Autoimmune liver diseases (AILDs) are common leading causes for liver cirrhosis and terminal stage of liver disease. They have variable prevalence among patients with liver disease and have two major clinical and biochemical presentations. Autoimmune hepatitis (AIH) is the typical example of hepatocellular AILD, but it can also be presented under a cholestatic pattern. AIH has a scoring diagnostic system and respond in most cases to the treatment with prednisolone and azathioprine. Primary biliary cirrhosis (PBC) is the second most common AILD, with a cholestatic presentation and characterized by positive antimitochondrial antibody (AMA). It has an excellent response and long term outcome with the administration of ursodeoxycholic acid (UDCA). Another AILD that is thought to be a variant of PBC is the autoimmune cholangitis, being a disease that has biochemical and histological features similar to PBC; but the AMA is negative. Primary sclerosing cholangitis (PSC) is a rare entity of AILD that has a cholestatic presentation and respond poorly to the treatment, with the ultimate progression to advance liver cirrhosis in most patients. Other forms of AILD include the overlap syndromes (OS), which are diseases with mixed immunological and histological patterns of two AILD; the most commonly recognized one is AIH-PBC overlap (AIH-PSC overlap is less common). The treatment of OS involves the trial of UDCA and different immunosuppressants. Here we present three case reports of unusual forms of chronic liver diseases that most likely represent AILD. The first two patients had a cholestatic picture, whereas the third one had a hepatocellular picture at presentation. We discussed their biochemical, immunological and histological features as well as their response to treatment and their outcomes. Then, we compared them with other forms of AILD.
Autoimmune liver disease; autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; autoimmune cholangitis; cholestasis; hepatocellular; ursodeoxycholic acid
Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases (AiLD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children. AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation. PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents as at least two variants, first the classical primary sclerosing cholangitis (PSC) mostly affecting adult men wherein the only (and non-specific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH. Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens, and automated technologies such as ELISAs and bead assays, become available to complement (or even compete with) traditional immunofluorescence procedures. We survey for the first time global trends in quality assurance impacting as it does on (1) manufacturers/purveyors of kits and reagents, (2) diagnostic service laboratories that fulfill clinicians’ requirements, and (3) the end-user, the physician providing patient care, who must properly interpret test results in the overall clinical context.
Autoantigen; Autoimmune hepatitis; Autoantibody; Primary biliary cirrhosis; Primary sclerosing cholangitis; Liver disease
Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are considered as putative autoimmune diseases of the liver. Whereas strong evidence that bacterial infection may trigger PBC exists, the etiologies for PSC and AIH remain unknown. Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases, their associations with environmental triggers and the subsequent implications have been difficult to elucidate. While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) have been suggested as genetic susceptibility factors for all three disorders, we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC, where Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, has recently been specifically associated with the pathogenesis of this devastating liver disease. Ultimately, the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers, establish infection and damage respective target organs.
Primary biliary cirrhosis; Novosphingobium; Natural killer T cells, Cytotoxic T lymphocyte antigen 4; Diabetes; Susceptibility loci; Non-obese diabetic congenic mice
The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardized definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC. The AIH-PBC overlap syndrome is the most common form, affecting almost 10% of adults with AIH or PBC. Single cases of AIH and autoimmune cholangitis (AMA-negative PBC) overlap syndrome have also been reported. The AIH-PSC overlap syndrome is predominantly found in children, adolescents and young adults with AIH or PSC. Interestingly, transitions from one autoimmune to another have also been reported in a minority of patients, especially transitions from PBC to AIH-PBC overlap syndrome. Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment. Therapy for overlap syndromes is empiric, since controlled trials are not available in these rare disorders. Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes. In end-stage disease, liver transplantation is the treatment of choice.
Autoimmune hepatitis; Immunosuppressive agents; Primary biliary cirrhosis; Primary sclerosing cholangitis; Ursodeoxycholic acid
CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
We describe a case of a young man with autoimmune hepatitis (AIH) following Epstein–Barr virus (EBV) infection, in whom a long follow-up showed favourable outcome with complete clinical recovery and failure to relapse after cessation of immunosuppressive therapy. The study underlines the importance of the differential diagnosis between primary EBV associated hepatitis with features of autoimmunity, in which there is a direct pathogenetic role of the virus, and EBV related AIH, in which EBV could act as the trigger of the immune mediated damage with probable differences between the two conditions with regard to the prognosis and the responsiveness to immunosuppressive treatment. The favourable outcome in our patient, better than most of the AIH cases, may be related both to the moderate necroinflammatory activity and to the low level of fibrosis at the beginning of the disease, or to the role of EBV as a trigger of AIH. The hypothesis that EBV related AIH could have a more favourable prognosis than most of the AIH cases in general needs to be confirmed in a larger series of studies.
Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4+ and CD8+ T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.
Autoimmune liver disease; Regulatory T cell; Th17; Lymphocytes; Recruitment; Mycophenolate mofetil
AIM: To assess the role of IgM and IgG immunohistochemistry (IHC) in the evaluation of autoimmune liver conditions - autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).
METHODS: Forty one biopsies from untreated patients diagnosed with autoimmune liver disease (AIH, n = 20; PBC, n = 13; PSC, n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected. IgM and IgG-positive plasma cells were counted in each sample.
RESULTS: A predominance of IgG-positive plasma cells was seen in AIH (90% of cases), PSC (75% of cases), and chronic hepatitis C (100% of cases), while IgM-positive plasma cells predominated in PBC (92.8% of cases). The IgM /IgG ratio (< 1 or ≥ 1) accurately distinguished PBC from AIH in 90.9% of cases (sensitivity = 92.3%, specificity = 90%), and PBC from either AIH or PSC in 87.8% of cases (sensitivity = 92.3%, specificity = 85.7%).
CONCLUSION: Plasmacytic infiltrates expressing predominantly IgM are characteristic of PBC, while other forms of liver disease analyzed in this study, including AIH, typically show an IgG-predominant plasma cell infiltrate. Our data indicate that IgM and IgG IHC may be a useful tool when PBC is a diagnostic consideration.
Autoimmune hepatitis; Primary sclerosing cholangitis; Primary biliary cirrhosis; Immunoglobulin; Immunohistochemistry
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the major forms of autoimmune liver diseases each characterized by the destruction of a specific liver cell type and the presence of differing auto-antibodies. We took a proteomic approach utilizing in situ matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to obtain profiles directly from liver samples of patients with PBC, PSC, AIH and controls. The ability to precisely localize the region for acquisition of MALDI MS allowed us to obtain profiles from bile ducts, inflammatory infiltrates and hepatocytes from each biopsy sample. Analysis tools developed to identify peaks and compare peaks across diseases and cell types were used to develop models to classify the samples. Using an initial set of testing samples from PBC patients and controls, we identified unique peaks present in bile ducts, inflammatory infiltrates and hepatocytes that could classify samples in a validation cohort with 88–91% accuracy. Interestingly, profiles of PSC and AIH did not differ significantly from PBC. Identification of proteins in these peaks may represent novel autoantigens or effector molecules. These findings illustrate the potential of a proteomic approach to autoimmune diseases with in situ MALDI MS.
autoimmune hepatitis; mass spectrometry; primary biliary cirrhosis; primary sclerosing cholangitis
AIM: To determine the prevalence and significance of primary biliary cirrhosis (PBC)-specific autoantibodies in first-degree relatives (FDRs) of Greek PBC patients.
METHODS: The presence of antimitochondrial antibodies (AMA) and PBC-specific antinuclear antibodies (ANA) were determined using indirect immunofluorescence assays, dot-blot assays, and molecularly based enzyme-linked immunosorbent assays in 101 asymptomatic for liver-related symptoms FDRs of 44 PBC patients. In order to specify our results, the same investigation was performed in 40 healthy controls and in a disease control group consisting of 40 asymptomatic for liver-related symptoms FDRs of patients with other autoimmune liver diseases namely, autoimmune hepatitis-1 or primary sclerosing cholangitis (AIH-1/PSC).
RESULTS: AMA positivity was observed in 19 (only 4 with abnormal liver function tests) FDRs of PBC patients and none of the healthy controls. The prevalence of AMA was significantly higher in FDRs of PBC patients than in AIH-1/PSC FDRs and healthy controls [18.8%, 95% confidence interval (CI): 12%-28.1% vs 2.5%, 95% CI: 0.1%-14.7%, P = 0.01; 18.8%, 95% CI: 12%-28.1% vs 0%, 95% CI: 0%-10.9%, P = 0.003, respectively]. PBC-specific ANA positivity was observed in only one FDR from a PSC patient. Multivariate analysis showed that having a proband with PBC independently associated with AMA positivity (odds ratio: 11.24, 95% CI: 1.27-25.34, P = 0.03) whereas among the investigated comorbidities and risk factors, a positive past history for urinary tract infections (UTI) was also independently associated with AMA detection in FDRs of PBC patients (odds ratio: 3.92, 95% CI: 1.25-12.35, P = 0.02).
