Correspondence: Taisuke Ito, M.D., Ph.D., Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu 431-1192, Japan. Email: firstname.lastname@example.org
A 38-year-old female patient suffered from alopecia areata totalis followed by human T-cell lymphotropic virus-1-associated myelopathy (HAM). These two diseases have recently been considered to be related to cell-mediated autoimmune reactions. Immunohistochemistry revealed accumulation of CXCR3+ CD8+ T cells around hair bulbs in alopecic lesions. Furthermore, flow cytometric analysis showed the elevated frequency of CD8+ human leukocyte antigen DR+-activated T cells at the initial time and declined at the hair regrowth phase with HAM. CD4+ CD25+ adult T-cell leukemia/lymphoma cells were elevated at hair loss phase and decreased after improvement of hair loss. These results suggest that autoreactive and cytotoxic CD8+ T cells induce not only alopecia areata but also HAM in ATL patients. This case highlights that the autoimmune reactions may play an important role in the pathogenesis of alopecia areata and HAM.
Alopecia areata (AA) has recently been considered as a tissue-specific autoimmune disease, although the autoantigen has not been fully determined.[1-4] An accumulation of CD4+ and CD8+ T cells in and around hair follicles is the characteristic feature of AA and histologically called “swarm of bees”. Melanogenesis-related proteins are strong candidate targets of CD8+ T cells (cytotoxic T cells, Tc1) that react with autoantigens after the collapse of hair follicle immune privilege.[6, 7] Recent studies also indicate that class I major histocompatibility complex-restricted CD8+ T cells can independently mediate the pathological response in AA. It is known that human T-cell lymphotropic virus-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), and may induce HTLV-1-associated myelopathy (HAM) if the patient's immunity against HTLV-1 highly operates. Here, we describe the development of AA in a patient with HAM.
A 38-year-old female patient felt itchy on her scalp 1 month prior to the scalp hair loss, and consequently suffered total hair loss. Therefore, she was referred to our outpatient clinic due to a 1-month history of total scalp hair loss (Fig. 1a). Dermoscopic observation revealed exclamation mark hairs and black dots in the hair-loss lesion. A biopsied specimen showed an accumulation of lymphocytes around the hair bulb (“swarm of bees”; Fig. 1b). There were some eosinophils in the dermis but not around hair bulbs. Given these results, her hair loss was diagnosed as alopecia areata totalis. She was topically treated with betamethasone butyrate propionate. One month after the treatment, she felt mild myalgia and walking disturbance, and was referred to the Department of Neurology at another hospital. She showed spastic paraplegia, bladder and rectal disturbance, and extensive deep tendon reflex. Bone marrow aspiration was performed, and HTLV-1 genome was detected by Southern blot analysis. Anti-HTLV-1 antibody was positive in her serum. Her mother was also positive for anti-HTLV-1 antibody. The patient was subsequently diagnosed as having HAM. She was treated with non-steroidal anti-inflammatory drugs and rehabilitation. Fortunately, her symptoms were not so developed, and stable for 6 months after the treatments.
Immunohistochemical analysis of the alopecia lesion revealed that both CD4+ (Fig. 1c) and CD8+ T cells (Fig. 1d) infiltrated around hair follicles. These T cells expressed CXCR3 (Fig. 1e), representing T-helper (Th)1 and Tc1 cells. CCR4+ cells (Th2 cells and tumor cells) accumulated to a lesser extent.
The patient's peripheral blood mononuclear cells (PBMC) were examined by flow cytometry at the time of diagnosis of AA and HAM and at the time of resolution (3 months after the topical treatment with betamethasone butyrate propionate). The frequency of T cells positive for CD4 and CD25, a combination marker of HTLV-1-infected tumor cells, was increased in the patient's PBMC at the time of diagnosis (5.2%; Fig. 2a), and decreased 3 months later (0.2%; Fig. 2b). CD4+ CCR4+ T cells, another T-cell population including the tumor cells, were also reduced in percentage (data not shown). During this clinical course, the percentage of CD8+ human leukocyte antigen-DR+ T cells (largely activated Tc1 cells) was elevated at the initial time (3.4%; Fig. 2c) and declined at the hair regrowth phase (0.3%; Fig. 2d). Thus, as the alopecia was improved, activated Tc1 cells as well as the tumor cells were decreased in the blood.
To our knowledge, this is the first reported case of AA with HAM. The pathogenesis of HAM remains incompletely understood, but the autoimmunity theory has been put forward.[9, 10] HTLV-1-infected cells infiltrate the spinal cord and reside in the neural tissues. HTLV-1-specific Tc1 cells recognize these infected cells and induce apoptosis of the infected cells and production of Bcl-3 protein. Consequently, inflammatory cytokines are produced in neural tissues, causing severe damage. While a relationship between HAM and autoimmunity has been well discussed, the association of HTLV-1 with a variety of autoimmune disorders including T-cell alveolitis, myopathy, uveitis, arthritis and Sjögren's syndrome has been reported.[11-14] There are significantly more HTLV-1-specific CD8+ T cells in patients with HAM and the other autoimmune disorders than in asymptomatic HTLV-1 carriers. Thus, the diversity, frequency and repertoire of HTLV-1-specific Tc1 clones may be related to the hyperimmune response in patients with HAM.
In our case, CXCR3+ CD4+ T cells, but not CCR4+ CD4+ T cells, were predominantly observed around the hair bulb. Therefore, it seems that the hair follicles were not attacked by ATLL tumor cells per se, but autoreactive Tc1 cells served as effector cells. It is tempting to speculate that activated Tc1 cells developed as a result of HTLV-1-infected tumor cell elimination and attacked hair follicle autoantigens.