A case of anti-laminin gamma-1 (p200) pemphigoid with bullous lesions on the lips, hands and feet showing antibodies to desmoglein 1.

An 87-years-old-man presented with bullous and erosive lesions exclusively on the lips, hands and feet. Histopathological and direct immunofluorescence studies suggested the diagnosis of bullous pemphigoid, but the serum anti-BP180 antibodies were negative. Strangely, anti-desmoglein 1 antibodies were positive, although no pemphigus-like features were found. Indirect immunofluorescence showed IgG reactivity with dermal side of 1 M NaCl-split skin. Immunoblotting showed positive reactivity with the 200 kDa laminin gamma-1 but not with type VII collagen. After the administration of prednisolone 20 mg/day, bullous lesions cleared within 2 weeks.

Morphological characteristics of the Lisfranc ligament.

BACKGROUND: This study aimed to clarify the morphological characteristics of the Lisfranc ligament and the cuneiform 1-metatarsal 2&3 plantar ligament (CMPL). METHODS: Forty legs from 20 cadavers were examined. Classification proceeded according to the number of fiber bundles in the Lisfranc ligament and the CMPL. Morphological features measured were fiber bundle length, width, thickness, and angle. RESULTS: In Type I-a, the Lisfranc ligament and the CMPL were a single fiber bundle; in Type I-b, the Lisfranc ligament was a single fiber bundle, and the CMPL was two fiber bundles; in Type II-a, the Lisfranc ligament was a two fiber bundle, and the CMPL was a single fiber bundle; in Type II-b, the Lisfranc ligament and the CMPL were two fiber bundles; in Type III-a, the Lisfranc ligament was three fiber bundles, and the CMPL was a single fiber bundle; in Type III-b, the Lisfranc ligament was three fiber bundles, and the CMPL was two fiber bundles; in Type IV, the Lisfranc ligament and the CMPL could not be separated. Type I-a was seen in 37.5%, Type I-b in 10%, Type II-a in 30%, Type II-b in 7.5%, Type III-a in 7.5%, Type III-b in 2.5%, and Type IV in 5%. The Lisfranc ligament was significantly larger than the CMPL in total fiber bundle width, total fiber bundle thickness, and total fiber bundle angle. CONCLUSION: The Lisfranc ligament had up to 3 fiber bundles and the CMPL had one or two fiber bundles; classifications were four types and two subgroups.

Morphological features of the deep component of the posterior inferior tibiofibular ligament.

PURPOSE: The deep component of the posterior inferior tibiofibular ligament (PITFL) was classified by type in this large-scale cadaveric study to provide basic information that will help elucidate the mechanisms underlying ankle joint posterior impingement syndrome. METHODS: This investigation examined 100 legs from 49 Japanese cadavers (mean age at death, 79 ± 11 years; 58 sides from men, 42 from women). In classification, absence of an independent fiber of the deep component of the PITFL were classified as Type I, an independent fiber of the deep component of the PITFL was classified as Type II-a, an independent fiber of the deep component of the PITFL with bundles of fibers connected to the posterior intermalleolar ligament (PIML) was classified as Type II-b, and an independent fiber of the deep component of PITFL with a band shape connected to the PIML was classified as Type III. RESULTS: A deep component of the PITFL was present in all specimens. An independent fiber of the deep component of the PITFL was present in 37 legs (37%), connecting to the deep component of the PITFL and PIML in 26 (70.3%). Several types of deep component of the PITFL were identified: Type I in 63 legs (63%); Type II-a in 11 (11%); Type IIb in 12 (12%); and Type III in 14 (14%). No significant differences were seen between the right and left legs. Type I male were significantly more than Type I female (p < 0.05). Type III female were significantly more than Type III male (p < 0.05). CONCLUSIONS: Strong relationships exist between the PITFL and PIML.

Morphological features of the posterior oblique ligament of the ulnar collateral ligament of the elbow joint.