CONCLUSION: In FDRs of Greek PBC patients, AMA prevalence is significantly increased and independently associated with past UTI. PBC-specific ANA were not detected in anyone of PBC FDRs.
Primary biliary cirrhosis; Antimitochondrial antibodies; Anti-gp210; Anti-sp100; Liver autoimmunity
Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.
B lymphocytes; somatic hypermutation; EBV; immunoglobulin genes; single cell PCR
Acoustic radiation force impulse (ARFI) is a new software-based technique that evaluates liver stiffness during B-mode ultrasonography. The purpose of this study was to evaluate the accuracy of ARFI in distinguishing patients with chronic autoimmune liver disease from healthy subjects.
Material and methods
We enrolled 9 adult patients (8 women, 1 man; age 48.1 ± 12.8 years) with chronic autoimmune disease (primary biliary cirrhosis (PBC, n = 3), autoimmune hepatitis (AIH, n = 2), primary sclerosing cholangitis (PSC, n = 1) and overlap syndromes, (n = 3) who underwent a liver biopsy and 11 healthy volunteers (age 34.7 ± 10.4 years; 7 women, 4 men). Liver stiffness was evaluated and expressed as the shear wave velocity (SWV) in m/sec. We used a US scanner Siemens-Acuson S2000, evaluating the right liver lobe and the left liver lobe.
The SWV was significantly higher in cases (right lobe: 1.51 ± 0.44; left lobe: 1.57 ± 0.40) than in controls (right lobe: 1.08 ± 0.10; left lobe: 1.12 ± 0.13) (right lobe: P = 0.002; left lobe: P = 0.013). We found no significant correlation between right and left lobe SWVs in cases (P = 0.779) or controls (P = 0.385). The SWV cut-off that best distinguished cases from controls was 1.25 m/sec (accuracy: AUC=0.885; sensitivity: 70.6%; specificity: 95.5%).
ARFI elastography is a noninvasive ultrasonographic technique that can differentiate healthy subjects from patients with fibrotic stages of chronic liver disease.
ARFI imaging; Primary biliary cirrhosis; Autoimmune hepatitis; Primary sclerosing cholangitis
Aim: Sera of patients with autoimmune liver diseases were investigated for the presence of autoantibodies binding to human biliary epithelial cells (BECs). Furthermore, their functional capacity was investigated by testing their capacity to fix complement as well as induce expression of various adhesion molecules and production of cytokines.
Methods: Sera from patients with various stages of primary sclerosing cholangitis (PSC; n=30), primary biliary cirrhosis (PBC; n=29), autoimmune hepatitis (AIH; n=25), and normal controls (n=12) were investigated for the presence of antibodies that reacted with unstimulated and cytokine stimulated BECs isolated from a normal healthy liver. To demonstrate organ specificity, lung epithelial cells (LECs) were used as control cells. Antibodies were tested for their functional capacity.
Results: Compared with controls (8%), significantly higher numbers of PSC patients (63%, p=0.001), but not PBC (37%, NS) or AIH (16%, NS) patients, had anti-BEC antibodies. In 90% of PSC patients, the autoantibodies reacted only with cytokine stimulated target cells. Lower numbers of PSC (6%), PBC (10%), and AIH (0%) patients had LEC antibodies. Other significant findings were that anti-BEC antibodies were found in (i) PSC patients with either the HLA-DRB1*0301 or DR2 allele compared with those without (p=0.007); and (ii) in PBC patients with end stage disease compared with those without (p=0.018). Furthermore, anti-BEC antibodies from PSC and PBC but not AIH patients induced BECs to produce high levels of the cytokine interleukin 6. IgM and IgG fractions isolated from PSC but not PBC and AIH sera induced significantly increased expression of the cell adhesion molecule CD44. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blot analysis of BEC membranes demonstrated a specific band of 40 kDa with PSC sera and 45, 42, 30, and 33 kDa bands with PBC sera, which were absent in control groups.
