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Immunoperoxidase demonstration of 'classical' anticolon antibody: (A) positive serum, (B) negative serum. Original magnification x 40.
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Sera and colonic tissue-bound immunoglobulin extracts from patients with ulcerative colitis and disease controls were examined immunohistochemically and by killer cell cytotoxicity assay for the presence of anticolonic epithelial autoantibodies. IgG yields in the tissue extracts from patients with colitis and control subjects were similar, and the...
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... [45][46][47][48][49] In separate studies, IgG antibodies to cytoskeleton proteins and EBM crypts adjacent to mucosal ulcers were isolated from the tissue of the affected colon. [50][51][52][53][54][55] Inflammation is accompanied by an increase in the content of normal ECM components and their degraded fragments, the formation of an excess of modified peptides and the demasking of latent epitopes with new immunogenic determinants capable of causing an autoimmune response, which contributes to the maintenance and aggravation of the initial inflammation. 9,56 In previous studies, we found that antigens localized in the EBM and the vascular wall of the mucosa of the normal colon, in UC, in addition to these structures are present in the intercellular fluid, which is accompanied by the formation of antibodies. ...
... In PSC patients without concomitant UC, a single study identified antibodies against a 9-amino acid sequence from hTM (not isoform specific) in 100% (8/8) of patients as compared with 69% (33/48) of UC patients and 0/6 PBC patients [30] . The findings of Das et al have been partly reproduced by others [31] , but given a number of critical concerns32333435 , further studies are required to conclusively confirm and elaborate the importance of the hTM5-CEP antigen in the pathogenesis of PSC. A Swedish group has reported on the presence of antibodies against isolated biliary epithelial cells (BEC) at high frequencies in sera from PSC (63%) and PBC (37%) patients, versus 8% of controls (1/12) [36] . ...
The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.
... These events would explain involvement of the normal gut microbiota as immunogens in UC, both directly and by inducing crossreactive antibodies against host epithelial antigens. [30][31][32][33][34][35] While the vast majority of intestinal bacteria occur in the gut lumen, adherent communities exist in association with the epithelium which are more likely to be involved in UC aetiology but little is known of the species composition or activities of these populations. Anecdotal evidence that antibiotics occasionally induce remission in some UC patients suggests that changes in microbiota species composition can affect the severity and duration of the condition. ...
The mucosa in ulcerative colitis (UC) is replete with antibody producing plasma B cells and polymorphonuclear leucocytes (PMN). This combination of effector cells requires a crosslinking antigen to evoke an antibody driven PMN inflammatory response via their Fc receptors. The stimulus for activation is thought to be commensal bacteria colonising the gut mucosa. The aim of this investigation was to compare the principal culturable bacterial populations on the rectal mucosa of UC patients, and to determine whether specific antibodies towards these bacteria can activate infiltrating PMN through opsonisation. This would provide an explanation for this chronic inflammatory condition.
Bacteria colonising rectal tissue were characterised using chemotaxonomic techniques. Systemic antibody responses were measured against total antigens and surface antigens of these organisms in UC and Crohn's disease (CD) patients, together with healthy controls. Antibody enhancement of the respiratory burst in PMN was also investigated, against a range of mucosal isolates.
Distinct differences were observed in some bacterial populations in UC biopsies, which were generally reflected in antibody responses towards these organisms. UC patients had higher IgG responses to surface antigens, primarily IgG1, whereas the response in CD was mainly IgG2. Antibodies from UC patients greatly enhanced the respiratory burst in PMN, in response to individual bacterial species.
Changes in mucosal bacteria, and a switch from internal to surface antigen/antibody reactivity of a predominantly IgG1 type, leads to greater opsonisation of the respiratory burst in PMN, providing a mechanism for maintaining the inflammatory state in UC.
... These events would explain involvement of the normal gut microbiota as immunogens in UC, both directly and by inducing crossreactive antibodies against host epithelial antigens. [30][31][32][33][34][35] While the vast majority of intestinal bacteria occur in the gut lumen, adherent communities exist in association with the epithelium which are more likely to be involved in UC aetiology but little is known of the species composition or activities of these populations. Anecdotal evidence that antibiotics occasionally induce remission in some UC patients suggests that changes in microbiota species composition can affect the severity and duration of the condition. ...
