RESUMO
In rheumatoid arthritis (RA) there is an unmet therapeutic need, as a substantial proportion of patients does not achieve low disease activity or remission despite the use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs). The Janus kinase (JAK) inhibitors are the most recently added drug category in the therapeutic armamentarium in RA. Upadacitinib tartrate (Rinvoq), a selective and reversible JAK1 inhibitor, inhibited interleukin (IL)-6 and IL-7 and ameliorated adjuvant-induced arthritis in preclinical studies. In phase III randomized controlled trials (RCTs), upadacitinib, as monotherapy or in combination with csDMARDs, showed efficacy in RA patients with inadequate response to csDMARDs or bDMARDs. In a head-to-head RCT, upadacitinib 15 mg once daily was superior to adalimumab in achieving remission and in patient-reported outcomes. Upadacitinib has a good safety profile but it may increase the risk for herpes zoster, and as a substrate of cytochrome P450 (CYP) enzyme CYP3A4 it should not be coadministered with strong CYP3A4 inducers. Upadacitinib is contraindicated in patients with active tuberculosis, serious infections, active malignancy and in patients with severe liver impairment. Upadacitinib has been approved for the treatment of moderate to severe RA.
Assuntos
Antirreumáticos , Artrite Reumatoide , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Tartaratos/uso terapêuticoRESUMO
BACKGROUND: Anti-C1q autoantibodies (autoAbs) are associated with systemic lupus erythematosus (SLE), but their presence in other rheumatic diseases has not been adequately investigated. OBJECTIVES: We aimed to assess anti-C1q autoAbs and circulating immune complexes (CICs) in systemic sclerosis (SSc). METHODS: In total 124 patients with SSc were studied; 106 were female and the median age was 59·4 years (range 25-81·4). Overall 75 (60·5%) had limited cutaneous SSc and 49 (39·5%) had diffuse cutaneous SSc. Also included were 25 patients with Sjögren syndrome (SjS), 29 with rheumatoid arthritis (RA), 38 with SLE and 53 healthy controls. Enzyme-linked immunosorbent assays with high- and low-salt buffers were used to measure anti-C1q antibodies and CICs. The former allows only anti-C1q antibody binding to C1q and the latter also allows IgG Fc to bind to C1q. RESULTS: Anti-C1q antibodies were present in 20 of 124 (16·1%) patients with SSc: five had high levels (> 80 RU mL-1 ) and 10 (50%) had moderate levels (40-80 RU mL-1 ). Anti-C1q antibodies were also present in one of 25 (4%) patients with SjS, one of 29 (3%) with RA (P < 0·05 for both) and three of 53 (6%) healthy controls (P < 0·01). Anti-C1q antibodies were detected in 13 of 38 (34%) patients with SLEs. Anti-C1q antibodies were more frequent in male than female patients with SSc (P = 0·005); this association remained after multivariate regression analysis. Anti-C1q antibody level was the most important factor in predicting the presence of pulmonary fibrosis, and the second most important in predicting pulmonary arterial hypertension. Fourteen patients with SSc (11·3%) had CICs. CONCLUSIONS: Anti-C1q autoAbs were frequently detected in patients with SSc, and their high levels predict the co-occurrence of pulmonary fibrosis or pulmonary arterial hypertension.
Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Complemento C1q/imunologia , Fibrose Pulmonar/sangue , Escleroderma Sistêmico/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Estudos de Coortes , Feminino , Voluntários Saudáveis , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Fatores Sexuais , Tomografia Computadorizada por Raios XRESUMO
The exposome represents all exogenous and endogenous environmental exposures that begin at preconception and carry on throughout life, while the microbiome reflects the microbial component of the exposome. We recently introduced the concept of infectome and autoinfectome as a means of studying the totality of infections throughout life that participate in the induction as well as the progression of autoimmune diseases in an affected individual. The investigation of the autoinfectome could help us understand why some patients develop more than one autoimmune disease, a phenomenon also known as mosaic of autoimmunity. It could also explain the infectious and autoantibody burden of various autoimmune rheumatic diseases. The close interplay between infections and the immune system should be studied over time, long before the onset of autoaggression and autoimmunity. Tracking down each individual's exposure to infectious agents (as defined by the autoinfectome) would be important for the establishment of a causative link between infection and autoimmunity.
Assuntos
Autoimunidade , Infecções/imunologia , Microbiota/imunologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Exposição Ambiental , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologiaRESUMO
The reasons underlying why autoimmune diseases overwhelmingly affect women more than men are not clear. Nor are the reasons why autoimmune disease is more prevalent in families. This review uses primary biliary cirrhosis (PBC) as a model autoimmune disease to discuss the familial risk, focusing mainly on mother-daughter pairs. PBC is a chronic cholestatic liver disease characterised by an immune-mediated inflammatory destruction of the small intrahepatic bile ducts, with fibrosis progressing to cirrhosis and subsequent liver failure. Epidemiological studies have demonstrated that first degree relatives of PBC patients are at higher risk of developing PBC, as well as other autoimmune diseases. This is especially true for the mothers, daughters and sisters of PBC patients. Multiple case reports have highlighted the complexity of mother-daughter pairs in PBC, and the need for follow-up of these individuals when one member of the pair is diagnosed with PBC. It may be the case that diagnosis in one individual may lead to early diagnosis in the other, even if they are asymptomatic. Early management of PBC may improve the prognosis in these patients. This review will examine the literature surrounding PBC in mothers and daughters.
