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Featured researches published by D.P. Bogdanos.


Gut | 2005

Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis.

Eirini I. Rigopoulou; E T Davies; Albert Parés; Kalliopi Zachou; Christos Liaskos; D.P. Bogdanos; Juan Rodés; George N. Dalekos; Diego Vergani

Background: Antinuclear antibodies (ANA) giving a rim-like/membranous (RL/M) or a multiple nuclear dot (MND) pattern are highly specific for primary biliary cirrhosis (PBC). Aim and subjects: To assess the prevalence of PBC specific ANAs, their Ig isotype, and their clinical significance in 90 PBC patients from Greece and Spain. Twenty eight patients with chronic hepatitis C, 23 patients with systemic lupus erythematosus, and 17 healthy subjects were studied as controls. Methods: PBC specific ANA reactivity was tested by indirect immunofluorescence using HEp2 cells as substrate and individual Ig class (IgG, IgA, IgM) and IgG subclass (IgG1, IgG2, IgG3, IgG4) specific antisera as revealing reagents. Results: Fourteen of 90 (15.6%) PBC patients had PBC specific ANA reactivity when an anti-IgG (total) antiserum was used as the revealing reagent while 58 (64.4%) were positive when specific antisera to each of the four IgG isotypes were used. The prevailing isotype was IgG3 for MND and IgG1 for RL/M. PBC patients with specific ANA, in particular of the IgG3 isotype, had significantly more severe biochemical and histological disease compared with those who were seronegative. None of the controls was positive. Conclusions: Disease specific ANA are present in the majority of patients with PBC when investigated at the level of immunoglobulin isotype. PBC specific ANA, in particular of the IgG3 isotype, are associated with a more severe disease course, possibly reflecting the peculiar ability of this isotype to engage mediators of damage.


Journal of Hepatology | 2004

Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis

D.P. Bogdanos; Harold Baum; Alessandro Grasso; M. Okamoto; Patrice Butler; Yun Ma; Eirini I. Rigopoulou; P. Montalto; E T Davies; Andrew K. Burroughs; Diego Vergani

BACKGROUND/AIMS Previous studies on patients with primary biliary cirrhosis (PBC) have shown extensive cross-reactivity between the dominant B- and T-cell epitopes of human pyruvate dehydrogenase complex-E2 (PDC-E2), and microbial mimics. Such observations have suggested microbial infection as having a role in the induction of anti-mitochondrial antibodies, through a mechanism of molecular mimicry. However the biological significance of these cross-reactivities is questionable, because PDC-E2 is so highly conserved among various species. METHODS Interrogating protein databases, ten non-PDC-E2 microbial sequences with high degree of similarity to PDC-E2(212-226) were found in Escherichia coli (6), Helicobacter pylori, Pseudomonas aeruginosa, Cytomegalovirus, and Haemophilus influenzae. We report on a study testing reactivity and competitive cross-reactivity against these respective peptides, and in some cases the parent protein, using sera from 55 patients with PBC, compared to reactivity of 190 pathological and 28 healthy controls. RESULTS Cross-reactivity to E. coli mimics was commonly seen in PBC, and in a subset of pathological controls except where there was no evidence of urinary tract infection and correlated with anti-mitochondrial reactivity. CONCLUSIONS E. coli/PDC-E2 cross-reactive immunity characterizes primary biliary cirrhosis; the large number of E. coli immunogenic mimics may account for the dominance of the major PDC-E2 autoepitope.


Hepatology | 2005

Primary biliary cirrhosis is characterized by IgG3 antibodies cross‐reactive with the major mitochondrial autoepitope and its Lactobacillus mimic

D.P. Bogdanos; Harold Baum; M. Okamoto; P. Montalto; Umesh C. Sharma; Eirini I. Rigopoulou; J. Vlachogiannakos; Yun Ma; Andrew K. Burroughs; Diego Vergani