Conclusion: Thus for the first time we have demonstrated the presence of functionally important autoantibodies to cell surface expressed antigens on the relevant target cells of destruction, namely BECs, in PSC and PBC. These finding have important implications for the pathogenesis of bile duct destruction in these patients.
autoimmune liver diseases; primary sclerosing cholangitis; primary biliary cirrhosis; adhesion molecules; cytokines
BACKGROUND—Primary sclerosing cholangitis (PSC) is considered to be a chronic autoimmune disease where infiltrating T lymphocytes have been implicated in the destruction of bile ducts. Altered function of these T cells may reflect abnormalities in the immune response leading to tissue damage.
AIM—We investigated the proliferative and functional capacity of freshly isolated liver derived T lymphocytes (LDLs) and natural killer (NK) cells from PSC patients.
METHODS—The proliferative responses to common mitogens such as phytohaemagglutinin (PHA), concanavalin A (Con A), and lipopolysaccharide (LPS) were studied, and the cytotoxic function of T lymphocytes was measured using allogeneic target cells. NK (CD56+/16+) cytotoxic function was measured using the two cell lines K562 (NK sensitive) and Raji lymphoma cells (NK resistant).
RESULTS—Compared with patients with primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and normal controls (without liver disease), in PSC: (1) LDLs contained a low percentage of T cells; (2) there was significantly decreased expression of interleukin (IL)-2 receptor (p<0.001) on activated T cells (HLA-DR+); (3) LDLs but not peripheral blood lymphocytes had significantly impaired proliferative responses to mitogens such as PHA, Con A, and LPS (p< 0.001); (4) no cytotoxic activity of PSC liver T and NK cells was recorded; (5) significantly higher levels of tumour necrosis factor α (TNF-α) and IL-1β but lower levels of IL-2, IL-10, and interferon γ were found in the supernatants of mitogen stimulated LDL cultures (p<0.001); (6) higher percentages of freshly isolated PSC LDLs contained intracytoplasmic TNF-α and IL-1β; and (7) pretreatment of PSC LDLs in vitro with neutralising TNF antibodies significantly enhanced proliferative responses and allowed IL-2 receptor expression following stimulation. In addition, the impaired cytolytic activity of both NK and T cells was partially restored. Impaired proliferative or functional capacity of liver derived T cells was not observed in either PBC or AIH patients.
CONCLUSIONS—We suggest that reduced T cell reactivity in liver infiltrating cells obtained from patients with PSC is due to high local production of TNF-α. Our findings indicate that the use of anti-TNF antibodies as an alternative treatment for PSC patients should be evaluated.
Keywords: autoimmune liver diseases; biliary epithelial cells; cytokines
BACKGROUND—Primary biliary cirrhosis (PBC) is an autoimmune disease in which the pathogenesis of progressive liver injury is poorly understood.
AIM—To provide novel insights into the pathogenesis of PBC related liver injury using cDNA array analysis, which simultaneously examines expression of many genes.
METHODS—Utilising cDNA arrays of 874 genes, PBC was compared with primary sclerosing cholangitis (PSC) associated cirrhosis and non-diseased liver. Differential expression of 10 genes was confirmed by real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
RESULTS—Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signalling, apoptosis, and oxidative stress. PBC was associated with increased expression of both Th1 and Th2 type molecules of the immune response. Fibrosis related gene expression featured upregulation of connective tissue growth factor and transforming growth factor beta3. Many more apoptosis associated molecules exhibited increased expression, consistent with apoptosis being a more active and regulated process, in PSC associated cirrhosis than in PBC. Increased expression of many genes of the Wnt and notch pathways implicated these highly conserved and linked pathways in PBC pathogenesis. The observed increases in expression of c-jun, c-myc, and c-fos related antigen 1 are consistent with increased Wnt pathway activity in PBC. Differential expression of four components of the Wnt pathway, Wnt-5a, Wnt-13, FRITZ, and beta-catenin, was confirmed by quantitative RT-PCR.
CONCLUSION—Many genes implicated in intrahepatic inflammation, fibrosis, and regeneration were upregulated in PBC cirrhosis. In particular, increased expression of a number of Drosophila homologues was seen in PBC.
Keywords: primary sclerosing cholangitis; apoptosis; fibrosis; connective tissue growth factor; Wnt; Th1/Th2; brain derived neurotrophic factor; notch
Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized serologically by cholestasis and the presence of high-titre antimitochondrial antibodies and histologically by chronic nonsuppurative cholangitis and granulomata. PBC patients often have concomitant autoimmune diseases, including arthropathies. This raises the question as to whether there are shared features in the pathogenesis of those diseases with the pathogenesis of PBC. Epidemiological and large case studies have indicated that although the incidence of rheumatoid arthritis (RA) is not significantly raised in PBC patients, there appears to be a higher rate of RA in PBC patients and their relatives. Genetic studies have demonstrated that several genes implicated in PBC have also been implicated in RA. Epigenetic studies provided a wealth of data regarding RA, but the findings on epigenetic changes in PBC are very limited. As well, certain infectious agents identified in the pathogenesis of PBC may also play a role in the pathogenesis of RA. These data suggest that although RA is not significantly present in PBC, some individuals with certain genetic traits and environmental exposures may develop both conditions. This concept may also apply to other concomitant diseases found in PBC patients.