Assuntos
Doenças Autoimunes/genética , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/imunologia , Linhagem , Feminino , HumanosAssuntos
Autoanticorpos/sangue , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/imunologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Antígenos Nucleares/sangue , Autoantígenos/sangue , Biomarcadores/sangue , Comorbidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Cirrose Hepática Biliar/sangue , Masculino , Pessoa de Meia-Idade , Mitocôndrias Hepáticas/imunologia , Complexo de Proteínas Formadoras de Poros Nucleares/sangue , Prevalência , Escleroderma Sistêmico/sangueRESUMO
Characterization of liver-specific autoantigens has given a fresh impetus to research in the pathogenesis of autoimmune liver diseases, viral-triggered and drug-induced autoimmunity affecting the liver. Intriguing is the fact that most of the liver-specific autoantigens are enzymes of key importance for cell's homeostasis. Detection of autoantibodies against the respective antigens is carried out for diagnostic and research purposes using indirect immunofluorescence, immunoblotting, enzyme-linked immunosorbent assays, radioimmunoassay, immunoprecipitation or assays determining inhibition of enzyme activity. In patients with autoimmune hepatitis, a liver disorder of unknown etiology and pathogenesis, disease-specific autoantibodies are frequently directed against drug metabolizing enzymes of phase 1, namely cytochrome P450 2D6 (CYP2D6). The same and other members of these families of enzymes (CYPs) have also been described as targets of liver-specific autoimmunity in chronic hepatitis C virus (HCV)-infected patients, patients with autoimmune hepatitis as part of the autoimmune polyglandular syndrome type-1 (APS-1) and drug-induced autoimmunity. How these enzymes become 'self targets' is not yet established. An antigen release following hepatocyte injury could provide the stimulus for an immune response towards epitopes on these enzymes but the highly-specific, antigen-restricted initiation of the observed autoimmune response is against such an explanation. Accordingly, in this review we will focus on the pathogenic role -if any- of autoimmune responses against liver-related CYPs in autoimmune hepatitis, HCV infection, APS-1 and drug-induced autoimmunity. Learning more about the specificity of antibody responses against these enzymes may help us better understand the mechanisms underlying liver autoimmunity and may facilitate the development of therapeutic and preventive interventions.
Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Sistema Enzimático do Citocromo P-450/imunologia , Fígado/enzimologia , Fígado/imunologia , Sequência de Aminoácidos , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Hepatite Autoimune/enzimologia , Hepatite Autoimune/imunologia , Humanos , Fígado/metabolismo , Fígado/patologia , Dados de Sequência Molecular , Especificidade de ÓrgãosAssuntos
Citocromo P-450 CYP1A2/imunologia , Doença Enxerto-Hospedeiro/imunologia , Fígado/imunologia , Animais , Autoantígenos , Transplante de Medula Óssea/efeitos adversos , Doença Crônica , Hepatite Autoimune/etiologia , Hepatite Autoimune/imunologia , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , RatosRESUMO
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.
Assuntos
Anticorpos Antinucleares/sangue , Isotipos de Imunoglobulinas/sangue , Cirrose Hepática Biliar/imunologia , Adulto , Idoso , Biomarcadores/sangue , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Hepatite C Crônica/imunologia , Humanos , Imunoglobulina G/sangue , Cirrose Hepática Biliar/patologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de DoençaRESUMO
The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.
Assuntos
Álcool Desidrogenase/imunologia , Autoanticorpos/imunologia , Hepatopatias Alcoólicas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Álcool Desidrogenase/antagonistas & inibidores , Consumo de Bebidas Alcoólicas , Animais , Especificidade de Anticorpos , Biomarcadores , Feminino , Antígenos de Superfície da Hepatite B/sangue , Cavalos , Humanos , Immunoblotting , Isoenzimas/imunologia , Hepatopatias Alcoólicas/enzimologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/químicaRESUMO
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.
