Abstract

Objectives. There have been many studies suggesting that localized scleroderma has a strong autoimmune background, although the lesions are usually limited to the skin and subcutaneous tissue. Here we summarize previous data on the autoimmunity of localized scleroderma, mostly published in the last two decades, because there has not been a review paper summarizing autoimmunity in this disorder.

Methods. We classified the previous reports into three categories: antinuclear antibodies; cytokine and soluble receptors; and cell adhesion molecules and cell surface molecules. In each category, we introduce the important investigations.

Results. High frequencies of antinuclear antibodies, detected by the indirect immunofluorescence method using cultured cells, are confirmed by many groups. The major autoantigens have been revealed to be histones. Recently, anti-topoisomerase II α antibody has been found to be detected highly frequently in localized scleroderma, while anti-topoisomerase I antibody, which is highly specific for systemic sclerosis, has not been detected in any case of localized scleroderma. In other studies, elevated serum cytokines and cell adhesion molecules suggest the immunoactivation of localized scleroderma.

Conclusions. Many previous studies conclude that localized scleroderma involves autoimmune abnormalities and is one of the organ-specific autoimmune disorders targeting mainly skin, although the types of autoimmune abnormality are different from systemic sclerosis.

Scleroderma is a chronic disease of unknown aetiology characterized by skin fibrosis and is divided into two clinical entities: localized scleroderma and systemic sclerosis (SSc). Localized scleroderma differs from SSc in that it is not accompanied by Raynaud's phenomenon, acrosclerosis and internal organ involvement and the life prognosis of patients with localized scleroderma is good.

In localized scleroderma, the lesions are usually limited to the skin and subcutaneous tissue as fatty tissue, muscle and sometimes bone beneath the cutaneous lesions, lacking Raynaud's phenomenon, arthritis or other systemic symptoms. Tuffanelli and Winkelmann classified localized scleroderma into the following three types [1], and this classification has been widely accepted:

  • Morphea is usually characterized by circumscribed, sclerotic plaques with an ivory-coloured centre and surrounding violaceous halo. Punctate morphea is considered to be a variant of morphea, in which there appear small plaque complexes.

  • Linear scleroderma appears in a linear, bandlike distribution, and scleroderma en bondes is a synonym of linear scleroderma. Frontal or frontoparietal linear scleroderma (en coup de sabre) is characterized by atrophy and a furrow or depression that extends below the level of the surrounding skin.

  • Generalized morphea, the most severe form of localized scleroderma, is characterized by widespread skin involvement with multiple indurated plaques, hyperpigmentation and frequent muscle atrophy. Although the diagnostic criteria for generalized morphea differ among investigators, we defined patients as having generalized morphea when they fulfilled the following two criteria: (i) four or more lesions more than 3 cm in diameter, irrespective of whether they were of the morphea or linear type; and (ii) involvement of two or more areas of the body out of seven areas, the seven areas being the head and neck, the right upper extremity, the left upper extremity, the anterior trunk, the posterior trunk, the right lower extremity and the left lower extremity [2]. Patients who did not meet these criteria were diagnosed as having morphea or linear scleroderma according to the morphological features. All of our studies were conducted using this classification.

Autoimmune abnormalities of localized scleroderma have been well recognized in the last two decades and recently this disease has generally been considered to have an autoimmune background. The first description of this concept was proposed by our study in 1983, which reported a high frequency of anti-nuclear antibodies (72.7%, 16/22), using cultured human cells as the substrate for detection by the indirect immunofluorescence method [3].

At present, the specificity of antinuclear antibodies in localized scleroderma is considered to be as described in the following sections (Table 1). In addition, immune activation was shown in localized scleroderma, suggested by the elevation of some cytokines (Table 2), soluble cell adhesion molecules and soluble cell surface antigens (Table 3).

Table 1.

