Increased serum levels of circulating CD40 ligand in patients with bullous pemphigoid: preliminary results.

BACKGROUND: Autoimmune bullous diseases are characterized by autoantibodies against specific adhesion molecules of the skin and/or mucous membrane. While these autoantibodies are known to play a primary role in the disease manifestation, it remains unknown how disease-specific autoreactive B cells and autoantibodies are induced. Recent studies have indicated the importance of the CD40 and CD40 ligand (CD40L) receptor-ligand pair in the immunopathogenesis of autoimmune diseases. CD40L circulates in soluble form, and some reports suggest that serum soluble CD40L (sCD40L) levels are increased in various autoimmune diseases. OBJECTIVES: To determine serum sCD40L levels in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), and to determine their correlation with clinical findings and laboratory findings. PATIENTS AND METHODS: Sera from 10 PV patients, 35 BP patients and 12 normal controls were subjected to ELISA assays to measure serum levels of sCD40L, anti-desmoglein-3 antibody and anti-BP180 antibody. RESULTS AND CONCLUSIONS: Circulating sCD40L levels were significantly elevated in BP patients, but not in PV patients. Serum sCD40L levels increased in the early stage of disease onset and recurrence in BP patients. In conclusion, circulating sCD40L levels may be a useful marker for early activation of autoimmune diathesis and, furthermore, an effective therapeutic target in patients with BP.

Serum chemokine profiles in patients with alopecia areata.

BACKGROUND: Although chemokines play an important role in various inflammatory diseases, there have been few studies about the role of chemokines in alopecia areata (AA). OBJECTIVES: To determine serum levels of chemokines in patients with AA and their clinical correlations. METHODS: Serum samples from 85 patients with AA, 20 patients with atopic dermatitis, 20 patients with psoriasis vulgaris and 28 normal controls were examined by the cytometric bead array assay assessing monokine induced by interferon (IFN)-gamma (MIG), RANTES, interleukin-8 (IL-8), IFN-inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and eotaxin levels. Secreted chemokine levels from peripheral blood mononuclear cells (PBMC) of patients with AA were also investigated. RESULTS: Serum MIG, RANTES, IL-8 and eotaxin levels were selectively increased in patients with AA compared with normal controls. Levels of MIG, RANTES and IL-8 secreted from PBMC of patients with AA were also increased. Furthermore, elevated serum MIG and RANTES levels significantly correlated with the disease activity. RANTES levels were nonsignificantly associated with a predisposition to atopy. CONCLUSIONS: These results suggest that MIG and RANTES play an important role in the development of AA and are useful as markers of disease activity and as therapeutic targets.

Serum chemokine profile in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune inflammatory disease causing blister formation at the dermoepidermal junction. Cutaneous infiltration of activated CD4+ T cells and eosinophils is an early event in blister formation during the disease process, suggesting that the trafficking of circulating leucocytes through the sites of inflammation is crucial in the pathogenesis of the disease. While the accumulated evidence suggests that some cytokines are involved in the pathogenesis, there have been few reports about serum chemokine profiles in patients with BP. OBJECTIVES: To determine serum profiles of various chemokines and their clinical association in patients with BP. METHODS: Concentrations of 10 chemokines - interferon (IFN)-gamma-inducible protein-10 (IP-10), monokine induced by IFN-gamma (MIG), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, eotaxin, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3 and growth-regulated oncogene-alpha- were measured in serum samples from 38 patients with BP, 16 with pemphigus vulgaris (PV) and 17 normal controls using a sandwich immunoassay-based multiplex protein array system. RESULTS: While there was no significant increase in any serum chemokine levels in patients with PV, serum levels of IP-10 and MCP-1 were significantly increased in patients with BP compared with healthy controls. Furthermore, serum levels of IP-10, MIG, MCP-1 and eotaxin in patients with BP increased significantly with disease severity as determined by the area affected. CONCLUSIONS: These observations suggest that an elaborately orchestrated network of chemokines, especially MCP-1 and IP-10, contributes to the pathomechanism of BP.

Increased serum levels of a proliferation-inducing ligand in patients with bullous pemphigoid.

BACKGROUND: B cells have been demonstrated to have critical roles in developing autoimmune bullous diseases. Recently identified tumor necrosis factor-like molecules, B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are essential molecules for B cell development, survival, and proliferation. Although the functions of APRIL have not been fully evaluated, recent studies suggest that circulating levels of APRIL are increased in various autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. OBJECTIVES: To determine serum APRIL levels in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), and compare those with clinical findings and laboratory findings. PATIENTS/METHODS: Sera from 15 PV patients, 43 BP patients, and 15 normal controls were subjected to ELISA assays to measure serum APRIL, BAFF, Dsg3, and BP180 levels. RESULTS AND CONCLUSIONS: Circulating APRIL levels were significantly elevated in BP patients but not in PV patients, and correlated with serum BAFF levels. Our study revealed that serum APRIL levels tended to be increased in the quite early stage of disease. In conclusion, circulating APRIL levels may be a useful marker for early activation of autoimmune diathesis, and furthermore, an effective therapeutic target molecule in patients with BP.

Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris.

BACKGROUND: BAFF [B-cell activating factor belonging to the tumour necrosis factor (TNF) family] is a member of the TNF superfamily that regulates B-lymphocyte proliferation and survival. It has been demonstrated that increased levels of soluble BAFF are associated with systemic autoimmunity in patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome, and in animal models of spontaneous autoimmune diseases. However, the significance of circulating BAFF in autoimmune bullous diseases is unknown. OBJECTIVES: To examine whether BAFF levels are elevated in the autoimmune blistering diseases pemphigus vulgaris (PV) and bullous pemphigoid (BP). METHODS: We examined sera obtained from 21 patients with PV, 39 patients with BP and 22 healthy donors. We performed enzyme-linked immunosorbent assays for soluble BAFF and each disease-specific antibody: antidesmoglein-3 antibody for PV and anti-BP180 antibody for BP. RESULTS: Significant elevations of serum BAFF levels were found in the patients with BP, but not with PV. There was apparently no significant association between the serum BAFF levels and titres of anti-BP180 antibodies in the patients with BP. However, serum BAFF levels tended to be more elevated in patients with a shorter disease duration. There was a tendency that BAFF levels increased before the anti-BP180 antibody levels increased at the onset of BP and quickly decreased in response to treatment. CONCLUSIONS: BAFF may be a useful marker for early activation of an autoimmune diathesis and may play a critical role in triggering activation of self-antigen-driven autoreactive B cells in BP.

Pseudoscleroderma associated with cancer.

In the period 1994-2002, we saw 71 patients with sclerotic skin changes; 66 were diagnosed with systemic sclerosis (SSc) while five (7%) were diagnosed with pseudoscleroderma associated with various malignancies. The mean duration of disease in these five patients was significantly shorter than that of patients with SSc. The incidence of positive antinuclear antibodies, Raynaud's phenomenon or oesophageal involvement in patients with pseudoscleroderma was significantly lower than that in patients with SSc. The distributions of skin sclerosis varied in each case. Serum basic fibroblast growth factor (bFGF) levels in the five patients with pseudoscleroderma were very elevated compared with levels in controls. Elevated expression of bFGF was detected on fibroblasts of affected skin and in one lung-cancer tissue sample obtained by excision.

Sclerosing panniculitis is associated with pulmonary hypertension in systemic sclerosis.

BACKGROUND: There have been no reports of patients with sclerosing panniculitis and systemic sclerosis (SSc). OBJECTIVES: To evaluate the incidence of sclerosing panniculitis in patients with SSc, and to investigate the clinical features of such cases. METHODS: In total, 128 patients with SSc treated at our clinic were investigated retrospectively. RESULTS: SSc patients with sclerosing panniculitis had pulmonary hypertension (PH), especially isolated PH, at a significantly higher incidence than those without. Among the SSc patients with PH, those with sclerosing panniculitis had pulmonary infarctions at a higher incidence than those without. CONCLUSIONS: Our results suggest that thrombosis caused by venous hypertension of the leg may be the main cause of PH in patients with SSc and sclerosing panniculitis. Sclerosing panniculitis may be a useful marker of PH in patients with SSc.

Autoantibodies to a collagen-specific molecular chaperone, heat-shock protein 47, in systemic sclerosis.

Heat-shock proteins are highly conserved and immunogenic proteins, which may be involved in the initiation and perpetuation of autoimmune diseases. Heat-shock protein 47 (HSP47) is expressed by collagen-secreting cells such as fibroblasts and serves as a collagen-specific molecular chaperone that plays a crucial role in collagen metabolism. Abnormal collagen accumulation and autoimmunity are characteristics of systemic sclerosis (SSc). We determined the presence and prevalence of autoantibodies to HSP47 in patients with SSc and also in tight-skin (TSK/+) mice, an animal model for SSc. Anti-HSP47 autoantibodies were present in SSc patients with a frequency of 26%, while patients with systemic lupus erythematosus, those with dermatomyositis, those with keloid and healthy subjects did not have anti-HSP47 antibodies. IgG1 and IgG2 were the major Ig isotypes of the autoantibodies. Patients positive for anti-HSP47 had a significantly shorter duration of disease than those who were negative. Anti-HSP47 autoantibodies were also positive in 79% of TSK/+ mice. Thus, autoantibodies to HSP47 were present in the sera from SSc patients as well as those from TSK mice, and may be associated with the pathogenesis of SSc.

Rheumatoid factor isotypes and anti-agalactosyl IgG antibodies in systemic sclerosis.