PURPOSE: The purpose of this basic research study was to clarify the morphological characteristics of the posterior oblique fibers (POL) of the ulnar collateral ligament using a large number of specimens. METHODS: This study examined 50 arms from 25 Japanese cadavers. Type classification was performed by focusing on the positional relationship between POL morphology and the joint capsule. The morphological features measured were fiber bundle length, width, and thickness. RESULTS: The POL was classified as follows: Type I, the POL's anterior and posterior edges are located on the surface of the joint capsule and can be separated as a single fiber bundle; Type II-a, the POL anterior edge can be separated, but the posterior edge cannot be separated; Type II-b, the POL posterior edge can be separated, but the anterior edge cannot be separated; and Type III, the POL cannot be separated from the joint capsule. Type I was seen in 23 elbows (46%), Type II-a in 6 elbows (12%), Type II-b in 7 elbows (14%), and Type III in 14 elbows (28%). CONCLUSION: The results of this study suggested that the POL could be classified into an independent type and an unclear type, and the presence of the unclear type was one of the factors that caused morphological variation.

Morphological features of the cervical ligament.

PURPOSE: The purpose of this study was to clarify the morphological characteristics of the cervical ligament (CL). METHODS: This study examined 80 legs from 40 Japanese cadavers. The CL was classified by the number of fiber bundles. The morphological features measured were fiber bundle length, width, thickness, and angle with the sagittal plane. RESULTS: The CL was classified as follows: Type I, the CL is a single fiber; Type II, the CL consists of a superficial fiber and an inferior fiber; and Type III, the CL consists of a superficial fiber, intermediate fiber, and inferior fiber. Type I was seen in 15 feet, Type II in 57 feet, and Type III in 8 feet. In comparisons of morphological features within each type, significant differences were seen in fiber bundle length, width, and angle between superior fiber bundles and inferior fiber bundles of Type II and Type III. In comparison among types, the total fiber bundle width was significantly wider in Type II and Type III than in Type I, and the angle was significantly smaller in Type III than in Type I. CONCLUSION: The results of this study suggested that each type may have different sub-talar joint control functions.

Morphological features of the posterior intermalleolar ligament.

PURPOSE: In the present study, the posterior intermalleolar ligament (PIML) was classified by type using large-scale cadavers to provide basic information to help elucidate the mechanism of ankle joint posterior impingement syndrome. METHODS: This investigation examined 100 legs from 49 Japanese cadavers (mean age at death, 79 ± 11 years; 58 sides from men, 42 from women). In the classification method, an absent PIML was classified as Type I, a PIML with one fiber bundle (attachment to one place) was Type II, a PIML with two fiber bundles (attachment to two places) was Type III, and a PIML with three fiber bundles (attachment to three or more places) was Type IV. Furthermore, according to other adhering tissues, they were further subdivided and classified by type. RESULTS: There were various types of PIML: 19 (19%) Type I; 24 (24%) Type II; 23 (23%) Type III; and 34 (34%) Type IV. A PIML was present in 81 legs (81%). There were no significant differences between men and women and between left and right sides. CONCLUSIONS: The complex relationships of the PIML with the surrounding ligaments and tissues are considered to be among the factors that make interpretation of imaging findings difficult.

Morphological features of the inferior fascicle of the anterior inferior tibiofibular ligament.

In this study, the inferior fascicle of the anterior inferior tibiofibular ligament (AITFL) was classified to provide basic information to help elucidate the mechanism of ankle joint anterolateral impingement, and the morphological features of each type were compared for the purpose of clarification. This investigation examined 100 feet from 52 cadavers. The AITFL was classified into four types according to the presence or absence of the inferior fascicle and the positional relationship between the AITFL and the inferior fascicle of the AITFL. The morphological features of the AITFL that were measured included the fibre bundle length, fibre bundle width, fibre bundle angle, and the distance between the joint levels. A distinct, independent inferior fascicle of the AITFL was identified in 15 feet (15%). There were no significant differences in the morphological features based on differences in the AITFL classification. Therefore, these findings suggest that the presence or absence of the inferior fascicle and the difference in the positional relationship between the AITFL and the inferior fascicle of the AITFL are less likely to be involved in impingement during ankle dorsiflexion.

Morphological features of the bifurcated ligament.