End-stage liver disease, due to cholestatic liver diseases with an autoimmune background such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), is considered a good indication for liver transplantation. Excellent overall patient and graft outcomes, based mostly on the experience from deceased donor liver transplantation (DDLT), have been reported. Due to the limited number of organ donations from deceased donors in most Asian countries, living donor liver transplantation (LDLT) is the mainstream treatment for end-stage liver disease, including that resulting from PBC and PSC. Although the initial experiences with LDLT for PBC and PSC seem satisfactory or comparable to that with DDLT, some aspects, including the timing of transplantation, the risk of recurrent disease, and its long-term clinical implications, require further evaluation. Whether or not the long-term outcomes of LDLT from a biologically related donor are equivalent to that of DDLT requires further observations. The clinical course following LDLT may be affected by the genetic background shared between the recipient and the living related donor.
Liver transplantation; Primary biliary cirrhosis; Primary sclerosing cholangitis; Living donor; Recurrence
The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.
Epstein-Barr virus; Chronic hepatitis; Liver disease; Chronic active Epstein-Barr virus; Post-transplant lymphoproliferative disorder; Infectious mononucleosis
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both autoimmune cholestatic liver disease and the association of these two conditions in the same patient is very rare. We report the case of a female patient presenting with a cholestatic liver disease and a panel of autoantibodies specific for PBC, including antibodies to mitochondrial E2-pyruvate dehydrogenase, gp-210 and Sp-100. Beside these findings, the liver biopsy revealed concentric fibrosis of small biliary ducts and the magnetic resonance cholangiography presented no abnormal findings. Diagnosis of small duct PSC/PBC overlapping was done. No description of this association was found in the literature. Clinical and serological features of this unusual finding are discussed.
Anti-mitochondrial antibodies; Autoimmune liver disease; Antinuclear antibodies; Primary biliary cirrhosis; Small duct primary sclerosing cholangitis; Overlapping syndromes
Multiple sclerosis and neurodegenerative diseases in which cells of the central nervous system (CNS) are lost or damaged are rapidly increasing in frequency, and there is neither effective treatment nor cure to impede or arrest their destructive course. The Epstein-Barr virus is a human gamma-herpesvirus that infects more than 90% of the human population worldwide and persisting for the lifetime of the host. It is associated with numerous epithelial cancers, principally undifferentiated nasopharyngeal carcinoma and gastric carcinoma. Individuals with a history of symptomatic primary EBV infection, called infectious mononucleosis, carry a moderately higher risk of developing multiple sclerosis (MS). It is not known how EBV infection potentially promotes autoimmunity and central nervous system (CNS) tissue damage in MS. Recently it has been found that EBV isolates from different geographic regions have highly conserved BARF1 epitopes. BARF1 protein has the neuroprotective and mitogenic activity, thus may be useful to combat and overcome neurodegenerative disease. BARF1 protein therapy can potentially be used to enhance the neuroprotective activities by combinational treatment with anti-inflammatory antagonists and neuroprotectors in neural disorders.
Epstein-Barr Virus; neuroregeneration; chronic inflammatory disorders; multiple sclerosis.