Antinuclear antibodies in localized scleroderma

Immunological abnormalities Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
Highly specific ANA     
Homogeneous ANA by indirect immunofluorescence using HeLa cells 73% – 0% 
Anti-single-stranded antibody 12 50% – – 
Anti-histone antibody 16 47% 20% 0% 
Anti-topoisomerase II α antibody 21 76% 14% 7% 
ANA commonly detected in SSc     
Anticentromere antibody 12% 42% 0% 
Anti-U3 RNP antibody 24 4% – – 
Anti-Th/To RNP antibody 25 4% – – 
Other autoantibodies     
Rheumatoid factor 17 60% – – 
Antiphospholipid antibody 23 46% 0% 5% 
Anti-hsp-73 antibody 28 33% 41% 0% 
Anti-mitochondria antibody 33 10% – 0% 
Anti-Fc-γ receptor antibody 30 54% 66% 0% 
Anti-fibrillin 1 antibody 34 28% – 6% 
Immunological abnormalities Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
Highly specific ANA     
Homogeneous ANA by indirect immunofluorescence using HeLa cells 73% – 0% 
Anti-single-stranded antibody 12 50% – – 
Anti-histone antibody 16 47% 20% 0% 
Anti-topoisomerase II α antibody 21 76% 14% 7% 
ANA commonly detected in SSc     
Anticentromere antibody 12% 42% 0% 
Anti-U3 RNP antibody 24 4% – – 
Anti-Th/To RNP antibody 25 4% – – 
Other autoantibodies     
Rheumatoid factor 17 60% – – 
Antiphospholipid antibody 23 46% 0% 5% 
Anti-hsp-73 antibody 28 33% 41% 0% 
Anti-mitochondria antibody 33 10% – 0% 
Anti-Fc-γ receptor antibody 30 54% 66% 0% 
Anti-fibrillin 1 antibody 34 28% – 6% 
Table 2.

Cytokine and soluble receptor abnormalities in localized scleroderma

Elevated factors Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
IL-2 38 27% 5% 0% 
IL-4 38 17% 5% 0% 
IL-6 38 47% 35% 0% 
sIL-2 receptor 41 21% 20% 0% 
sIL-6 receptor 42 24% 35% 0% 
sgp130 42 42% 5% 0% 
Elevated factors Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
IL-2 38 27% 5% 0% 
IL-4 38 17% 5% 0% 
IL-6 38 47% 35% 0% 
sIL-2 receptor 41 21% 20% 0% 
sIL-6 receptor 42 24% 35% 0% 
sgp130 42 42% 5% 0% 
Table 3.

Abnormalities of soluble forms of cell adhesion molecules and cell surface molecules in localized scleroderma

Elevated factors Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
sICAM-1 43 25% 35% 0% 
sVCAM-1 44 19% 35% 3% 
sE-selectin 44 20% 40% 0% 
sCD23 45 20% 25% 5% 
sCD4 46 18% 10% 5% 
sCD8 46 20% 30% 0% 
sCD30 47 33% 33% 0% 
Elevated factors Reference Frequency in localized scleroderma Frequency in systemic sclerosis Frequency in healthy controls 
sICAM-1 43 25% 35% 0% 
sVCAM-1 44 19% 35% 3% 
sE-selectin 44 20% 40% 0% 
sCD23 45 20% 25% 5% 
sCD4 46 18% 10% 5% 
sCD8 46 20% 30% 0% 
sCD30 47 33% 33% 0% 

We summarize the previous studies related to an autoimmune background and immune activation, the latter of which is comparable to the diffuse form of SSc. Many previous studies conclude that localized scleroderma involves autoimmune abnormalities, though they are different from SSc.

Antinuclear antibody

In an indirect immunofluorescence test for antinuclear antibody, the sensitivity varied with the type of substrate used and cultured human cell substrates were shown to increase sensitivity compared with animal tissue sections. Therefore, cultured human cells such as HEp-2 cells are widely used in the screening test for antinuclear antibody at the clinical level nowadays.

The first investigation on the frequency of antinuclear antibody in localized scleroderma using cultured human cell substrates was reported by us in 1983 and demonstrated greater sensitivity (72.7%) [3] than the animal tissue sections used in previous reports [4–7]. The high frequency of antinuclear antibody in localized scleroderma by an indirect immunofluo- rescence method using cultured cells was confirmed by other groups [8–11]. Immunofluorescence staining patterns, including homogeneous, speckled or nucleolar stainings, were not uniform in localized scleroderma, suggesting the heterogeneity of antinuclear antibody in localized scleroderma, although a major immunofluorescence pattern was homogeneous with chromosomal staining; the major nuclear antigens of this homogeneous pattern with chromosomal staining were not identified at that time, because anti-double-stranded DNA (dsDNA) or anti-topoisomerase I antibody were not detected [3].

