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Autoimmune hepatitis: evolving concepts
Autoimmunity Reviews 3 (2004) 207–214
Autoimmune hepatitis: evolving concepts Ioannis Diamantis*, Dimitrios T. Boumpas Department of Internal Medicine and Division of Rheumatology, Clinical Immunology and Allergy, Medical School, University of Crete, P.O. Box 2208, Heraklion GR-71003, Greece Received 12 July 2003; accepted 21 September 2003
Abstract The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. A loss of tolerance against its own antigens may result in autoimmune hepatitis (AIH). The current paradigm holds that the disease is the result of self-perpetuating autoimmune process triggered by yet unknown factors (infections, chemicals, drugs) in a genetically susceptible host. To date, several putative hepatocellular surface antigens have been identified: P450-IID6 (recognized by the anti-LKM-1 autoantibodies) a membrane bound asialoglycoprotein receptor (a liver-specific membrane protein), a cytosolic UGA-suppressor tRNA associated protein (recognized by anti-SMA and anti-LP antibodies) and argininosuccinate lysate and formiminotransferase cyclodeaminase (recognized by ant-LC1 antibodies). In contrast to other chronic hepatitides patients with AIH display significant T cell hypereactivity to autologous liver antigens. Tissue injury seems to be mediated by CD4q or CD8q T cells andyor by antibody-dependent cell mediated cytotoxicity. 䊚 2004 Elsevier B.V. All rights reserved. Keywords: Liver autoantigens; Autoantibodies; Cytotoxic T cells; Injury
1. Introduction Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. The mean annual incidence of AIH among Northern Europeans is 1.9 per 100 000. It accounts for the 2.6% of the transplantations in Europe and 5.9% in US. Women are affected more than men (ration 3.6:1) but all ages and ethnic groups are succeptible w1x. Prednisone alone or in combination with azathioprine improves symptoms, laboratory tests, hisAbbreviations: AIH, autoimmune hepatitis; NK, natural killer; TCR, T cell receptor; TNF, tumor necrosis factor. *Corresponding author. Fax: q30-2810-394796. E-mail address: [email protected] (I. Diamantis).
tological findings and immediate survival. Liver transplantation has been associated with 5 year patient and graft survivals that exceed 80%. Recurrent disease after transplantation has usually been mild and manageable w2x. 2. Diagnosis and classification Liver biopsy is essential to establish the diagnosis, evaluate disease severity and determine the need for treatment. Other diagnostic markers used to establish the diagnosis are g-globulin levels, antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and antibodies to liverykidney microsome type 1 (anti-LKM1).
1568-9972/04/$ - see front matter 䊚 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2003.09.003
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AIH has been subclassified in to three types. Type 1 AIH, the most common form of the disease worldwide is associated with ANA andyor SMA. It affects all age groups, and is associated with HLA-DR3 and -DR4 in Caucasian Northern Europeans and North American patients. DRB10301 and DRB10401 influence disease expression and behavior as well as susceptibility. Caucasian patients with type I and DRB10301 are younger, and have a higher frequency of treatment failure, relapse after drug withdrawal, and requirement for liver transplantation than patients with other alleles. In contrast, patients with DRB10401 are typically older, frequently have concurrent autoimmune diseases and respond better to corticosteroids w3x. Type 2 AIH is characterized by anti-LKM1. It is more common in Europe and some South American countries than in US and has been associated with DRB10701 w4x. Type 3 is the least established form of the disease and it is characterized by the presence of anti-SLAyLP in serum (see below). Patients have clinical and laboratory findings indistinguishable from patients with type 1 AIH and respond well to corticosteroids w3x. 3. Pathogenesis of AIH A loss of tolerance against the patient’s own liver is regarded as the primary pathogenetic mechanism. This implies an antigen-driven process directed—at least initially—towards hepatic autoantiges. A genetic predisposition is thought to be an absolute prerequisite. The presence of lymphocytes in the liver is commonly considered to be associated with disease pathogenesis. Lymphocyte infiltration is well documented in inflammatory conditions such as autoimmune and viral liver disease, and the term ‘liver infiltrating lymphocytes’ has been used to describe hepatic lymphocytes in these conditions, suggesting that these lymphocytes play an active role in hepatic damage and necrosis. The predominant histological finding of mononuclear infiltrating cells in tissue lesions of the liver with AIH are CD8q T cells. These findings—albeit circumstantial—suggest that lymphocytes play an active role in hepatic damage and necrosis. A number of key
molecules involved in the interaction between effector and target cell and in the subsequent cytolytic process are differentially expressed in the liver of AIH patients implicating an immune process in the pathogenesis of the disease. These include HLA, cell adhesion, lymphocyte activation and co-stimulatory molecules, as well as cytokines. 4. HLA class I molecules Normally, these molecules participate in immune reactions by binding to peptides derived from endogenously synthesized antigens, such as viral proteins in infected cells, and presenting them primarily to CD8q T cells. Although data showing the expression of these molecules in normal hepatocytes are controversial, due mainly to use of different techniques and antibodies, immunohistochemical analysis using the antibody HP-1H8, which recognizes a b2-microglobulin conformational epitope showed positivity in both hepatocyte and sinusoidal cells of tissues with AIH w5x. 5. HLA class II molecules These molecules bind to peptides derived from an endocytosed antigen, and are primarily recognized by CD4q T cells HLA class II molecules are expressed on B cells, macrophages, dendritic cells, Kupffer cells, a variety of epithelial cells and activated T lymphocytes. Aberrant expression of MHC class II molecules has been found in a variety of autoimmune processes, and there are reports of the de-novo expression of HLA class II antigens in hepatocytes of AIH patients w6x. 6. Autoantigens Patients with AIH show significant T cell reactivity to autologous liver antigens whereas very low, if any reactivity can be detected in patients with HCV and HBV infection. During remission due to immunosuppressive treatment, T cell reactivity to liver antigens becomes undetectable. Data examining the TCR repertoire of infiltrating T cells are lacking at present. Moreover, the relative contribution (if any) of autoreactive T cells with