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of pyruvate dehydrogenase complex E2 subunit (PDC‐E2) antimitochondrial antibodies (AMAs). Anti–PDC‐E2 antibodies cross‐react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC‐E2212‐226 and hsps is a cross‐reactive target. Having found that this same motif is present only in β‐galactosidase of Lactobacillus delbrueckii (BGAL LACDE), we hypothesized that this homology would also lead to cross‐reactivity. The mimics were tested via ELISA for reactivity and competitive cross‐reactivity using sera from 100 AMA‐positive and 23 AMA‐negative PBC patients and 190 controls. An Escherichia coli (ECOLI) PDC‐E2 mimic that has been pathogenetically linked to PBC but lacks this motif has been also tested. Anti‐BGAL266‐280 LACDE antibodies were restricted to AMA‐positive patients (54 of 95, 57%) and belonged to immunoglobulin (Ig) G3. Of the 190 controls, 22 (12%; P < .001) had anti‐BGAL266‐280 antibodies, mainly of the IgG4 subclass. ECOLI PDC‐E2 reactivity was virtually absent. BGAL266‐280/PDC‐E2212‐226 reactivity of the IgG3 isotype was found in 52 (52%) AMA‐positive PBC patients but in only 1 of the controls (P < .001). LACDE BGAL266‐280/PDC‐E2212‐226 reactivity was due to cross‐reactivity as confirmed via competition ELISA. Antibody affinity for BGAL266‐280 was greater than for PDC‐E2 mimics. Preincubation of a multireactive serum with BGAL266‐280 reduced the inhibition of enzymatic activity by 40%, while marginal effect (12%) or no effect (2%) was observed in human or ECOLI PDC‐E2 mimics. In conclusion, IgG3 antibodies to BGAL LACDE cross‐react with the major mitochondrial autoepitope and are characteristic of PBC. (HEPATOLOGY 2005;42:458–465.)


Liver International | 2007

Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis

Eirini I. Rigopoulou; E T Davies; D.P. Bogdanos; Christos Liaskos; Maria G. Mytilinaiou; George K. Koukoulis; George N. Dalekos; Diego Vergani

Background/Aims: Primary biliary cirrhosis (PBC) is characterised by the presence of immunoglobulin (Ig) G antimitochondrial antibodies (AMA), which are routinely detected by indirect immunofluorescence (IFL) using composite rodent tissue substrate. The IgG subclass distribution and clinical significance of IFL‐detected AMA in patients with PBC have not been previously studied in detail.


Scandinavian Journal of Gastroenterology | 2004

Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross‐reactivity

D.P. Bogdanos; H. Baum; F. Gunsar; D. Arioli; D. Polymeros; Yun Ma; A. K. Burroughs; Diego Vergani

Background: Primary biliary cirrhosis (PBC) is an immune‐mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti‐mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. Methods: Having found that urease beta (UREB) 22–36 antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC‐E2 212–226 , the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross‐reactivity. The UREB/PDC‐E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. Results: Reactivity to PDC‐E2 212–226 was found in 104 patients but to UREB 22–36 in only 2. In these two patients, the double reactivity was not cross‐reactive. The lack of surface antibody accessibility to UREB 22–36 , as demonstrated through three‐dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB 22–36 might act as a cross‐reactive CD4 T‐cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC‐E2 212–226 , gave a positive response. All seven were unresponsive to HELPY UREB 22–36 . The pattern of reactivity to HELPY antigens by immunoblot was similar between anti‐PDC‐E2‐positive and negative PBC cases, as well as between PBC patients and controls. Conclusion: Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross‐reactivity. It is therefore likely that, when present, cross‐reactivity between self and microbes is of biological importance.


Digestive and Liver Disease | 2003

Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

D.P. Bogdanos; Harold Baum; Patrice Butler; Eirini I. Rigopoulou; E T Davies; Yun Ma; Andrew K. Burroughs; Diego Vergani

BACKGROUND AND AIMS Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI. METHODS AND SUBJECTS PBC-specific ANA reactivities were investigated in 20 women with rUTI but without liver disease, some of whom were AMA-seropositive; 40 women with PBC, with or without rUTI; and 104 pathological and 23 healthy controls. RESULTS Among the women with rUTI but without liver disease, 8 (80%) of 10 AMA-positive women reacted with sp100 compared with none of the 10 AMA-negative women. Among the PBC patients, 14 (74%) of 19 with rUTI and 1 (4.8%) of the 21 without rUTI reacted with sp100. None of the rUTI women without liver disease reacted with gp210 or LBR. None of 127 pathological and healthy controls had PBC-specific ANA reactivity. CONCLUSIONS Anti-sp100 reactivity strongly correlates with AMA seropositivity in rUTI women, with or without evidence of primary biliary cirrhosis. These findings provide additional support to the notion that E. coli infection is involved in the induction of PBC-specific autoimmunity. Additional factors must be involved in the progression to overt autoimmune disease.