INTRODUCTION: Damage to the bifurcate ligament is one of the most difficult injuries to diagnose from imaging techniques. A probable reason for this is that the morphological characteristics of this structure have yet to be sufficiently elucidated. We, therefore, endeavored to elucidate the morphological characteristics of the bifurcate ligament through a large-scale study involving numerous specimens. MATERIALS AND METHODS: This study included 100 feet from 52 formalin-fixed cadavers. The bifurcate ligament was classified into three types: presence of both calcaneonavicular ligament and calcaneocuboid ligament (Type I); absence of calcaneocuboid ligament (Type II); and absence of calcaneonavicular ligament (Type III). Morphological characteristics of the bifurcate ligament were determined by measuring fiber bundle length, width, and thickness at the center of each ligament. RESULTS: This classification resulted in 68 Type I feet (68%), 32 Type II feet (32%), and 0 Type III feet (0%). The calcaneonavicular ligament was 20.8 ± 2.9 mm long, 4.9 ± 1.2 mm wide, and 3.8 ± 1.1 mm thick. The calcaneocuboid ligament was approximately 10.5 ± 2.7 mm long, 4.7 ± 2.4 mm wide, and 1.5 ± 0.6 mm thick. The bifurcate ligament was located deep under the extensor hallucis brevis and extensor digitorum brevis muscles in all specimens. The calcaneal origin of the calcaneonavicular ligament was situated deep under the interosseous talocalcaneal ligament in all specimens. Two sides were identified in which the calcaneocuboid ligament was located deep under the dorsal calcaneocuboid ligament. CONCLUSION: Such variations and positional relationships were suggested to be factors complicating the diagnostic imaging of bifurcate ligament injuries. The present study results will likely form useful basic data for diagnostic imaging.

Kinesthetic perception based on integration of motor imagery and afferent inputs from antagonistic muscles with tendon vibration.

The perceptual integration of afferent inputs from two antagonistic muscles, or the perceptual integration of afferent input and motor imagery are related to the generation of a kinesthetic sensation. However, it has not been clarified how, or indeed whether, a kinesthetic perception would be generated by motor imagery if afferent inputs from two antagonistic muscles were simultaneously induced by tendon vibration. The purpose of this study was to investigate how a kinesthetic perception would be generated by motor imagery during co-vibration of the two antagonistic muscles at the same frequency. Healthy subjects participated in this experiment. Illusory movement was evoked by tendon vibration. Next, the subjects imaged wrist flexion movement simultaneously with tendon vibration. Wrist flexor and extensor muscles were vibrated according to 4 patterns such that the difference between the two vibration frequencies was zero. After each trial, the perceived movement sensations were quantified on the basis of the velocity and direction of the ipsilateral hand-tracking movements. When the difference in frequency applied to the wrist flexor and the extensor was 0Hz, no subjects perceived movements without motor imagery. However, during motor imagery, the flexion velocity of the perceived movement was higher than the flexion velocity without motor imagery. This study clarified that the afferent inputs from the muscle spindle interact with motor imagery, to evoke a kinesthetic perception, even when the difference in frequency applied to the wrist flexor and extensor was 0Hz. Furthermore, the kinesthetic perception resulting from integrations of vibration and motor imagery increased depending on the vibration frequency to the two antagonistic muscles.

Skewed TGFß/Smad signalling pathway in T cells in patients with Behçet's disease.

OBJECTIVES: Behçet's disease (BD) is a multi-systemic inflammatory disease, characterised by recurrent oral aphthosis, genital ulcers, skin lesions and uveitis. We have reported excessive Th1 cell activity in patients with BD. More recently, Th17 cells were suggested to associate with several autoimmune diseases. This study was designed to investigate the role of Th17 related cytokines and signalling molecules in patients with BD. METHODS: We examined mRNA expressions of Th1 and Th17 related cytokines and related signalling molecules in PBMC of 12 patients with BD and 14 normal controls (NC) using quantitative RT-PCR. We studied expressions of the Th17 related cytokines in other four BD patients' skin lesions by immunofluorescence. RESULTS: Major Th17 related cytokines were not detected in unstimulated PBMC in patients with BD. After stimulation, mRNA expressions of TGFß receptor type 1, IL-12 receptor ß2 and suppressor of cytokine signalling protein (SOCS) 1 on PBMC were significantly enhanced in patients with BD, as compared with NC (p<0.05). mRNA expression of RORC, a key transcription factor for Th17 cell differentiation, was comparable between BD and NC. CD4+ T cells infiltrating into BD skin lesion expressed TGFß1 much more than those infiltrating into non-Behçet's disease erythema nodosum. CONCLUSIONS: These findings suggest that TGFß/Smad signalling pathway of T cells is overactive in patients with BD.

The effects of kinesthetic illusory sensation induced by a visual stimulus on the corticomotor excitability of the leg muscles.