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specificity for liver antigens in the tissue injury is still in question w7x. At least two such hepatocellular surface antigens have been reported: (1) P450-IID6, the autoantigen recognized by anti-LKM-1 autoantibodies and (2) membrane bound asialoglycoprotein receptor, a liver-specific membrane protein that is unique to hepatocytes and is preferentially expressed at high density on periportal hepatocytes. The surface expression of asialoglycoprotein receptor on hepatocytes has also been shown to be associated with high titer circulating antibodies in AIH w8x. Additional information refers to autoantibodies against a soluble liver antigen (anti-SLA) and against a cytoplasmic antigen shared by liver and pancreas (anti-LP), whose specific major autoantigens were initially believed to be glutathione-Stransferase subunit proteins and liver cytokeratins 8 and 18, respectively. Newer studies have shown that the anti-SLA and anti-LP is one and the same antibody, and that it has a high specificity for AIH. The target autoantigen has been cloned, characterized and proposed to be a cytosolic UGA-suppressor tRNA associated protein not specific to the liver. Finally, anti-LC1 another autoantibody, which reacts with a liver-specific cytosolic antigen, has also received some attention. This antigen is not expressed on the surface of hepatocytes, however, as serum antibody titres parallel liver disease activity, it has been suggested that anti-LC1 might also participate in the pathogenetic mechanisms responsible for liver injury. Two possible molecular targets for this autoantibody have recently been identified: argininosuccinate lyase and formiminotransferase cyclodeaminase w9x. 7. Cell adhesion molecules Although the adhesion molecules responsible for the initial antigen-independent interaction between cytotoxic T cells and target cells are expressed at very low levels, it has been shown that inflammatory mediators, including cytokines, strongly induce some of these molecules in a variety of autoimmune processes including AIH. For instance, intercellular adhesion molecule-1y CD54, a molecule restricted to sinusoidal lining cells and scattered mononuclear cells in normal
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liver is strongly induced in hepatocytes of AIH patients, particularly in areas of periportal inflammation. Similarly, LFA-3yCD58 (the target cell counter-receptor of the T-cell molecule LFA-2y CD2), which is not detected in normal hepatocytes is clearly expressed in the hepatocellular membrane of AIH patients, particularly in those periportal and lobular areas, which are more severely infiltrated w10x. Enhanced intra-hepatic expression of lymphocyte activation antigens as well as cellular and vascular adhesion molecules in AIH can be considered as further evidence for a leading role of T-cell-mediated immune mechanisms in the pathogenesis of tissue damage in this disease. 8. Lymphocyte activation CTLA-4 is expressed on the surface of activated CD4 T helper cells and competes with CD28 for the B7 ligand downregulating the second signal for T cell activation (Fig. 1). In type 1 autoimmune hepatitis, a polymorphism of the cytotoxic T lymphocyte antigen—4 (CTLA-4) gene has been recognized. The substitution of a guanine for an adenine at position 49 in the CTLA-4 gene results in a threonine for alanine substitution in the expressed protein that could have functional consequences. The same polymorphism has been described in primary biliary cirrhosis, and it may be one of the several autoimmune promoters that are not disease-specific w11x. Among other costimulatory molecule interactions, interactions between CD40 and CD154 are critical for both cellular and humoral immune responses (thus linking the two components of the disease) and their study could be relevant for AIH w12x. 9. Cytokines Type 1 and type 2 cytokines constitute an immunoregulatory network that is characterized by redundant action and extensive cross-regulatory function (Fig. 2). The cytokine network influences the occurrence, clinical expression and outcome of autoimmune hepatitis. Different cytokine profiles have been described in children with type 1 and type 2 autoimmune
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Fig. 1.
hepatitis, and a type 2 cytokine response differentiates autoimmune hepatitis from chronic viral hepatitis. Interleukin-2 and IL-4 are found less commonly and at lower serum levels in adults with type 1 autoimmune hepatitis than in normal subjects. Type 1 cytokines predominate in the liver during active inflammation and type 2 cytokines
Fig. 2.
predominate in the circulation during remission. These findings suggest that cytokine profiles change during disease activity either as a cause or a consequence of the immune response. The genes responsible for cytokine production are being sequenced and an important polymorphism involving substitution of an adenine for a
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guanine at position y308 of the TNF-A gene (TNFA*2) has already been described in type 1 autoimmune hepatitis. The TNFA*2 allele is carried on the 8.1 ancestral haplotype of Northern Europeans, and this linkage disequilibrium may combine the genetic propensity for autoantigen presentation with the cytokine milieu that favors a cytotoxic immune response. The adenine substitution at position y308 of the TNF-A gene is associated with high inducible and constitutive levels of TNF-a, and it favors a type 1 cytokine response. The polymorphism occurs mainly in young patients with type 1 autoimmune hepatitis and in individuals who respond less well to corticosteroid therapy. These findings imply an effect on disease severity w13,14x. Other cytokine immune modulators are also under genetic control, and their occurrence and functional consequences in autoimmune hepatitis must be fully defined. Cytokine genes that have not yet been assessed but may be worthy of further study include IL-2, IL-4, IL-6 and IFN-g w15,16x. 10. Destruction of hepatocytes Immune-mediated liver cell injury could result from the clonal expansion of cytotoxic T cells sensitized to autoantigen (cell-mediated cytotoxicity), andyor from the unmodulated production of autoantibodies directed against hepatocyte membrane constituents (antibody-dependent cellmediated cytotoxicity).