We have the impression that patients with early onset have more elevated titres of antinuclear antibodies and hope to confirm this after accumulation of more cases.

Anti-single-stranded DNA antibody

The first report on the presence of anti-single-stranded DNA (ssDNA) antibody was by Rodnan et al. in 1977 [4], although this was an abstract and the details were not described. Seven years after this report, Falanga et al. described the high titre of anti-ssDNA antibody in linear scleroderma; all seven patients were initially found to have antibodies to dsDNA using the Farr technique; however, their detailed investigation using the Crithidia luciliae assay and ssDNA labelled with iodine 131 disclosed high titres of antibodies to ssDNA and absent double-stranded DNA antibodies [12]. Moreover, anti-ssDNA antibody was considerably higher than the mean for unselected patients with systemic lupus erythematosus (SLE). The next year, they showed a positive correlation between anti-ssDNA antibody and joint contracture or active disease with a duration of longer than 2 yr [8].

We have also confirmed elevated levels of anti-single-stranded antibodies of the IgG and IgM isotypes by enzyme-linked immunosorbent assay (ELISA) analysis in localized scleroderma [13]. Moreover, we found that the patients with linear scleroderma accompanied by muscle involvement, such as muscle sclerosis, muscle atrophy or muscle convulsion, had significantly elevated levels of anti-ssDNA antibody compared with patients without muscle involvement [14]. The titre of anti-ssDNA antibody is well correlated with disease activity and responds to oral corticosteroid treatment in patients with severe muscle involvement; two typical cases are shown in Fig. 1 (Takehara, unpublished data).

Fig. 1.

Clinical course, treatment and titres of anti-ssDNA antibodies. Case 1 was a 15-yr-old female who complained of disturbed movement of her left lower leg. She was treated successfully with betamethasone at 1 mg per day. Case 2 was a 9-yr-old male who complained of a rapid increase in multiple sclerotic plaques. He was treated successfully with prednisolone at 10 mg per day.

Fig. 1.

Clinical course, treatment and titres of anti-ssDNA antibodies. Case 1 was a 15-yr-old female who complained of disturbed movement of her left lower leg. She was treated successfully with betamethasone at 1 mg per day. Case 2 was a 9-yr-old male who complained of a rapid increase in multiple sclerotic plaques. He was treated successfully with prednisolone at 10 mg per day.

Subsequently, Falanga et al. reported the high frequency (59%) of anti-ssDNA antibody in morphea and generalized morphea, with the highest levels of ssDNA binding observed in patients with generalized morphea [14]. The frequency of antibodies to ssDNA was higher in patients with clinical evidence of active lesions compared with inactive disease.

Ruffatti et al. also confirmed the high frequency (38.5%) of anti-ssDNA antibody by ELISA in 52 patients with localized scleroderma and found that the anti-ssDNA antibodies in localized scleroderma were mainly characterized by high levels of IgM and IgA isotypes [15]. In contrast, the IgG isotype of anti-ssDNA antibodies significantly prevailed in SLE.

Thus, the clinical significance of anti-ssDNA antibody in localized scleroderma was widely accepted, although the major nuclear antigen had still not been identified at this time, because anti-ssDNA antibody does not produce any staining with the indirect immunofluorescence method of antinuclear antibody detection.

Antihistone antibody

One decade after the first report of the high frequency of antinuclear antibody in localized scleroderma [3], we found evidence suggesting the presence of antihistone antibodies in a preliminary study by the new technique of immunoblotting analysis using crude nuclear antigens. Later, we confirmed the presence of antihistone antibody by ELISA and by immunoblotting analysis using purified histone antigens [16].