A novel method of visual stimulus, reported by Kaneko et al. [14], induced a vivid kinesthetic illusion and increased the corticomotor excitability of the finger muscles without any overt movement. To explore the effect of this method on the lower limbs, motor evoked potentials (MEP) were recorded from the left tibialis anterior (TA) and soleus muscles using transcranial magnetic stimulation (TMS). A computer screen that showed the moving image of an ankle movement was placed over the subject's leg, and its position was modulated to induce an illusory sensation that the subject's own ankle was moving (illusion condition). TMS was delivered at rest and at two different times during the illusion condition (ankle dorsiflexion phase: illusion-DF; ankle plantarflexion phase: illusion-PF). The MEP amplitude of the TA, which is the agonist muscle for ankle dorsiflexion, was significantly increased during the illusion-DF condition. This indicated that the visual stimulus showing the moving image of an ankle movement could induce a kinesthetic illusion and selectively increase the corticomotor excitability in an agonist muscle for an illusion, as was previously reported for an upper limb. The MEP amplitude of the soleus, which is the agonist muscle for ankle plantarflexion, increased during the illusion-PF condition, but not significantly. Because of the vividness of the illusory sensation was significantly greater during the illusion-DF condition than the illusion-PF condition, we concluded that the vividness of the illusory sensation had a crucial role in increasing corticomotor excitability.

Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behçet's disease.

Excessive T helper type 1 (Th1) cell activity has been reported in Behçet's disease (BD). Recently, association of Th17 cells with certain autoimmune diseases was reported, and we thus investigated circulating Th17 cells in BD. CD4(+) CD45RO(-) (naive) T cells were cultured with Th0-, Th1-, Th2- and Th17-related cytokines and antibodies, and their mRNA was studied by real-time polymerase chain reaction (PCR). When naive CD4(+) T cells were cultured with Th1- and Th17-related cytokines, interferon (IFN)-γ mRNA and interleukin (IL)-17 mRNA were up-regulated, respectively, in BD patients. Naive CD4(+) T cells cultured in a Th17 cell-inducing condition expressed IL-23 receptor (IL-23R) mRNA excessively. IL-17 mRNA expression was induced only when naive CD4(+) T cells were cultured in the presence of IL-23. CD4(+) T cells cultured with Th17 cytokines expressed excessive RAR-related orphan receptor C (RORC) mRNA. Using intracellular cytokine staining, we found that CD45RO(+) (memory) CD4(+) T cells producing IL-17 and IFN-γ simultaneously were increased significantly. Memory CD4(+) T cells producing IFN-γ but not IL-17 decreased profoundly in BD patients. CD4(+) T cells producing IL-17 and IFN-γ simultaneously were found in BD skin lesions. Collectively, we found excessive CD4(+) T cells producing IL-17 and IFN-γ (Th1/Th17) cells in patients with BD, and possible involvement of IL-23/IL-23R pathway for the appearance of excessive Th1/Th17 cells.

The effect of motor imagery on gain modulation of the spinal reflex.

Motor imagery is well known to have a facilitatory effect on the corticospinal tract, but conflicting opinions have arisen concerning its effect on spinal reflex excitability. The purpose of this study was to clarify the effects of motor imagery on gain modulation of the spinal reflex by focusing on the physiological differences between the H-reflex and the stretch reflex. In experiment 1, there were three conditions: rest, motor imagery of ankle dorsiflexion (MI-DF), and motor imagery of ankle plantarflexion (MI-PF). The subjects were instructed to imagine 100% maximum voluntary isometric contraction (MI-100) in each direction of movement. To examine the effects of the imagined effort level on spinal reflex excitability, the subjects also imagined 50% maximum voluntary contraction (MI-50) in experiment 2. The soleus H-reflex and the stretch reflex amplitude and background EMG (bEMG) activity were measured. There were no significant differences in bEMG activity between the H-reflex and stretch reflex measurements. In experiment 1, although the H-reflex amplitude did not change significantly among the three conditions, the stretch reflex amplitude increased significantly under the MI-DF and MI-PF conditions compared to the rest condition. In addition, the stretch reflex amplitude under the MI-100 condition was significantly larger than that under the MI-50 condition in experiment 2. These results indicate that motor imagery has a selective facilitatory effect on stretch reflex pathways. Furthermore, this excitability change may occur in untargeted antagonist muscles as well as targeted agonist muscles and may depend on the imagined effort level.

Effect of joint position on the electromyographic activity of the semitendinosus muscle.