Hepatology | 2004

Unusual suspects in primary biliary cirrhosis.

Diego Vergani; D.P. Bogdanos; Harold Baum

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that affects mainly middle-aged women and is characterized by an immune-mediated inflammatory destruction of the small intrahepatic bile ducts, progressing to cirrhosis and subsequent liver failure.1 The diagnostic hallmark of PBC is the presence of high-titer antibodies directed to mitochondria (AMA) and in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2).1 The principal B2 and T (both CD43 and CD84) cell epitopes on PDC-E2 have been defined and shown to colocalize within the inner lipoyl-binding domain of the subunit, overlapping amino acids (aa) 208-237 (PDC-E2208–237). PDC-E2208–237 is physically exposed on the molecule’s surface, and this may partially explain its particular antigenicity.5 The mechanism by which this short sequence becomes the focus of PBC-specific antimitochondrial immune responses remains obscure.6 Interplay of genetic and environmental factors is invariably invoked to justify the emergence of the autoimmune aggression in PBC.1 There is an increasing body of circumstantial evidence implicating an external trigger—be it an infectious agent or other environmental factor—in the pathogenesis of PBC (see reviews7,8). This includes clustering of cases within families with the affected members of the same family acquiring the disease at the same time rather than at the same age; clustering of cases within geographical areas; geographical variation of disease’s prevalence; effect of migration with migrating populations acquiring the prevalence of the disease of the host population; absence of disease’s equivalent in childhood; poor response to immunosuppressive therapy; weak human leucocyte antigens (HLA) associations; granulomatous lesions resembling those due to mycobacteria; epidemiological association with infectious agents. The evidence in support of a viral trigger is indirect7,8: the elevated levels of IgM may be due to virusinduced polyclonal activation; AMA (and in particular antiPDC-E2 antibodies) belong to the IgG3 isotype as antiviral antibody responses frequently do; akin to viral hepatitis, PBC recurs after liver transplantation, the recurrence, as in viral hepatitis, occurring earlier and being more aggressive if higher doses of immunosuppressive are used; a transmissible factor from lymph nodes of patients with PBC can promote in vitro aberrant expression of the PDC-E2 on biliary epithelial cells. Despite the evidence, whether PBC has an infective component, bacterial or viral, remains to be defined. We are dealing with an “enigmatic” disease, the pathogenesis of which is “poorly understood” as emphasized by two papers9,10 published, respectively, in the November issue and this issue of HEPATOLOGY. Both papers provide suggestive evidence that a microbe may be the driving force leading to PBC; both emphasize the role of the genetic background. The similarity between the two papers ends here. Selmi et al.9 link the ubiquitous microorganism Novosphingobium aromaticivorans (N. aromaticivorans) to the development of PBC. Having found a striking amino acid similarity between human PDC-E2208–237, the major mitochondrial autoepitope and the corresponding sequence on PDC-E2 of N. aromaticivorans, these authors9 provide evidence that the newly identified sequence may act as a bridge to autoimmunity through a mechanism of molecular mimicry. Molecular mimicry (Fig. 1) requires that recognition of an immunogenic determinant on an exogenous agent, bacterium, or virus leads to the formation of antibodies or effector T cells which can react with homologous epitopes on a host protein.11,12 The sharing of a linear amino acid sequence or a conformation fit between a microorganism and a host “self” determinant is the initial step of this process. Autoimmunity provoked by molecular mimicry should occur only when the microbial and host determinants are similar enough to cross-react, yet different enough to break immunological tolerance.11,12 Antibodies or T lymphocytes may then cross-react with a selfprotein, thereby causing cellular injury leading to cell destruction. Once the infectious agent initiates this process, it need not be present during the autoimmune destruction that follows. In this situation, the microbial agent may have been cleared, but elements of the immune Abbreviations: PBC, primary biliary cirrhosis; AMA, anti-mitochondrial antibody; PDC, pyruvate dehydrogenase complex; HLA, human leucocyte antigens; N. aromaticivorans, Novosphingobium aromaticivorans. From the 1Institute of Liver Studies and 2Division of Life Sciences, King’s College London, Denmark Hill Campus, London, UK. Received October 14, 2003; accepted October 30, 2003. Supported by the Children’s Liver Disease Foundation (Bogdanos, CLDF, Birmingham, UK). Address reprint requests to: Diego Vergani, Professor of Liver Immunopathology, Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK. E-mail: [email protected]; fax: 44-20-7346-3700. Copyright