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The predominant mechanisms of liver cell destruction in autoimmune hepatitis are unknown. Both cell-mediated and antibody-dependent pathways are probably involved. Cell-mediated destruction has been evoked because of lack of direct evidence that autoantibodies are non-pathogenic, and autoantigens have been defined against which liver-infiltrating lymphocytes have highly specific reactivity. Antibody-dependent cell-mediated mechanisms have been evoked because unmodulated autoantibody production against normal liver membrane constituents has been detected w1 x . Cell-mediated cytodestruction requires clones of liver-infiltrating, antigen-primed lymphocytes with cytolytic activity. The cytolytic effector T cells attach to the target cells by adhesion molecules induced by the proinflammatory cytokines; liver cell injury may also result from the release of lymphokines. The cytotoxic T cells are sensitized to autoantigen presented by class I MHC molecules. Apoptotic cell death has been described in cases of hepatitis especially fulminant hepatitis w17x. Programmed cell death is accomplished mainly by the interaction of Fas receptors on the liver cell surface with Fas ligand. Other apoptotic pathways, such as that between TNF-a and TNF receptor I may also be involved. Homeostasis is maintained by antiapoptotic mechanisms that include the release of cytokines such as IL-4, IL-7 and IL-15, which up-regulate expression of the antiapoptotic
Fig. 1. Mechanisms of autoantigen presentation and CD4 T helper cell activation. Autoantigen is optimally oriented in the antigenbinding groove of the HLA DR molecule by a salt bridge between a negatively charged amino acid residue at position P4 on the antigenic peptide (aspartic acid or glutamic acid) and a positively charged amino acid residue at position DRb71 (lysine or arginine) within the HVR3 of the antigen binding groove. The peptide-HLA DR complex is recognized by the TCR of an uncommitted CD4 T helper cell, and the first signal of immunocyte activation is completed. The critical contact point for completion of the first signal is at the TCR-P4-HVR3 interface. Completion of the second signal of immunocyte activation requires ligation of CD28 expressed by the CD4 T helper cell and B7 expressed by the antigen presenting cell. This second signal can be blocked by CTLA-4, which is expressed by activated CD4 T helper cells (Adapted from Czaja AJ 2001 Understanding the pathogenesis of autoimmune hepatitis Am. J. Gastroenterol. 96; 1224–1231). Fig. 2. Mechanisms of cytokine immunoregulation. Activated CD4 T helper cells release cytokines that stimulate expansion of cytotoxic T lymphocytes (CTL) and B cell production of autoantibodies. Th1 immune response can be accentuated by a polymorphism of the gene governing TNF-a production and it may favor a cytotoxic (CTL) response by producing excess levels of TNFa. Th2 response is stimulated by IL-4 and IL-10, and it favors an autoantibody response. Uncontrolled autoantibody production has been described in autoimmune hepatitis, but the reasons are unclear (Adapted from Czaja AJ 2001 Understanding the pathogenesis of autoimmune hepatitis Am. J. Gastroenterol. 96; 1224–1231).
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protein Bcl-2 w18x. The role of these interactions in AIH needs to be further explored. Antibody-dependent cell-mediated cytotoxicity implies aberrant regulation of immunoglobulin G production by plasma cells. Immunoglobulin G interacts with normal cell surface proteins and the antigen-antibody complex is targeted by natural killer cells that have Fc receptors for the immunoglobulin complex. Natural killer cells are not antigen-primed, and their specificity relates to the antibody-antigen complex on the liver cell membrane. Linkage with this complex results in cell-mediated cytolysis w1x. 11. Genetic predisposition to AIH Patients with AIH and their families share a genetic background, which favors the development of autoimmune diseases. However, in the absence of studies with homozygotic twins, the analysis of the extent to which genetic abnormalities may lead to the development of the disease is difficult. Several genes are believed to contribute to the genetic predisposition to develop AIH. By binding target peptides, MHC alleles may be a determinant of the risk of developing AIH and, most probably, participate in the pathogenesis of the disease. HLA-DR3 and HLA-DR4 alleles have long been proposed as risk factors for type 1 AIH in Caucasian patients and in patients from Japan, respectively. These alleles encode positions 67–72 of the DRb polypeptide chain, with either lysine or arginine at position 71. This position is located at the edge of the a-helix of the antigen-binding groove, where it can interact with both the bound antigen and the T-cell receptor. Differences in a single amino acid at this position can affect the steric relationship between antigen and T cell, thus influencing the immunoreactivity of the effector cells responsible for the disease, and hence the risk, the variable clinical manifestations of type 1 AIH and the outcome after corticosteroid therapy. Lysine at position 71 is correlated with an increased risk for type 1 AIH in Caucasian patients. Conversely, in patients from Japan, Argentina, Brazil and Mexico, arginine rather than lysine at position 71 is associated with an increased risk for type 1 AIH.