The overlapping epidemiology of multiple sclerosis (MS) and Epstein-Barr virus (EBV), the increased risk to develop MS after infectious mononucleosis (IM) and the localization of EBV-infected B-cells within the MS brain suggest a causal link between EBV and MS. However, the underlying mechanism is unknown. We hypothesize that EBV-infected B-cells are capable of eliciting a central nervous system (CNS) targeting autoimmune reaction. To test this hypothesis we have developed a novel experimental model in rhesus monkeys of IM-like disease induced by infusing autologous B-lymphoblastoid cells (B-LCL). Herpesvirus papio (HVP) is a lymphocryptovirus related to EBV and was used to generate rhesus monkey B-LCL. Three groups of five animals were included; each group received three intravenous infusions of B-LCL that were either pulsed with the encephalitogenic self peptide MOG34–56 (group A), a mimicry peptide (981–1003) of the major capsid protein of cytomegalovirus (CMVmcp981–1003; group B) or the citrullinated MOG34–56 (cMOG34–56; group C). Groups A and B received on day 98 a single immunization with MOG34–56 in incomplete Freund’s adjuvant (IFA). Group C monkeys were euthanized just prior to day 98 without booster immunization. We observed self-peptide-specific proliferation of T-cells, superimposed on similar strong proliferation of CD3+CD8+ T-cells against the B-LCL as observed in IM. The brains of several monkeys contained perivascular inflammatory lesions of variable size, comprising CD3+ and CD68+ cells. Moreover, clusters of CD3+ and CD20+ cells were detected in the meninges. The only evident clinical sign was substantial loss of bodyweight (>15%), a symptom observed both in early autoimmune encephalitis and IM. In conclusion, this model suggests that EBV-induced B-LCL can elicit a CNS targeting inflammatory (auto)immune reaction.
Evidence suggests that Epstein-Barr virus (EBV) plays a role in triggering or perpetuating disease activity in multiple sclerosis (MS).
We investigated 100 subjects (50 clinically isolated syndrome [CIS], 25 relapsing-remitting [RR] MS, 25 primary progressive [PP] MS) for 1) evidence of EBV reactivation and 2) disease activity as indicated by serial gadolinium (Gd)-enhanced MRIs over a 5-year period. EBV DNA in blood was quantified by real-time quantitative PCR and EBV serology for anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG), anti-viral capsid antigen (VCA) IgG, and anti-EBV IgM. Data were analyzed using repeated measures analysis, analysis of variance, and logistic regression analysis.
All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035).
The correlation between elevated Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) and gadolinium-enhancing lesions suggests an association between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) disease activity. The heightened immune response to EBV in MS is specifically related to EBNA-1 IgG, a marker of the latent phase of the virus. The lack of association between acute viral reactivation in the peripheral blood and Gd+ lesions suggests a limited role of the former in driving disease activity.
= confidence interval;
= clinically isolated syndrome;
= Epstein-Barr virus nuclear antigen 1;
= Epstein-Barr virus;
= Expanded Disability Status Scale score;
= field of view;
= human leukocyte antigen;
= immunoglobulin G;
= interquartile range;
= major histocompatibility complex;
= multiple sclerosis;
= oligoclonal IgG bands;
= odds ratio;
= phocine herpesvirus type 1;
= primary progressive multiple sclerosis;
= relapsing-remitting multiple sclerosis;
= echo time;
= repetition time;
= viral capsid antigen;
= varicella zoster virus.
Autoimmune and cholestatic liver disease account for a significant part of end-stage liver disease and are leading indications for liver transplantation. Especially cholestatic liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis) appear to be different from other chronic liver diseases with regards to pathogenesis. Portal fibroblasts located in the connective tissue surrounding bile ducts appear to be different from hepatic stellate cells with regards to expression of marker proteins and response the profibrogenic and mitogenic stimuli. In addition there is increasing evidence for a cross talk between activated cholangiocytes and portal myofibroblasts. Several animal models have improved our understanding of the mechanisms underlying these chronic liver diseases. In the present review, we discuss the current concepts and ideas with regards to myofibroblastic cell populations, mechanisms of fibrosis, summarize characteristic histological findings and currently employed animal models of autoimmune and cholestatic liver disease.
Cholestasis; Fibrosis; Portal myofibroblasts; Hepatic stellate cells; Primary biliary cirrhosis; Primary sclerosing cholangitis; Cirrhosis
Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.
Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology that is characterized by the presence of circulatory autoantibodies and inflammatory histological changes in the liver. Although the pathogenesis of AIH is not known, it is thought that, in a genetically predisposed individual, environmental factors such as viruses can trigger the autoimmune process. Herpes simplex virus, Epstein-Barr virus, measles virus, and hepatitis viruses are thought to play a role in the etiology of AIH. Proteins belonging to these viruses may be similar to the amino acid chains of different autoantigens in the liver, this causes immune cross reactions and liver tissue damage. We report a case of severe AIH following varicella zoster infection in a 23-year-old man, and speculate that, based on the molecular mimicry hypothesis, the liver damage was caused by an immune cross reaction to the viral proteins. Varicella-zoster-induced AIH has not been reported previously.
Autoimmune liver disease; Varicella zoster virus; Infection