The semitendinosus (ST) muscle has a tendinous intersection within the muscle belly that separates the ST muscle into distinct proximal and distal compartments. Thus far, no study has compared the electromyographic (EMG) activities between the proximal and distal compartments of the human ST muscle. This study aimed to investigate the intramuscular EMG activity patterns of the proximal and distal compartments of the ST muscle by altering the hip and knee joint positions. The study population comprised eight healthy male volunteers. They performed ramp isometric knee flexion tasks form the relaxed state to the maximal voluntary contraction (MVC) state with (1) the hip and knee at 90 degrees and 0 degrees, respectively (90-0 position), (2) both the hip and knee at 00 (0-0 position), and (3) the hip and knee at 0 degrees and 90 degrees, respectively (0-90 position). Fine-wire electrodes were inserted into the proximal and distal compartments of the ST muscle and the individual EMG activities were recorded. In the 90-0 position, the EMG activity of the distal compartment was higher than that of the proximal compartment at 60%, 80%, and 90% MVC. Moreover, in the 0-90 position, the EMG activity of the proximal compartment was higher than that of the distal compartment at 60% MVC. These results indicated that the lengthened or shortened muscle conditions induced regional differences in the EMG activity patterns, while the two compartments showed equivalent activity when the muscle length was moderate.

Peripherally administered ghrelin induces bimodal effects on the mesolimbic dopamine system depending on food-consumptive states.

Ghrelin induces orexigenic behavior by activation of growth hormone secretagogue 1 receptors (GHSRs) in the ventral tegmental area (VTA) as well as hypothalamus, suggesting the involvement of mesolimbic dopamine system in the action of ghrelin. The present study aimed to identify neuronal mechanisms by which peripherally administered ghrelin regulates the mesolimbic dopamine system under different food-consumptive states. Ghrelin was administered to rats peripherally (3 nmol, i.v.) as well as locally into the VTA (0.3 nmol). Dopamine in the nucleus accumbens shell (NAc) was measured by microdialysis. Peripheral administration of ghrelin decreased dopamine levels in the NAc when food was removed following ghrelin administration. This inhibitory effect was mediated through GABA(A) and N-methyl-D-aspartate (NMDA) receptors in the VTA. In contrast, when animals consumed food following ghrelin administration, dopamine levels increased robustly. This stimulatory effect was mediated through NMDA receptors, but not through GABA(A) receptors, in the VTA. Importantly, both the inhibitory and stimulatory effects of ghrelin primarily required activation of GHSRs in the VTA. Furthermore, local injection of ghrelin into the VTA induced dopamine release in the NAc and food consumption, supporting the local action of ghrelin in the VTA. In conclusion, peripherally administered ghrelin activates GHSRs in the VTA, and induces bimodal effects on mesolimbic dopamine neurotransmission depending on food-consumptive states.

Association analysis between canine behavioural traits and genetic polymorphisms in the Shiba Inu breed.

The relationships between behavioural trait data and the genotype of 15 polymorphisms in eight neurotransmitter-related genes were analysed in 77 dogs of the Shiba Inu breed, an indigenous Japanese dog. The data were obtained from a 26-item questionnaire on the dog's behaviour, distributed to the dog's owners, through veterinary hospitals and the Shiba Inu breed magazine. A factor analysis of the questionnaire items extracted eight factors accounting for 66.8% of the variance. An association analysis between these factors and genetic polymorphisms indicated that the polymorphism of c.471T>C in the solute carrier family 1 (neuronal/epithelial high-affinity glutamate transporter) member 2 (SLC1A2) gene was significantly associated with Factor 1, referred to as 'aggression to strangers'. This association remained stable in separate analyses of data from surveys obtained from the hospitals and those obtained from the magazine. The results suggest that the c.471T>C polymorphism is associated with some types of aggressive behaviour in the Shiba Inu. Further studies using other dog breeds are necessary to extend these findings to dogs in general.

Kinesthetic illusory feeling induced by a finger movement movie effects on corticomotor excitability.