Interestingly, the HLA-DR alleles affect not only the susceptibility, but also the severity of the disease. This is probably based on the ability of HLA-DR alleles to induce changes in the number of immunocytes by influencing one of the following variables: (i) the density of the antigen-presenting complexes on the surface of the antigen-presenting cells; (ii) the ability of CD4 Thelper cells to respond to multiple antigenic peptides presented by a single allele of the MHC; and (iii) the ability of different HLA-DR molecules to present the same peptide w19,20x. Recent data implicate the tyrosine phosphatase CD45 gene to show a genetic link with the development of AIH. Analysis of 190 AIH patients showed a 77 CyG mutation in the gene in a significantly higher frequency when compared with 210 healthy blood donors. The CD45 tyrosine phosphatase plays an important role in normal antigen receptor mediated signaling in T and B cells w21x. 12. Novel pathogenic factors Recent results demonstrate that in comparison with normal controls the livers of AIH patients show an increased expression of inducible nitric oxide synthase, as well as nitrotyrosine (a result of the reaction between oxidant peroxynitrites and cellular proteins). This evidence suggests that oxidative damage to cellular structures may play a role in the pathogenesis of AIH w22x. 13. Summary Autoimmune hepatitis (AIH) is an unresolving, predominantly periportal hepatitis, associated with hypergammaglobulinemia and tissue autoantibodies thought to be initiated by CD4 T cells that recognize self-antigen (s). The effector cells differentiate into functional phenotypes according to cytokines in the microenvironment and the nature of the triggering antigen. Hepatocytes can express class II molecules and present antigenic peptides through a bystander mechanism. NK T cells reside in the normal liver but may be involved in liver cell damage possibly through the expression of Fas ligand. Autoantibodies may also participate in the process by complexing with antigen on the
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hepatocyte membrane surface and by interacting with mononuclear cells with Fc receptors. Molecular mimicry may generate cross-reactivities that predispose the immune system to cross-react with self-antigens. Multiple exposures to pathogens with antigenic similarities may prime a crossreactive subset of T cells in the genetically predisposed host. Autoimmunity against one self-antigen may then spread through molecular mimicry to other homologous self-antigens and may lead to overt autoimmune disease. Response to tissue injury may vary from individual to individual and may explain the heterogeneity in the expression and outcome of the disease. Take-home messages – The diagnosis of autoimmune hepatitis is based on criteria that include clinical symptoms, hypergammaglobulinemia and circulating autoantibodies. Immunosuppressive therapy with prednisolone alone or in combination with azathioprine prolongs survival. – A loss of tolerance against the patient’s own liver is regarded as the pathogenic mechanism. – Several putative hepatocellular surface antigens have been identified. – Presence of T cell hyperactivity against autologous liver antigens. – Tissue injury mediated by cell and antibody mediated mechanisms.
References w1x Czaja AJ. Autoimmune hepatitis. Evolving concepts and treatment strategies. Dig Dis Sci 1995;40(2):435 –56. w2x Soloway RD, Summerskill WH, Baggenstoss AH, Geall MG, Gitnick GL, Elveback IR, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972;63(5):820 –33. w3x Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol 1995;90(8):1206 –11. w4x Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, et al. Chronic active hepatitis associated with antiliverykidney microsome antibody type 1: a second type of autoimmune hepatitis. Hepatology 1987;7(6):1333 –9.
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w5x Lobo-Yeo A, Senaldi G, Portmann B, Mowat AP, MieliVergani G, Vergani D. Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease. Hepatology 1990;12(2):224 –32. w6x Van den Oord JJ, De Vos R, Desmet VJ. HLA expression in liver disease. Prog Liver Dis 1990;9:73 –88. w7x Wen L, Peakman M, Mieli-Vergani G, Vergani D. Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin Exp Immunol 1992;89(1):78 –82. w8x Treichel U, McFarlane BM, Seki T, Krawitt EL, Alessi N, Stickel F, et al. Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis. Gastroenterology 1994;107(3):799 –804. w9x Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Buschenfelde KH, et al. Identification of target antigen for SLAyLP autoantibodies in autoimmune hepatitis. Lancet 2000;355(9214):1510 –5. w10x Autschbach F, Meuer SC, Moebius U, Manns M, Hess G, Meyer zum Buschenfelde KH, et al. Hepatocellular expression of lymphocyte function-associated antigen 3 in chronic hepatitis. Hepatology 1991;14(2):223 –30. w11x Agarwal K, Jones DE, Daly AK, James OF, Vaidya B, Pearce S, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol 2000;32(4):538 –41. w12x Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996;274(5288):782 –4. w13x Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 1999;30(4):851 –6. w14x Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 1999;117(3):645 –52. w15x Peters M. Actions of cytokines on the immune response and viral interactions: an overview. Hepatology 1996;23(4):909 –16. w16x al Wabel A, al Janadi M, Raziuddin S. Cytokine profile of viral and autoimmune chronic active hepatitis. J Allergy Clin Immunol 1993;92(6):902 –8. w17x Rivero M, Crespo J, Fabrega E, Casafont F, Mayorga M, Gomez-Fleitas M, et al. Apoptosis mediated by the Fas system in the fulminant hepatitis by hepatitis B virus. J Viral Hepat 2002;9(2):107 –13. w18x Elkon KB, Marshak-Rothstein A. B cells in systemic autoimmune disease: recent insights from Fas-deficient mice and men. Curr Opin Immunol 1996;8(6):852 –9. w19x Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 2000;174:250 –9.
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w20x Manns MP, Kruger M. Immunogenetics of chronic liver diseases. Gastroenterology 1994;106(6):1676 –97. w21x Vogel A, Strassburg CP, Manns MP. 77 CyG mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link. Genes Immun 2003;4(1):79 –81.
w22x Sanz-Cameno P, Medina J, Garcia-Buey L, GarciaSanchez A, Borque MJ, Martin-Vilchez S, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol 2002;37(6):723 –9.