Liver International | 2006

Origin of cross‐reactive autoimmunity in primary biliary cirrhosis

D.P. Bogdanos; Diego Vergani

The immune system is designed to protect the host from foreign invaders (1, 2). In doing so, cells of the immune system are educated to discriminate between endogenous ‘self’ tissues and exogenous ‘non-self’ components (1, 2). But errors do occur, with more than 80 clinically distinct autoimmune diseases being currently recognised affecting some 5% of North American and European populations (3, 4). In many of these disorders, the disease process begins months or even years before the appearance of clinical symptoms. This creates the opportunity to intervene early in the process to either treat the disease at a stage when it may be more responsive to treatment or to slow down the progress of autoimmune destruction. Akin to the clearance of foreign antigens, immunity towards self-antigens is highly restricted to individual peptides within autoantigens (5–7). There is evidence to show that the highly diverse immune response seen in various autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis and diabetes originate from reactivity to a single protein or even a single autoepitope which spreads in an ‘intramolecular’ or ‘intermolecular’ manner, selecting new antigenic targets within a single protein or in different proteins of a macromolecular complex (8, 9). Studies have naturally concentrated on the search for initial targets, with myelin basic protein, myelin oligodendroglial glycoprotein and proteolipid protein being prime candidates in multiple sclerosis and glutamic acid decarboxylase and insulin in insulin dependent diabetes. In primary biliary cirrhosis (PBC), a chronic cholestatic liver disease characterised by progressive destruction of the small intrahepatic bile ducts, there is a consensus as to the primary and dominant target of the autoimmune response (10, 11). The disease is characterised by a highly specific antibody response directed against mitochondria (AMA) recognising the inner mitochondrial oxoacid dehydrogenase complex (OADC) and in particular the pyruvate dehydrogenase complex E2 subunit (PDCE2) (10–12). The breakdown of immune-tolerance to self-PDC-E2 appears to be a fundamental step in the pathogenesis of PBC, there being an almost complete association between seropositivity for antiPDC-E2 autoantibodies and present or future development of the bile duct lesions characteristic of the disease (13–15). AMA characteristic of PBC are only those directed against E2 subunits of the OADCs, including PDC, 2-oxoglutarate dehydrogenase complex (OGDC) and branched-chain 2oxoacid (BCOADC) and also against subunits E1a, Elb and E3 binding protein (E3BP), formerly known as protein X, of the PDC (12). More than 95% of the PBC patients have antibodies against PDC-E2 complex whose principal target is the inner lipoyl-binding domain (12). The association of AMA with PBC is so striking that the diagnosis of PBC has to be questioned, as Dame Sheila Sherlock taught, in the absence of this biomarker. There are a number of AMA features, which are puzzling (12, 16). Mitochondrial antigens are ubiquitous while the autoimmune response is confined to biliary epithelial cells of the small intrahepatic bile ducts. A protein complex of the inner mitochondrial membrane becomes a major B-cell and T-cell target in spite of being sheltered from the immune system by two membrane barriers. We do not know why OADC – and not other mitochondrial proteins – are targeted by the autoimmune assault. We are also unable to explain why the AMA pattern byWestern blot differs from one patient to another (Fig. 1). While a minority of PBC sera react with all the subunits, most react with a combination thereof. Also, the intensity of the reaction varies (Fig. 1) (10, 12, 16). Finally, we cannot understand the relationship between antimitochondrial immunity and the pathogenesis of the disease (17–21). Yet, there is a consensus that the study of pathogenetic mechanisms in PBC should start from AMA and its targets in view of the unique link between autoantibody and disease (13–15, 21). As shown in a key study by the Newcastle group, AMA can precede the clinical onset of the This Editorial accompanies the article entitled ‘PDC-E3BP is not a dominant T-cell autoantigen in primary biliary cirrhosis’ which appeared in Liver International 2006, Volume 26, Pages 406–413. Liver International 2006: 26: 633–635 r 2006 The Authors Journal compilation r 2006 Blackwell Munksgaard