By ELISA, antihistone antibodies were demonstrated in 47% (23/49) of patients with localized scleroderma and in 87% (13/15) of patients with generalized morphea. Immunoblotting analysis revealed that predominant antigens were histones H1 and H3. Reactivity against H2A and H2B was also observed. The presence of antihistone antibodies correlated with that of anti-ssDNA antibody.

Further studies revealed the clinical characteristics associated with antihistone antibodies in patients with localized scleroderma. The presence of antihistone antibodies strongly correlated with the number of morphea lesions, total number of lesions and number of involved areas of the body; however, it did not correlate with the presence or number of linear lesions. If we followed the classification definition of generalized morphea described in the introduction section of the present article, antihistone antibodies would be a good serological marker for generalized morphea, with 87% sensitivity and 74% specificity [2].

In addition, we determined the reactivity of antihistone antibodies with five individual histones (H1, H2A, H2B, H3 and H4) as native forms in each subgroup of localized scleroderma by ELISA. In all three groups, IgG antihistone antibodies reacted strongly with H1, H2A and H2B, and IgM antihistone antibodies reacted strongly with H1 and H2B [17]. A homogeneous immunofluorescence pattern with chromosomal staining on HEp-2 cells was completely abolished by absorption with total histones, suggesting that antihistone antibodies produced homogeneous staining by the indirect immunofluorescence technique. These data suggest that antihistone antibodies in localized scleroderma are directed against native chromatin, since H1, H2A and H2B occupy a relatively exposed component of native chromatin.

Antihistone antibodies were originally considered a highly specific serological marker of drug-induced lupus erythematosus, although our studies led to the idea that antihistone antibodies are commonly detected in both SSc [18] and localized scleroderma [3, 16, 17]: this concept was confirmed by other groups [10, 19].

Rheumatoid factor

Rheumatoid factor is generally considered to be a serological marker of rheumatoid arthritis, although a low titre was widely detected in various autoimmune disorders. In localized scle-roderma, we investigated rheumatoid factor to assess the cross-reactivity of antihistone antibodies. By employing a latex agglutination test, IgM rheumatoid factor was detected in 60% of 20 patients with localized scleroderma and in 82% of those with generalized morphea [17]. In addition, an absorption test of rheumatoid factor activity with human IgG revealed no cross-reactivity of antihistone antibodies with rheumatoid factor. The high frequency of rheumatoid factor was confirmed by other investigators [9].

Anti-topoisomerase II antibody

Anti-topoisomerase I antibody is highly specific for diffuse cutaneous SSc [20] and is not detected in localized scleroderma [3, 8]. However, our recent study revealed that patients with localized scleroderma were frequently positive for anti-topoisomerase II α antibody (76%, 35/46), although this antibody is not completely specific for localized scleroderma: 14% (5/37) in systemic sclerosis, 8% (2/26) in SLE and 10% (2/20) in dermatomyositis [21]. Immunoblotting analysis confirmed the lack of cross-reactivity of anti-topoisomerase II α antibody with topoisomerase I. In addition, anti-topoisomerase II α antibody was shown to be able to inhibit topoisomerase II α enzymatic activity.

Topoisomerases, which are ubiquitous enzymes, can modulate the topological state of DNA, which is critical for important biological processes such as DNA replication, nucleoside assembly and transcription. Topoisomerase I breaks and rejoins only one of the two strands for each DNA strand-passing reaction, while topoisomerase II breaks and rejoins both strands. Thus, the topoisomerase family are targeting antigens both in SSc and in localized scleroderma, although disease specificity is quite different. As described before, anti-topoisomerase I antibody is almost exclusively detected in SSc, whereas antitopoisomerase II α antibody was first reported in idiopathic pulmonary fibrosis [22] and various autoimmune conditions. The frequency (76%) in localized scleroderma, especially in generalized morphea (85%, 11/13), is predominantly high.