The World of Autoimmunity; Literature Synopsis Retro-inverso gonadotrophin-releasing hormone immunogen Gonadotrophin-releasing hormone (GnRH) vaccines are usually used for the inhibition of gonadotrophin secretion and gonadal function, such as in cases of sex hormones-dependent cancers. Fromme et al. (Endocrinology 2003;144:3262) report on a retro-inverso GnRH which is composed of D-amino acids assembled in the reverse order in relation to the parent L-peptide. These peptides succeeded in eliciting high titers of anti-GnRH antibodies in rabbits and mice. These antibodies are selective for mammalian GnRH, and could inhibit GnRH-stimulated signal transduction in COS-1 cells expressing the human GnRH receptor. The great advantage of these peptides is their resistance to cleavage by proteolytic enzymes and thus they might be orally active. The retro-inverso GnRH peptides could also elicit antibodies to GnRH without conjugation to ovalbumin or Freud’s complete adjuvant. Treatment of paraneoplastic cerebellar degeneration with intravenous immunoglobulin Paraneoplastic cerebellar degeneration (PCD) is a neuro-degenerative disease associated with autoantibodies against Purkinje cells of the cerebellum. The treatment options usually fail in most cases. Widdess-Walsh et al. (J Neuro-Oncol 2003;63:187) report a case of PCD treated with intravenous immunoglobulin (IVIg) and review additional similar cases. According to this review, most patients that were treated with IVIg and had a good response — were treated within 1 month of symptoms onset. However, patients who were treated 1–3 months post-symptoms onset had usually a stable disease course, whereas those treated after 3 months of symptoms onset did not benefit from IVIg as they had a poor outcome. The authors therefore recommend an early trial of high dose IVIg (2 gykg body weight) and intravenous methylprednisolone for any patients having PCD and positive autoantibodies. Epitope spreading following immunization with thyroglobulin peptide Thyroglobulin is the autoantigen targeted by autoantibodies in autoimmune diseases of the thyroid. It contains 3 20mer peptides bearing epitopes of autoantibodies associated with Graves’ disease. Thrasyvoulides and Lymberi (Clin Exp Immunol 2003;132:401) immunized rabbits with thyroglobulin, and these animals had reactivity against only one of the three peptides, TgP41. This peptide was also used for immunization, which was followed by a strong serological response against the immunizing peptide, but also against intact human and rabbit thyroglobulin. As evident from immunoadsorption and ELISA, immunization and TgP41 induced intramolecular B-cell epitope spreading, turning this peptide into a dominant immunogenic epitope of experimentally induced thyroglobulin-specific antibodies. BPI-ANCA and susceptibility to infections Patients having defects in the transporter associated with antigen presentation (TAP) have recurrent Gramnegative bacterial lung infections. Schulz et al. (Clin Exp Immunol 2003;133:252) report the presence of antineutrophil cytoplasmic autoantibodies against the bactericidalypermeability-increasing protein (ANCABPI) in 5 of 6 of these patients. BPI is a potent neutrophil antibiotic that neutralizes endotoxin efficiently. IgG from these patients could also inhibit the antimicrobial function of BPI in vitro. Inhibition of BPI by ANCA is a possible mechanism of how these autoantibodies may contribute to increases susceptibility to infections.
Autoimmune hepatitis: evolving concepts Ioannis Diamantis*, Dimitrios T. Boumpas Department of Internal Medicine and Division of Rheumatology, Clinical Immunology and Allergy, Medical School, University of Crete, P.O. Box 2208, Heraklion GR-71003, Greece Received 12 July 2003; accepted 21 September 2003
Abstract The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. A loss of tolerance against its own antigens may result in autoimmune hepatitis (AIH). The current paradigm holds that the disease is the result of self-perpetuating autoimmune process triggered by yet unknown factors (infections, chemicals, drugs) in a genetically susceptible host. To date, several putative hepatocellular surface antigens have been identified: P450-IID6 (recognized by the anti-LKM-1 autoantibodies) a membrane bound asialoglycoprotein receptor (a liver-specific membrane protein), a cytosolic UGA-suppressor tRNA associated protein (recognized by anti-SMA and anti-LP antibodies) and argininosuccinate lysate and formiminotransferase cyclodeaminase (recognized by ant-LC1 antibodies). In contrast to other chronic hepatitides patients with AIH display significant T cell hypereactivity to autologous liver antigens. Tissue injury seems to be mediated by CD4q or CD8q T cells andyor by antibody-dependent cell mediated cytotoxicity. 䊚 2004 Elsevier B.V. All rights reserved. Keywords: Liver autoantigens; Autoantibodies; Cytotoxic T cells; Injury
1. Introduction Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. The mean annual incidence of AIH among Northern Europeans is 1.9 per 100 000. It accounts for the 2.6% of the transplantations in Europe and 5.9% in US. Women are affected more than men (ration 3.6:1) but all ages and ethnic groups are succeptible w1x. Prednisone alone or in combination with azathioprine improves symptoms, laboratory tests, hisAbbreviations: AIH, autoimmune hepatitis; NK, natural killer; TCR, T cell receptor; TNF, tumor necrosis factor. *Corresponding author. Fax: q30-2810-394796. E-mail address: [email protected] (I. Diamantis).
tological findings and immediate survival. Liver transplantation has been associated with 5 year patient and graft survivals that exceed 80%. Recurrent disease after transplantation has usually been mild and manageable w2x. 2. Diagnosis and classification Liver biopsy is essential to establish the diagnosis, evaluate disease severity and determine the need for treatment. Other diagnostic markers used to establish the diagnosis are g-globulin levels, antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and antibodies to liverykidney microsome type 1 (anti-LKM1).