BACKGROUND: Rheumatoid factor isotypes and anti-agalactosyl IgG antibodies (anti-AG IgG) have been reported to be detected and correlated with the disease activity in some collagen diseases. OBJECTIVES: To study the frequency and the clinical significance of IgM, IgG and IgA rheumatoid factor (IgM-RF, IgG-RF and IgA-RF) and anti-AG IgG in patients with systemic sclerosis (SSc). METHODS: Seventy-nine serum samples from patients with SSc were examined by specific enzyme-linked immunosorbent assays. RESULTS: The levels of IgM-, IgG-, IgA-RF and anti-AG IgG were significantly higher in SSc patients than in normal healthy controls. The levels of IgM- and IgA-RF were significantly higher in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. IgM-, IgG- and IgA-RF and anti-AG IgG were significantly elevated in 39%, 32%, 23% and 35% of 79 SSc patients, respectively. The prevalence of pulmonary fibrosis, oesophageal involvement and cutaneous telangectasias in patients with elevated IgA-RF levels was significantly higher than in those with normal levels. The incidence of pitting scars of digits in those with elevated IgG-RF levels and the incidence of contracture of phalanges in those with elevated IgM-RF levels were significantly higher than in those with normal levels. The frequency of increased erythrocyte sedimentation rate in patients with elevated IgG-RF and the frequency of increased C-reactive protein in those with elevated IgM-RF were significantly greater than in those with normal levels. CONCLUSIONS: IgM-, IgG-, IgA-RF and anti-AG IgG can be serum indicators of specific clinical manifestations in SSc patients.

Serum levels of tissue inhibitor of metalloproteinase-1 and 2 in patients with eosinophilic fasciitis.

BACKGROUND: Serum levels of tissue inhibitor of metalloproteinases (TIMPs) have been reported to be elevated in patients with various connective tissue diseases. However, there has been no report that evaluates TIMPs in patients with eosinophilic fasciitis (EF). OBJECTIVES: To determine serum TIMP-1 and TIMP-2 levels in patients with EF and to investigate their clinical significance. METHODS: Immunohistochemical stainings were performed in normal and EF skin samples. Serum TIMP-1 and TIMP-2 levels of 11 patients with EF and 12 healthy individuals were also measured with specific enzyme-linked immunosorbent assays. RESULTS: The fascia of EF patients was stained only by TIMP-1. Serum TIMP-1 levels (mean +/- SD) were significantly higher in EF patients than in healthy individuals (206.3 +/- 65.4 vs. 145.2 +/- 36.2 ng mL(-1), P < 0.01). Serum TIMP-1 levels in EF patients were significantly correlated with serum gamma-globulin and IgG levels (r = 0.86, P < 0.05; r = 0.83, P < 0.005, respectively). CONCLUSIONS: These results suggest that TIMP-1 is involved in the pathogenesis of EF, and that TIMP-1 may be a useful marker for the disease activity as well as serum gamma-globulin or IgG levels.

Clinical features of patients with systemic sclerosis accompanied by rheumatoid arthritis.

OBJECTIVE: To determine the incidence of patients with both systemic sclerosis and rheumatoid arthritis (SSc-RA) and the clinical features of those with SSc-RA. METHODS: All 173 patients with systemic sclerosis in our clinic were investigated. RESULTS: Of the 173 patients with systemic sclerosis, 9 (5.2%) developed rheumatoid arthritis (RA). At the first visit, arthritis prior to Raynaud's phenomenon, increased C-reactive protein (CRP), and elevated rheumatoid factor (RF) were seen in patients with SSc-RA at a significantly higher incidence than in those without (44.4% versus 4.8%, p < 0.01; 55.6% versus 13.6%, p < 0.001; 247.2 +/- 312.1 versus 47.9 +/- 54.3 IU/ml, p < 0.001, respectively). Furthermore, in 8 of the 9 patients with SSc-RA, CRP was increased before the diagnosis of RA. CONCLUSION: These results suggest that systemic sclerosis patients with elevated RF and a history of arthralgia prior to Raynaud's phenomenon should be followed up with serial measurements of CRP due to their risk of developing RA.

Plasma plasmin-alpha2-plasmin inhibitor complex levels are increased in systemic sclerosis patients with pulmonary hypertension.

OBJECTIVE: To determine the frequency and clinical significance of plasma plasmin-alpha(2)-plasmin inhibitor complex (PIC) in patients with systemic sclerosis (SSc). METHODS: Plasma samples from 74 patients with SSc and 32 healthy volunteers were examined by a specific enzyme-linked immunosorbent assay. RESULTS: Elevated plasma PIC levels were present in 35 of the 74 patients (47.3%) with SSc. The patients with elevated plasma PIC levels had pulmonary hypertension (PH) at a significantly higher incidence than those with normal PIC levels (31.4 vs 7.7%, P<0.01). When PH was classified into isolated PH (IPH) and secondary PH (SPH), the presence of IPH was significantly greater in patients with elevated PIC levels than in those with normal levels (25.7 vs 5.1%, P<0.02). CONCLUSIONS: These results suggest that plasma PIC levels may be a marker of PH, especially IPH, in patients with SSc.