Background: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteri...Background: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteristic serological markers for DH, these antibodies do not bind to normal papillary skin structures. Aims: To test the possibility of IgA immune com-plex precipitation within the vessel walls as a first step in the pathogenesis of skin symptoms, we analysed immunoglobulin, complement, and epidermal TG deposition along the vascular system of DH skin. Methods: Punch biopsy specimen were taken from 116 DH patients’ skin,and evaluated for the presence of vascular immune precipitates by direct immunofl uorescence. Skin samples from 16 DH patients were also studied for tissue and epidermal TGs. Results: In 74 (64% ) of the 116 DH skin studied, significant vascular staining accompanied the DH-specific granular IgA fluorescence (IgA and C3 in 39 patients; IgA alone in 18; IgA, C3 and IgM together in five; IgM alone in 12). In most cases (92% ), the precipitates were detected in the small vessels of the papillary dermis; however, a subpapillary vascular fluorescence was also observed in a few patients (8% ). Skin IgA colocalized with epidermal TG in the vessel walls and within the scattered papillary peri-and intervascular DH bodies. Tissue TG did not colocalize either with the immunoglobulins or with the complement precipitates of the dermis. Furthermore, we could not detect keratinocyte TG in the DH bodies nor in the vessel walls. Conclusions: These findings support possible immune complex precipitation in the vessel walls of DH skin and further confirm the significance of epidermal but not tissue TG in the pathomechanism of skin symptoms.展开更多
Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients...Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254- 288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+ /LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+ /LKM1 + sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKMl in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.展开更多
文摘Background: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteristic serological markers for DH, these antibodies do not bind to normal papillary skin structures. Aims: To test the possibility of IgA immune com-plex precipitation within the vessel walls as a first step in the pathogenesis of skin symptoms, we analysed immunoglobulin, complement, and epidermal TG deposition along the vascular system of DH skin. Methods: Punch biopsy specimen were taken from 116 DH patients’ skin,and evaluated for the presence of vascular immune precipitates by direct immunofl uorescence. Skin samples from 16 DH patients were also studied for tissue and epidermal TGs. Results: In 74 (64% ) of the 116 DH skin studied, significant vascular staining accompanied the DH-specific granular IgA fluorescence (IgA and C3 in 39 patients; IgA alone in 18; IgA, C3 and IgM together in five; IgM alone in 12). In most cases (92% ), the precipitates were detected in the small vessels of the papillary dermis; however, a subpapillary vascular fluorescence was also observed in a few patients (8% ). Skin IgA colocalized with epidermal TG in the vessel walls and within the scattered papillary peri-and intervascular DH bodies. Tissue TG did not colocalize either with the immunoglobulins or with the complement precipitates of the dermis. Furthermore, we could not detect keratinocyte TG in the DH bodies nor in the vessel walls. Conclusions: These findings support possible immune complex precipitation in the vessel walls of DH skin and further confirm the significance of epidermal but not tissue TG in the pathomechanism of skin symptoms.
文摘Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254- 288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+ /LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+ /LKM1 + sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKMl in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.