Antiphospholipid antibody

Antiphospholipid antibodies are detected in a variety of autoimmune disorders, including SLE and infectious diseases, and in patients receiving drugs such as procainamide and chlopromazine. Patients with these antibodies are considered to have a higher risk of vascular thrombosis. Localized scleroderma and drug-induced lupus share many immunological characteristics. Antihistone antibodies and anti-ssDNA antibodies are commonly observed in both diseases, but anti-double-stranded DNA antibodies were absent. Therefore we investigated whether antiphospholipid antibodies were detected in patients with localized scleroderma [23]. Exceeding our expectations, IgM and/or IgG anticardiolipin antibodies were positive in 46% of patients with localized scleroderma, 67% of those with generalized morphea, 35% of those with linear scleroderma and 30% of those with morphea. In generalized morphea, the frequency of IgM anticardiolipin antibody (61%) was much higher than that of IgG antibody (28%). In contrast, anti-β2 glycoprotein I antibody was not detected in any case.

In the same study, lupus anticoagulant by screening and confirmatory coagulation tests was detected in 24% (5/21) of sera from patients with localized scleroderma; all five patients had generalized morphea. Careful clinical investigation for thrombosis revealed one case with pulmonary embolism. We feel that more careful observation and follow-up for thrombosis should be required for patients with generalized morphea with antiphospholipid antibodies.

Antinuclear antibodies commonly detected in SSc

Localized scleroderma and SSc share the same main clinical features of skin sclerosis; however, the clinical features of the two diseases are quite different and they are generally considered to be two different clinical entities. In both diseases, autoantibodies are commonly detected and immunological abnormalities are involved in the pathogenesis of both diseases.

The most representative autoantibodies very frequently detected in diffuse cutaneous SSc are anti-topoisomerase I antibody and anti-RNA polymerase antibody. Anti-topoisomerase I antibody has not been detected in any study of localized scleroderma, as described before [3, 8], and anti-RNA polymerase antibody has not been detected in any case of localized scleroderma either (Takehara, unpublished data).

In contrast, several autoantibodies are well known to occur in limited cutaneous SSc, and the most representative autoantibody of limited cutaneous SSc is anticentromere antibody. In localized scleroderma, only one study reported three cases with anti-centromere antibody and without evidence of Raynaud's phenomenon, acrosclerosis or visceral involvement during the follow-up period [8]. However, none of the other studies which screened for the presence of anticentromere antibody failed to detect this antibody [2, 3, 7, 10, 19, 20], and cases with localized scleroderma having anticentromere antibody seem to be exceptionally rare in this clinical entity.

Anti-U3 RNA antibody was reported to be detected in three of 70 patients with localized scleroderma using RNA immunoprecipitation analysis [24]. The presence of antibodies to Th/To RNP was also reported by the same group and was detected in 4% (3/70) of patients with localized scleroderma by the same method [25]. These two autoantibodies were originally identified in patients with SSc having antinucleolar antibody and were considered to be a serological marker antibody for SSc. However, these observations may explain the fact that a small number of sera from patients with localized scleroderma produced nucleolar staining by the indirect immunofluorescence method. The clinical significance of the presence of these antibodies has not yet been clarified.

Other autoantibodies

Previous studies show that stress proteins such as histone H2B, heat shock protein 73 (hsp-73), hsp-90 and ubiquitin may have an important role in the pathogenesis of various autoimmune diseases. As described before, histone H2B is an autoantigen in localized scleroderma, SLE and other disorders [17, 26], and histone H2B was defined as a member of the stress protein family [27]. Therefore, we next investigated the presence of autoantibody against hsp-73 in localized scleroderma and detected it in 33% of cases (19/57). This frequency was comparable with 30% (9/30) in SLE and 41% (13/32) in SSc [28].

In addition, recent studies have revealed that localized scleroderma shares the same autoantibodies with other autoimmune conditions. Anti-Fcγ receptor autoantibodies, originally found in autoimmune mice [29], were detected in 54% of patients with localized scleroderma [30], the same percentage as found in SSc, SLE and Sjögren syndrome [31, 32]. Autoantibodies to mitochondria generally considered to be detected in primary biliary cirrhosis (PBC), were detected in six of 60 patients with localized scleroderma [33]. These patients may constitute a unique subset of localized scleroderma designated the multiple plaque type of generalized morphea with later onset, although only one patient showed laboratory abnormalities suggestive of PBC. Next, Arnett et al. reported that autoantibodies to fibrillin 1 were detected in 28% (14/50) patients with localized scleroderma [34]. Fibrillin 1 is the major component of microfibrils and fibrillin 1 gene abnormalities have been shown to be related to the animal model of scleroderma, the tight-skin mouse 1 (TSK1) [35] and the native American population with a high incidence of diffuse SSc [36]. Autoantibody to fibrillin 1 is also detected in 94% of native American patients and 87% of Japanese patients with diffuse SSc, and less commonly in Caucasian (34%) and African American (7%) SSc patients [37].