1568-9972/04/$ - see front matter 䊚 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2003.09.003
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AIH has been subclassified in to three types. Type 1 AIH, the most common form of the disease worldwide is associated with ANA andyor SMA. It affects all age groups, and is associated with HLA-DR3 and -DR4 in Caucasian Northern Europeans and North American patients. DRB10301 and DRB10401 influence disease expression and behavior as well as susceptibility. Caucasian patients with type I and DRB10301 are younger, and have a higher frequency of treatment failure, relapse after drug withdrawal, and requirement for liver transplantation than patients with other alleles. In contrast, patients with DRB10401 are typically older, frequently have concurrent autoimmune diseases and respond better to corticosteroids w3x. Type 2 AIH is characterized by anti-LKM1. It is more common in Europe and some South American countries than in US and has been associated with DRB10701 w4x. Type 3 is the least established form of the disease and it is characterized by the presence of anti-SLAyLP in serum (see below). Patients have clinical and laboratory findings indistinguishable from patients with type 1 AIH and respond well to corticosteroids w3x. 3. Pathogenesis of AIH A loss of tolerance against the patient’s own liver is regarded as the primary pathogenetic mechanism. This implies an antigen-driven process directed—at least initially—towards hepatic autoantiges. A genetic predisposition is thought to be an absolute prerequisite. The presence of lymphocytes in the liver is commonly considered to be associated with disease pathogenesis. Lymphocyte infiltration is well documented in inflammatory conditions such as autoimmune and viral liver disease, and the term ‘liver infiltrating lymphocytes’ has been used to describe hepatic lymphocytes in these conditions, suggesting that these lymphocytes play an active role in hepatic damage and necrosis. The predominant histological finding of mononuclear infiltrating cells in tissue lesions of the liver with AIH are CD8q T cells. These findings—albeit circumstantial—suggest that lymphocytes play an active role in hepatic damage and necrosis. A number of key
molecules involved in the interaction between effector and target cell and in the subsequent cytolytic process are differentially expressed in the liver of AIH patients implicating an immune process in the pathogenesis of the disease. These include HLA, cell adhesion, lymphocyte activation and co-stimulatory molecules, as well as cytokines. 4. HLA class I molecules Normally, these molecules participate in immune reactions by binding to peptides derived from endogenously synthesized antigens, such as viral proteins in infected cells, and presenting them primarily to CD8q T cells. Although data showing the expression of these molecules in normal hepatocytes are controversial, due mainly to use of different techniques and antibodies, immunohistochemical analysis using the antibody HP-1H8, which recognizes a b2-microglobulin conformational epitope showed positivity in both hepatocyte and sinusoidal cells of tissues with AIH w5x. 5. HLA class II molecules These molecules bind to peptides derived from an endocytosed antigen, and are primarily recognized by CD4q T cells HLA class II molecules are expressed on B cells, macrophages, dendritic cells, Kupffer cells, a variety of epithelial cells and activated T lymphocytes. Aberrant expression of MHC class II molecules has been found in a variety of autoimmune processes, and there are reports of the de-novo expression of HLA class II antigens in hepatocytes of AIH patients w6x. 6. Autoantigens Patients with AIH show significant T cell reactivity to autologous liver antigens whereas very low, if any reactivity can be detected in patients with HCV and HBV infection. During remission due to immunosuppressive treatment, T cell reactivity to liver antigens becomes undetectable. Data examining the TCR repertoire of infiltrating T cells are lacking at present. Moreover, the relative contribution (if any) of autoreactive T cells with
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specificity for liver antigens in the tissue injury is still in question w7x. At least two such hepatocellular surface antigens have been reported: (1) P450-IID6, the autoantigen recognized by anti-LKM-1 autoantibodies and (2) membrane bound asialoglycoprotein receptor, a liver-specific membrane protein that is unique to hepatocytes and is preferentially expressed at high density on periportal hepatocytes. The surface expression of asialoglycoprotein receptor on hepatocytes has also been shown to be associated with high titer circulating antibodies in AIH w8x. Additional information refers to autoantibodies against a soluble liver antigen (anti-SLA) and against a cytoplasmic antigen shared by liver and pancreas (anti-LP), whose specific major autoantigens were initially believed to be glutathione-Stransferase subunit proteins and liver cytokeratins 8 and 18, respectively. Newer studies have shown that the anti-SLA and anti-LP is one and the same antibody, and that it has a high specificity for AIH. The target autoantigen has been cloned, characterized and proposed to be a cytosolic UGA-suppressor tRNA associated protein not specific to the liver. Finally, anti-LC1 another autoantibody, which reacts with a liver-specific cytosolic antigen, has also received some attention. This antigen is not expressed on the surface of hepatocytes, however, as serum antibody titres parallel liver disease activity, it has been suggested that anti-LC1 might also participate in the pathogenetic mechanisms responsible for liver injury. Two possible molecular targets for this autoantibody have recently been identified: argininosuccinate lyase and formiminotransferase cyclodeaminase w9x. 7. Cell adhesion molecules Although the adhesion molecules responsible for the initial antigen-independent interaction between cytotoxic T cells and target cells are expressed at very low levels, it has been shown that inflammatory mediators, including cytokines, strongly induce some of these molecules in a variety of autoimmune processes including AIH. For instance, intercellular adhesion molecule-1y CD54, a molecule restricted to sinusoidal lining cells and scattered mononuclear cells in normal
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liver is strongly induced in hepatocytes of AIH patients, particularly in areas of periportal inflammation. Similarly, LFA-3yCD58 (the target cell counter-receptor of the T-cell molecule LFA-2y CD2), which is not detected in normal hepatocytes is clearly expressed in the hepatocellular membrane of AIH patients, particularly in those periportal and lobular areas, which are more severely infiltrated w10x. Enhanced intra-hepatic expression of lymphocyte activation antigens as well as cellular and vascular adhesion molecules in AIH can be considered as further evidence for a leading role of T-cell-mediated immune mechanisms in the pathogenesis of tissue damage in this disease. 8. Lymphocyte activation CTLA-4 is expressed on the surface of activated CD4 T helper cells and competes with CD28 for the B7 ligand downregulating the second signal for T cell activation (Fig. 1). In type 1 autoimmune hepatitis, a polymorphism of the cytotoxic T lymphocyte antigen—4 (CTLA-4) gene has been recognized. The substitution of a guanine for an adenine at position 49 in the CTLA-4 gene results in a threonine for alanine substitution in the expressed protein that could have functional consequences. The same polymorphism has been described in primary biliary cirrhosis, and it may be one of the several autoimmune promoters that are not disease-specific w11x. Among other costimulatory molecule interactions, interactions between CD40 and CD154 are critical for both cellular and humoral immune responses (thus linking the two components of the disease) and their study could be relevant for AIH w12x. 9. Cytokines Type 1 and type 2 cytokines constitute an immunoregulatory network that is characterized by redundant action and extensive cross-regulatory function (Fig. 2). The cytokine network influences the occurrence, clinical expression and outcome of autoimmune hepatitis. Different cytokine profiles have been described in children with type 1 and type 2 autoimmune
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Fig. 1.
