leading to hair loss in alopecia areata. It is speculated that MIF in inflammatory diseases may be produced by multiple cellular sources such as activated T lymphocytes and monocytes. On the basis of our immunohistochemical results, we speculate that activated T cells might be a potential source of serum MIF. MIF is known to stimulate the production of proinflammatory cytokines such as IL-1 and TNF-α by macrophage and vice versa (Bacher et al., 1996Bacher M. Metz C.N. Calandra T. et al.An essential regulatory role for macrophage migration inhibitory factor in T-cell activation.Proc Natl Acad Sci USA. 1996; 93: 7849-7854Crossref PubMed Scopus (596) Google Scholar). From the data available to date, together with these results, we believe that a positive feedback loop may be the cause of the inflammatory interaction between IL-1, TNF-α, and MIF in this disease. It is known that the proinflammatory mediators IL-1 and TNF-α are potent inhibitors of hair follicle cell proliferation with a concomitant inhibition of hair growth (Philpott et al., 1996Philpott M.P. Sanders D.A. Bowen J. Kealey T. Effects of interleukins, colony- stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata.Br J Dermatol. 1996; 135: 942-948Crossref PubMed Scopus (141) Google Scholar). Therefore, these inflammatory cytokines may be implicated in the induction or continuation of damage of hair follicles and MIF may play an important part in the pathophysiology of inflammatory hair loss conditions such as alopecia areata. Whereas alopecia areata is a common disease, treatment of its extensive form is difficult and its outcome is not easily predicted. Recent work demonstrated that anti-MIF antibodies have a potent therapeutic action in the severe inflammatory condition such as murine hepatitis (Kobayashi et al., 1999Kobayashi S. Nishihira J. Watanabe S. Todo S. Prevention of lethal acute hepatic failure by antimacrophage migration inhibitory factor antibody in mice treated with bacille Calmette-Guerin and lipopolysaccharide.Hepatology. 1999; 29: 1752-1759Crossref PubMed Scopus (68) Google Scholar). We assume that the elevated serum levels of MIF may reflect the inflammatory symptoms in extensive alopecia areata and that control of MIF production may have important therapeutic implications. This research was supported by a Grant-in-Aid for research (No. 11670813–00) from the Ministry of Education, Science, and Culture of Japan.