Clinical & Developmental Immunology | 2005

A Study of Molecular Mimicry and Immunological Cross-reactivity between Hepatitis B Surface Antigen and Myelin Mimics

D.P. Bogdanos; Heather Smith; Yun-Yun Ma; Harold Baum; Giorgina Mieli-Vergani; Diego Vergani

On the basis of the reported association between hepatitis B vaccination (HBvacc) and autoimmune demyelinating complications such as multiple sclerosis (MS), we have looked for aminoacid similarities between the small hepatitis B virus surface antigen (SHBsAg), and the MS-autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) that could serve as targets of immunological cross-reactivity. Twenty-mer peptides spanning 4 SHBsAg/MOG and 1 SHBsAg/MBP mimicking pairs, were constructed and tested by ELISA as targets of cross-reactive responses. A total of 147 samples from 58 adults were collected before HBvacc (58/58), and post-HBvacc (48/58 before the second and 41/58 before the third boost). Eighty-seven sera from anti-SHBsAg antibody negative patients with various diseases were tested as pathological controls. Reactivity to at least one of the SHBsAg peptides was found in 8 (14%) pre-HBvacc subjects; amongst the remaining 50, reactivity to at least one of the SHBsAg peptides appeared in 47 (94%) post-HBvacc. Reactivity to at least one of the MOG mimics was present in 4 (8%) pre-HBvacc and in 30 (60%) post-HBvacc (p < 0.001). Overall 30/50 (60%) vaccinees had SHBsAg/MOG double reactivity on at least one occasion compared to none before-vaccination and in 2 (2%) of the pathological controls (p < 0.001 for both). SHBsAg/MOG double reactivity was cross-reactive as confirmed by inhibition studies. At 6 months post-vaccination, 3 of the 4 anti-MOG reactive cases before vaccination and 7 of the 24 (29%) of the anti-MOG reactive cases at 3 months post-vaccination had lost their reactivity to MOG5-24. There was no reactivity to the SHBsAg/MBP mimics. None of the vaccinees reported symptoms of demyelinating disorders. In view of the observed SHBsAg/MOG cross-reactivity, the vaccines possible role as an immunomodulator of viral/self cross-reactivity must be further investigated.


Autoimmunity | 2002

Neonatal liver disease associated with placental transfer of anti-mitochondrial antibodies.

Simon Hannam; D.P. Bogdanos; E T Davies; Munther Hussain; Bernard C. Portmann; Giorgina Mieli-Vergani; Diego Vergani

Background: Anti-mitochondrial antibody is the diagnostic hallmark of primary biliary cirrhosis. Its role in the aetiology of primary biliary cirrhosis is controversial. Methods: Two cases of neonatal hepatitis seropositive for anti-mitochondrial antibody are described. Anti-mitochondrial antibody Ig isotype and epitopic specificity were investigated by immunofluorescence and enzyme immunoassays. Results: In both infants anti-mitochondrial antibody was of the G class, mainly G1 and G3 subclasses, and reacted with two synthetic peptides reproducing major M2 epitopic regions: inner lipoyl domain pyruvate dehydrogenase complex (PDC)-E2162-176 and PDC-E3 binding protein (PDC-E3BP)86-100. One infant also reacted with outer lipoyl domain PDC-E235-49, and 2-oxoglutarate dehydrogenase complex (OGDC)-E299-113. An identical pattern of reactivity was present in their mothers, indicating the maternal origin of the antibodies. Anti-mitochondrial antibody disappeared in the infants with the disappearance of the liver pathology. Conclusions: The simultaneous disappearance of hepatitis and anti-mitochondrial antibody in the infants suggests a possible causal link between the two.

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Yun Ma

King's College London

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M. Okamoto

University of Cambridge

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E T Davies

University of Cambridge

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