Background and aims: The mucosa in ulcerative colitis (UC) is replete with antibody producing plasma B cells and polymorphonuclear leucocytes (PMN). This combination of effector cells requires a crosslinking antigen to evoke an antibody driven PMN inflammatory response via their Fc receptors. The stimulus for activation is thought to be commensal bacteria colonising the gut mucosa. The aim of this investigation was to compare the principal culturable bacterial populations on the rectal mucosa of UC patients, and to determine whether specific antibodies towards these bacteria can activate infiltrating PMN through opsonisation. This would provide an explanation for this chronic inflammatory condition. Methods: Bacteria colonising rectal tissue were characterised using chemotaxonomic techniques. Systemic antibody responses were measured against total antigens and surface antigens of these organisms in UC and Crohn’s disease (CD) patients, together with healthy controls. Antibody enhancement of the respiratory burst in PMN was also investigated, against a range of mucosal isolates. Results: Distinct differences were observed in some bacterial populations in UC biopsies, which were generally reflected in antibody responses towards these organisms. UC patients had higher IgG responses to surface antigens, primarily IgG1, whereas the response in CD was mainly IgG2. Antibodies from UC patients greatly enhanced the respiratory burst in PMN, in response to individual bacterial species. Conclusions: Changes in mucosal bacteria, and a switch from internal to surface antigen/antibody reactivity of a predominantly IgG1 type, leads to greater opsonisation of the respiratory burst in PMN, providing a mechanism for maintaining the inflammatory state in UC.
... Classical anticolon antibodies-both those directed against colonic mucopolysaccharide (Snook et al 1991, Chapman et al 1986, W right and Truelove 1966 and those mediating colonocyte specific cytotoxicity-have been identified in 30-80% o f patients (Shorter et al 1970, Das et al 1984 Colon bound and circulating antibodies some o f which demonstrate specificity for the disease and some which appear to parallel the disease activity, have also been described (O ' Hara et al 1995, Khoo et al 1995, Takahashi et al 1990, Das et al 1984 (Zauli et al 1985), anti-smooth muscle and anti-erythrocyte antibodies (Yates et al 1992) Hibi et al investigated mucosal and peripheral blood lymphocytes; the frequency o f serum anticolon antibodies was 71% in ulcerative colitis estimated by E LIS A with isolated rat colon epithelium (Hibi et al 1990). Circulating antibodies to the UCAg have also been identified, which appear to parallel disease activity (Takahashi et al 1990). ...
Aims: To investigate the roles of autoimmunity and microvascular injury in the pathogenesis of ulcerative colitis. Background: The aetiology of ulcerative colitis is unknown. A putative mucosal autoantigen, (UCAg), had been identified as tropomyosin, the presence of ANCA in ulcerative colitis suggested involvement of vascular factors; and disease demarcation suggested vascular anatomical distribution of disease. Methods: Using the monoclonal antibody 7E12H12, cellular localisation of the target antigen, UCAg, was studied. Comparative immunohistochemical studies were made of the staining patterns of 7E12H12 and anti-tropomyosin antibodies. The nature of the UCAg was examined further using SDS-PAGE and Western blotting. A novel dot-blot technique examined potential binding between tropomyosin and 7E12H12. In-vitro angiography examined the relation between vascular factors and the distribution of disease. The frequency of ANCA and the target antigen(s) was examined in patients with inflammatory bowel disease. Results: Immunohistochemistry demonstrated plasma membrane localisation of UCAg and revealed additional supranuclear staining. Comparative immunostaining experiments failed to show a similar localisation pattern for tropomyosin. There was no relation between UCAg expression and disease activity. SDS-PAGE, Western blotting and dot-blot experiments confirmed the presence of UCAg and tropomyosin in colon protein extracts, but no reactivity between 7E12H12 and tropomyosin. In-vitro angiography of resected ulcerative colitis colon specimens revealed a consistent relationship between the marginal artery of the colon and disease extent. ANCA were found in 57% of patients with ulcerative colitis. Novel antigenic targets for ANCA were identified: ANCA directed against bactericidal/permeability increasing protein were found in 27% of patients. Conclusions: UCAg is not tropomyosin, but the nature of this antigen remains to be determined. Novel target antigens for ANCA, present in vasculitis, have been identified in ulcerative colitis. The extent of disease appears to be determined by the anatomy of the marginal artery. These data suggest a microvascular pathogenesis for ulcerative colitis.
... this study, I have established, with the help of clinical and technical staff from the Depts of Physiology, Infection, Immunology and Surgery, the occurence of ANCA Several different types of autoantibodies have been described in inflammatory bowel disease [Nielsen et al, 1983; Snook et al, 1989; Saxon et al, 1990; Duerr et al, 1991; Broberger et al, 1959; Perlmann et al, 1967; Das et al, 1984; Skogh et al, 1982;Skogh et al, 1986; Chapman et al, 1986;Snook et al, 1991]. Although none of the autoantibodies have been proved to be of pathogenic significance, it has been shown in both ulcerative colitis and Crohn's, that IgG and complement can be present on the apical surface of enterocytes, in vivo ...