The present study aimed to clarify whether a kinesthetic illusion arises in our experimental condition (visual stimulus) and whether corticomotor excitability changes in parallel with the kinesthetic illusion. The visual stimulus was a movie in which someone else's limb was being moved. The computer screen showing the movie was installed at an appropriate portion of the subject's forearm, so that the performer's hand appeared as if it were the subject's hand (illusion). The experience of kinesthetic illusion under this condition was verified by interview using a visual analog scale. Healthy male subjects participated in this experiment. Transcranial magnetic stimulation was applied to induce motor-evoked potential (MEP) from the first dorsal interosseous and abductor digiti minimi muscle. Each subject was instructed to watch the same computer display shown as in the illusion, with his own stationary hand in full view (non-illusion) and to watch a display of non-biological movement (moving text) (sham) as the control conditions. The present results showed significant facilitation of MEP under the illusion compared with the control conditions for the index finger abducting in the movie, although not for adducting. MEP in the abductor digiti minimi showed no change during either abduction or adduction of the little finger. The present study demonstrated that an illusion of self-motion can be created by a video of a moving abstract index finger, and inputs to the corticomotor pathways during the self-motion illusion facilitated the corticomotor excitability. The excitatory effect of the illusion depended on the movement direction of the index finger.

Complexity of the HVR-1 quasispecies and disease activity in patients with hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) easily undergoes genomic changes, especially in the hypervariable region (HVR) in the N-terminus of the E2/NS1 region. The quasispecies nature of HCV may have important biological implications in relation to viral persistence; however, the relationship between disease activity of chronic HCV infection and development of the genomic complexity have yielded conflicting results. We explored the changes in the complexity of the HVR-1 in the natural course of chronic HCV infection with and without elevation of serum alanine transaminase (ALT) levels. MATERIALS AND METHODS: Ten patients with chronic hepatitis C proven by liver biopsy, who showed persistent elevation of the serum ALT levels, and 15 patients with chronic HCV infection and persistently normal serum ALT levels (PNAL) were enrolled in this study. The number of the HCV quasispecies was determined twice for each patient at an interval of mean 2.5 years by fluorescence single-strand conformation polymorphism and sequence analysis. RESULTS: There was no significant difference in the changes in the number of quasispecies during the follow-up period between chronic hepatitis C and PNAL. There was also no significant difference in the change in the number of variable nucleotides sites between the two groups. In these patients, the number of quasispecies and the diversity of HVR-1 were correlated with platelet counts and serum hyaluronic acid levels previously shown to be associated with disease progression. CONCLUSION: Our results suggested that the disease activity is not always related to the generation of the HVR-1 quasispecies complexity.

Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity.

BACKGROUND: Mucous membrane pemphigoid (MMP), a chronic autoimmune subepithelial blistering disease, is associated with circulating IgG and/or IgA autoantibodies against several basement membrane zone antigens. The heterogeneity of clinical presentation and diversity of target autoantigens have contributed to difficulties in characterizing this condition immunologically. OBJECTIVES: To analyse serum autoantibody profile and HLA class II alleles in MMP patients and to correlate this with the clinical presentation of disease. METHODS: Well-defined subgroups consisting of 124 patients with MMP were examined for IgG and IgA reactivity with immunoblotting using human epidermal, dermal and placental amnion proteins. The results were further analysed on the basis of detailed clinical (sites of involvement and disease severity) and immunopathological criteria (immunofluorescence study and HLA class II alleles). RESULTS: Immunoblot assay revealed that the majority of MMP patients had IgG (93 of 124, 75%) and/or IgA autoantibodies (63 of 124, 51%) to BP180 (including its soluble ectodomains, 120-kDa LAD-1 and 97-kDa LABD97 antigens). Other antigens targeted predominantly by IgG autoantibodies included: BP230 in 34 (27%), beta4 integrin in 26 (21%), and laminin 5 in three (2%). All the BP230+ sera and 23 (88%) beta4 integrin+ sera also reacted with at least one of the BP180 antigens. Over 85% of patients with reactivity to beta4 integrin had ocular involvement. In most cases of MMP, more severe clinical features were associated with antibody reactivity to multiple basement membrane zone antigens, as well as reactivity to multiple BP180 component antigens. Dual BP180/LAD-1 reactivity with IgG and IgA was associated with a more severe phenotype. In addition, the subset-dependent autoantibody reactivity correlated well with specific HLA class II alleles, DQB1*0301, DRB1*04 and DRB1*11. CONCLUSIONS: Our results confirmed that BP180 is a major autoantigen targeted by the sera of patients with MMP. The disease-prevalent HLA class II alleles and humoral autoimmune response against the particular subsets of antigenic epitope(s) within BP180 ectodomain may contribute to the clinicopathological significance and disease severity of MMP.