Assuntos
Helicobacter pylori/imunologia , Epitopos Imunodominantes/imunologia , Cirrose Hepática Biliar/imunologia , Mitocôndrias/imunologia , Complexo Piruvato Desidrogenase/imunologia , Urease/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/imunologia , Proteínas de Bactérias/imunologia , Estudos de Coortes , Reações Cruzadas , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Cirrose Hepática Biliar/sangue , Masculino , Pessoa de Meia-Idade , Mimetismo Molecular , Complexo Piruvato Desidrogenase/análise , Estudos de Amostragem , Sensibilidade e Especificidade , Domínios de Homologia de src/imunologiaRESUMO
Liver Kidney Microsomal autoantibody type 1(LKM1) directed to cytochrome P4502D6 (CYP2D6) characterises autoimmune hepatitis type-2 (AIH-2), but is also found in a proportion of chronic hepatitis C virus (HCV) infected patients, CYP2D6252-271 being a major B- cell autoepitope. Molecular mimicry and immunological cross-reactivity between CYP2D6252-271, HCV polyprotein and the infected cell protein 4 (ICP4) of herpes simplex virus type 1 (HSV-1) have been suggested as triggers for the induction of LKM1, but reactivity and cross-reactivity to the relevant sequences have not been investigated experimentally. CYP2D6252-271 and its viral homologues were constructed and tested by ELISA in the sera of 46 chronically infected HCV patients, 23 of whom were LKM1 positive. Reactivity to the E1 HCV and ICP4 HSV1 mimics was frequently found in HCV infected patients irrespectively of their LKM1 status; viral/self cross-reactivity (as indicated by inhibition studies), however, was present in the only 2 of the 23 LKM1 seropositive HCV patients, who possessed the HLA allotype B51. Our results indicate that in HCV infected patients virus/self cross-reactivity is dependent on a specific immunogenetic background, a finding awaiting confirmation by studies in larger series of patients.
Assuntos
Autoanticorpos/metabolismo , Antígenos HLA-B/metabolismo , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/metabolismo , Hepatite C Crônica/imunologia , Rim/imunologia , Microssomos Hepáticos/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Sítios de Ligação de Anticorpos , Reações Cruzadas , Citocromo P-450 CYP2D6/sangue , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Antígeno HLA-B51 , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismoRESUMO
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.
Assuntos
Anticorpos Antinucleares/sangue , Antígenos Nucleares/imunologia , Cirrose Hepática Biliar/imunologia , Infecções Urinárias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Mitocôndrias Hepáticas/imunologia , RecidivaRESUMO
Autoantibodies to smooth muscle (SMA) and nuclear components (ANA) arise in the natural course of chronic infection with hepatitis C virus. In view of the growing evidence for 'molecular mimicry' as a mechanism of autoimmunity we investigated whether cross-reactive immune reactions between host smooth muscle/nuclear components and HCV antigens may contribute to the formation of SMA and ANA in chronic HCV infection. Computer-assisted protein database search methods were used to identify three smooth muscle (smoothelin698-717, myosin1035-1054, vimentin69-88) and three nuclear (matrin722-741, histone H2A11-30, replication protein A133-152) host antigens with the highest local sequence similarity to the HCV polyprotein and 20-mer peptides corresponding to these regions were constructed. Sera from 51 children with chronic HCV infection [median age: 8 (2-16); 27 boys], 26 SMA positive and five ANA positive, were tested for reactivity to the synthesized HCV peptides and their human homologues by enzyme linked immunosorbent assay (ELISA). Sera from patients with HBV infection and chronic liver disease of different aetiologies were used as controls. 'Double reactivity' to HCV peptides and smooth muscle/nuclear homologues was associated strongly with HCV infection (P < 0.001 for both). Humoral cross-reactivity was established as the basis for double recognition by competition ELISA. Double-reactivity to smooth muscle and HCV peptide antigens correlated with SMA positivity by indirect immunofluouresence (P = 0.05). Of 15 patients double-reactive to myosin1035-1054 and its HCV homologue, 13 recognized whole myosin by immunoblot. These results suggest that ANA and SMA in chronic HCV infection may arise, at least in part, as a consequence of cross-reactive immune responses to HCV and host smooth muscle/nuclear antigens.
Assuntos
Anticorpos Antinucleares/imunologia , Autoantígenos/genética , Antígenos da Hepatite C/genética , Hepatite C Crônica/imunologia , Músculo Liso/imunologia , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática/métodos , Epitopos/genética , Humanos , Immunoblotting , Mimetismo Molecular , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
The pathogenesis of autoimmune liver disease and autoimmunity associated with chronic viral hepatitis remains poorly understood. One of the major hurdles to a deeper understanding of these pathological processes is the absence of clearly defined inductive mechanisms, which, if identified and characterised, could guide clinical strategies for their prevention or allow therapeutic intervention. Molecular mimicry leading to crossreactive autoimmune responses has gained strong experimental support in the past decade. A fundamental premise of this hypothesis is the involvement of a mimicking environmental trigger. In view of the numerous viral and bacterial agents epidemiologically linked to autoimmune liver diseases, we and others have proposed molecular mimicry to be an important mechanism in these diseases. We also propose similar crossreactive mechanisms to operate in the generation of autoimmunity in viral hepatitis. This review focuses on molecular mimicry at the level of the B-cell, as few data on T-cell crossreactivity in liver disease are thus far available.
Assuntos
Doenças Autoimunes/imunologia , Hepatopatias/imunologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/terapia , Autoimunidade , Linfócitos B/imunologia , Hepatite Viral Humana/etiologia , Hepatite Viral Humana/imunologia , Hepatite Viral Humana/terapia , Humanos , Hepatopatias/etiologia , Hepatopatias/terapia , Linfócitos T/imunologiaRESUMO
Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.