... 6 It was later also detected in keratinocytes and the lining epithelium of the gall bladder and common hepatic biliary ducts. 7 With two and three colour immunofluorescent staining this study re-examined the tissue distribution of the Mr 40 kD putative autoantigen; particular emphasis was placed on its spatial relation to the apical codeposition of IgGl and activated complement found on colonic enterocytes in active ulcerative colitis but not in Crohn's colitis. '2 The staining pattern found is compatible with the notion that the Mr 40 kD antigen is involved in the IgGI mediated complement activation on the apical epithelial surface in ulcerative colitis lesions.' Methods TISSUE SPECIMENS Diseased mucosal tissue samples (n=98) excised from surgically resected colons or obtained by endoscopic biopsy were collected from 22 patients with ulcerative colitis (median age 37; range, 17-65 years). ...
The intestinal expression pattern and general tissue distribution of the M(r) 40 kD putative epithelial autoantigen in ulcerative colitis were re-examined by in situ two and three colour immunofluorescence staining including the murine monoclonal antibody 7E12H12. The intestinal distribution was also compared with the epithelial codeposition of IgG1 and activated complement (C3b and terminal complement complex) seen selectively in ulcerative colitis. The M(r) 40 kD antigen was found for the first time in goblet cells of normal terminal ileum and proximal colon but not in rectal goblet cells. By contrast, colonic enterocytes expressed this antigen apically with increasing intensity in a distal direction, expanding to intense cytoplasmic expression in rectal enterocytes. The antigen was also expressed by the epithelium of the fallopian tubes, major bile ducts, gall bladder, and epidermis but not by proximal gastrointestinal tract epithelium or 13 other extra-gastrointestinal organs. Activated complement and IgG1 often colocalised with the M, 40 kD antigen apically on the surface epithelium in active ulcerative colitis but not in Crohn's disease. Our results support the idea that an autoimmune response to this antigen, leading to complement activation mediated by IgG1, is a possible pathogenetic mechanism for epithelial damage and persistent inflammation in ulcerative colitis.
Wilks and Moxon (1875)1 realised that there was an ulcerative condition of the colon which was non-infective. There was little progress in the management of ulcerative colitis over the next 59 years and in 1933, an article by Hardy and Bulmer2, about the natural history of the disease, indicated that one third of their patients died within a year of onset of the disease.
Ulcerative colitis (UC) and Crohn's disease (CrD) are idiopathic inflammatory bowel diseases of unknown etiology. It is widely accepted that CD4-positive T lymphocytes are increased in the lymph follicles of the intestinal mucosa in CrD, while, B lymphocytes infiltrate to the damaged mucosa in UC. Previous studies demonstrated that there were excessive amounts of type Th1 cytokines present in CrD, whereas, type Th2 cytokines are predominant in UC. However, the precise mechanisms of the infiltration and activation of the lymphocytes are still unclear. Gut associated lymphoid tissue (GALT) plays a major role in the mucosal immune mechanisms initiated by Peyers's patch cells and affects the mucosa through the lymphocytes homing receptor system. However, there are few reports about the immunological reactions between mesenteric lymph nodes and intestinal mucosa in IBD. The aim of this study was to clarify the roles of immunologically activated lymphocytes in the mesenteric lymph nodes in UC and CrD patients. [Materials and methods] Mesenteric lymph nodes obtained during surgery from 15 cases of UC (UC high group (Clinical activity index ≧ 11) n = 7 and UC low group (Clinical activity index ≦ 10) n = 8) and 10 cases of CrD were examined immunohistochemically. [Results] The germinal center was characterized by the aggregation of Ki67-positive cells and follicular dentritic cell-positive cells. The number of germinal centers was significantly decreased in the UC high group compared to the other groups. In addition, the Ki67-positive cells were diffusely localized and unaggregated in the UC high group. Double immunostaining of Ki67 and the lymphocyte surface markers CD3 or CD19 demonstrated that only 3% of Ki67-positive cells expressed CD3 and approximately 30% expressed CD19 in the UC high group. In contrast, there were significantly increased CD83-positive cells and HECA-452-positive venules observed in the mesenteric lymph nodes of CrD. [Conclusions] This study shows that the extrafollicular B lymphocytes, which develop independently of germinal center formation, play important roles in the acute exacerbation of UC, while the Th1 dominant mucosal immune system is prevalent in the lymph nodes of CrD.