hepatitis, and a type 2 cytokine response differentiates autoimmune hepatitis from chronic viral hepatitis. Interleukin-2 and IL-4 are found less commonly and at lower serum levels in adults with type 1 autoimmune hepatitis than in normal subjects. Type 1 cytokines predominate in the liver during active inflammation and type 2 cytokines
Fig. 2.
predominate in the circulation during remission. These findings suggest that cytokine profiles change during disease activity either as a cause or a consequence of the immune response. The genes responsible for cytokine production are being sequenced and an important polymorphism involving substitution of an adenine for a
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guanine at position y308 of the TNF-A gene (TNFA*2) has already been described in type 1 autoimmune hepatitis. The TNFA*2 allele is carried on the 8.1 ancestral haplotype of Northern Europeans, and this linkage disequilibrium may combine the genetic propensity for autoantigen presentation with the cytokine milieu that favors a cytotoxic immune response. The adenine substitution at position y308 of the TNF-A gene is associated with high inducible and constitutive levels of TNF-a, and it favors a type 1 cytokine response. The polymorphism occurs mainly in young patients with type 1 autoimmune hepatitis and in individuals who respond less well to corticosteroid therapy. These findings imply an effect on disease severity w13,14x. Other cytokine immune modulators are also under genetic control, and their occurrence and functional consequences in autoimmune hepatitis must be fully defined. Cytokine genes that have not yet been assessed but may be worthy of further study include IL-2, IL-4, IL-6 and IFN-g w15,16x. 10. Destruction of hepatocytes Immune-mediated liver cell injury could result from the clonal expansion of cytotoxic T cells sensitized to autoantigen (cell-mediated cytotoxicity), andyor from the unmodulated production of autoantibodies directed against hepatocyte membrane constituents (antibody-dependent cellmediated cytotoxicity).
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The predominant mechanisms of liver cell destruction in autoimmune hepatitis are unknown. Both cell-mediated and antibody-dependent pathways are probably involved. Cell-mediated destruction has been evoked because of lack of direct evidence that autoantibodies are non-pathogenic, and autoantigens have been defined against which liver-infiltrating lymphocytes have highly specific reactivity. Antibody-dependent cell-mediated mechanisms have been evoked because unmodulated autoantibody production against normal liver membrane constituents has been detected w1 x . Cell-mediated cytodestruction requires clones of liver-infiltrating, antigen-primed lymphocytes with cytolytic activity. The cytolytic effector T cells attach to the target cells by adhesion molecules induced by the proinflammatory cytokines; liver cell injury may also result from the release of lymphokines. The cytotoxic T cells are sensitized to autoantigen presented by class I MHC molecules. Apoptotic cell death has been described in cases of hepatitis especially fulminant hepatitis w17x. Programmed cell death is accomplished mainly by the interaction of Fas receptors on the liver cell surface with Fas ligand. Other apoptotic pathways, such as that between TNF-a and TNF receptor I may also be involved. Homeostasis is maintained by antiapoptotic mechanisms that include the release of cytokines such as IL-4, IL-7 and IL-15, which up-regulate expression of the antiapoptotic
Fig. 1. Mechanisms of autoantigen presentation and CD4 T helper cell activation. Autoantigen is optimally oriented in the antigenbinding groove of the HLA DR molecule by a salt bridge between a negatively charged amino acid residue at position P4 on the antigenic peptide (aspartic acid or glutamic acid) and a positively charged amino acid residue at position DRb71 (lysine or arginine) within the HVR3 of the antigen binding groove. The peptide-HLA DR complex is recognized by the TCR of an uncommitted CD4 T helper cell, and the first signal of immunocyte activation is completed. The critical contact point for completion of the first signal is at the TCR-P4-HVR3 interface. Completion of the second signal of immunocyte activation requires ligation of CD28 expressed by the CD4 T helper cell and B7 expressed by the antigen presenting cell. This second signal can be blocked by CTLA-4, which is expressed by activated CD4 T helper cells (Adapted from Czaja AJ 2001 Understanding the pathogenesis of autoimmune hepatitis Am. J. Gastroenterol. 96; 1224–1231). Fig. 2. Mechanisms of cytokine immunoregulation. Activated CD4 T helper cells release cytokines that stimulate expansion of cytotoxic T lymphocytes (CTL) and B cell production of autoantibodies. Th1 immune response can be accentuated by a polymorphism of the gene governing TNF-a production and it may favor a cytotoxic (CTL) response by producing excess levels of TNFa. Th2 response is stimulated by IL-4 and IL-10, and it favors an autoantibody response. Uncontrolled autoantibody production has been described in autoimmune hepatitis, but the reasons are unclear (Adapted from Czaja AJ 2001 Understanding the pathogenesis of autoimmune hepatitis Am. J. Gastroenterol. 96; 1224–1231).