Cytokines and their soluble receptors

The autoantibody production in localized scleroderma described above can be partially attributed to abnormal T-cell and/or B-cell activation. Some major lymphocyte activations are mediated through circulating cytokines such as IL-2, IL-4 and IL-6. In our previous study, serum IL-2 levels in 27% (13/48) of patients with localized scleroderma, serum IL-4 levels in 17% (8/48) and serum IL-6 levels in 47% (23/48) were elevated, while none of the healthy controls had elevated levels of cytokines of these types [38]. Moreover, activated lymphocytes express cytokine receptors on their surface and a soluble part of these receptors is released in proportion to the state of activation. We have investigated these receptors. Soluble IL-2 receptor (sIL-2R) levels have been shown to be elevated in various autoimmune disorders, such as SLE and SSc [39, 40]. As in the case of the above systemic autoimmune disorders, serum levels of sIL-2R were shown to be frequently elevated (21%, 10/48), and they correlated with the number of sclerotic lesions and the number of involved areas [41]. Two surface transmembrane protein receptors of IL-6 (sIL-6R), a ligand-binding submit of 80 kDa and a transducting 130 kDa glycoprotein (gp130), were known to be related to signal pathways. The soluble form of IL-6 receptor is capable of activation of the IL-6 pathway, although soluble forms of gp130 (sgp190) inhibit IL-6 activity through the binding of IL-6 receptors by activating signalling pathways. In localized scleroderma, elevated sIL-6R levels significantly correlated with the number of linear lesions and the number of body areas involved [42]. Elevated sgp130 levels were also associated with the number of total lesions and the number of body areas involved [42].

Soluble cell adhesion molecules

Cell adhesion molecules are important in a variety of inflammatory and immune-mediated mechanisms, including lymphocyte recruitment and targeting. Intracellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (CD62P) were expressed by activated endothelial cells. Soluble forms of these molecules are serological indicators of immune activation. In localized scleroderma, the targeting organ is limited to the circumscribed skin, although elevated levels of soluble ICAM-1 (25%, 12/48), elevated soluble VCAM-1 (19%, 11/59) and elevated soluble E-selectin (20%, 12/59) were detected [43, 44].

Soluble cell surface antigens of lymphocytes

Several soluble cell surface antigens of lymphocytes are known as serological indicators of immune activation: soluble CD23 (sCD23) is an indicator of B-cell activation, soluble CD4 and CD8 (sCD4 and sCD8) of T-cell activation, and soluble CD30 (sCD30) of Th2-type lymphocyte. All these molecules have been shown to be elevated in various autoimmune disorders and we have investigated these molecules in localized scleroderma, where elevated frequencies of sCD23 (20%, 10/49), sCD4 (18%, 9/49), sCD8 (20%, 10/49) and sCD30 (33%, 18/55) were confirmed [45–47].

Conclusion

As described above, the presence of autoantibodies and the elevated serological markers suggesting immune activation show that localized scleroderma is one of the organ-specific autoimmune disorders targeting skin. Among three subsets of localized scleroderma, generalized morphea is considered to have a stronger autoimmune background than the other two types.

Whether the presence of various autoantibodies is related to the pathogenesis of cutaneous lesions remains to be determined. In addition, complicated cytokine cascades seem to be involved in the development of this disorder. Soma et al. reported cases of localized scleroderma having multiple lesions, although they belong to Blaschko's lines [47]. We hypothesize that mutant cells derived from one cell origin distributed in the lesions of Blaschko's line may be a target for the autoimmune reaction of localized scleroderma. More investigation to reveal the detailed process of the development of localized scleroderma is being conducted in our laboratory.

The authors have declared no conflicts of interest.

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