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protein Bcl-2 w18x. The role of these interactions in AIH needs to be further explored. Antibody-dependent cell-mediated cytotoxicity implies aberrant regulation of immunoglobulin G production by plasma cells. Immunoglobulin G interacts with normal cell surface proteins and the antigen-antibody complex is targeted by natural killer cells that have Fc receptors for the immunoglobulin complex. Natural killer cells are not antigen-primed, and their specificity relates to the antibody-antigen complex on the liver cell membrane. Linkage with this complex results in cell-mediated cytolysis w1x. 11. Genetic predisposition to AIH Patients with AIH and their families share a genetic background, which favors the development of autoimmune diseases. However, in the absence of studies with homozygotic twins, the analysis of the extent to which genetic abnormalities may lead to the development of the disease is difficult. Several genes are believed to contribute to the genetic predisposition to develop AIH. By binding target peptides, MHC alleles may be a determinant of the risk of developing AIH and, most probably, participate in the pathogenesis of the disease. HLA-DR3 and HLA-DR4 alleles have long been proposed as risk factors for type 1 AIH in Caucasian patients and in patients from Japan, respectively. These alleles encode positions 67–72 of the DRb polypeptide chain, with either lysine or arginine at position 71. This position is located at the edge of the a-helix of the antigen-binding groove, where it can interact with both the bound antigen and the T-cell receptor. Differences in a single amino acid at this position can affect the steric relationship between antigen and T cell, thus influencing the immunoreactivity of the effector cells responsible for the disease, and hence the risk, the variable clinical manifestations of type 1 AIH and the outcome after corticosteroid therapy. Lysine at position 71 is correlated with an increased risk for type 1 AIH in Caucasian patients. Conversely, in patients from Japan, Argentina, Brazil and Mexico, arginine rather than lysine at position 71 is associated with an increased risk for type 1 AIH.
Interestingly, the HLA-DR alleles affect not only the susceptibility, but also the severity of the disease. This is probably based on the ability of HLA-DR alleles to induce changes in the number of immunocytes by influencing one of the following variables: (i) the density of the antigen-presenting complexes on the surface of the antigen-presenting cells; (ii) the ability of CD4 Thelper cells to respond to multiple antigenic peptides presented by a single allele of the MHC; and (iii) the ability of different HLA-DR molecules to present the same peptide w19,20x. Recent data implicate the tyrosine phosphatase CD45 gene to show a genetic link with the development of AIH. Analysis of 190 AIH patients showed a 77 CyG mutation in the gene in a significantly higher frequency when compared with 210 healthy blood donors. The CD45 tyrosine phosphatase plays an important role in normal antigen receptor mediated signaling in T and B cells w21x. 12. Novel pathogenic factors Recent results demonstrate that in comparison with normal controls the livers of AIH patients show an increased expression of inducible nitric oxide synthase, as well as nitrotyrosine (a result of the reaction between oxidant peroxynitrites and cellular proteins). This evidence suggests that oxidative damage to cellular structures may play a role in the pathogenesis of AIH w22x. 13. Summary Autoimmune hepatitis (AIH) is an unresolving, predominantly periportal hepatitis, associated with hypergammaglobulinemia and tissue autoantibodies thought to be initiated by CD4 T cells that recognize self-antigen (s). The effector cells differentiate into functional phenotypes according to cytokines in the microenvironment and the nature of the triggering antigen. Hepatocytes can express class II molecules and present antigenic peptides through a bystander mechanism. NK T cells reside in the normal liver but may be involved in liver cell damage possibly through the expression of Fas ligand. Autoantibodies may also participate in the process by complexing with antigen on the
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hepatocyte membrane surface and by interacting with mononuclear cells with Fc receptors. Molecular mimicry may generate cross-reactivities that predispose the immune system to cross-react with self-antigens. Multiple exposures to pathogens with antigenic similarities may prime a crossreactive subset of T cells in the genetically predisposed host. Autoimmunity against one self-antigen may then spread through molecular mimicry to other homologous self-antigens and may lead to overt autoimmune disease. Response to tissue injury may vary from individual to individual and may explain the heterogeneity in the expression and outcome of the disease. Take-home messages – The diagnosis of autoimmune hepatitis is based on criteria that include clinical symptoms, hypergammaglobulinemia and circulating autoantibodies. Immunosuppressive therapy with prednisolone alone or in combination with azathioprine prolongs survival. – A loss of tolerance against the patient’s own liver is regarded as the pathogenic mechanism. – Several putative hepatocellular surface antigens have been identified. – Presence of T cell hyperactivity against autologous liver antigens. – Tissue injury mediated by cell and antibody mediated mechanisms.
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The World of Autoimmunity; Literature Synopsis Retro-inverso gonadotrophin-releasing hormone immunogen Gonadotrophin-releasing hormone (GnRH) vaccines are usually used for the inhibition of gonadotrophin secretion and gonadal function, such as in cases of sex hormones-dependent cancers. Fromme et al. (Endocrinology 2003;144:3262) report on a retro-inverso GnRH which is composed of D-amino acids assembled in the reverse order in relation to the parent L-peptide. These peptides succeeded in eliciting high titers of anti-GnRH antibodies in rabbits and mice. These antibodies are selective for mammalian GnRH, and could inhibit GnRH-stimulated signal transduction in COS-1 cells expressing the human GnRH receptor. The great advantage of these peptides is their resistance to cleavage by proteolytic enzymes and thus they might be orally active. The retro-inverso GnRH peptides could also elicit antibodies to GnRH without conjugation to ovalbumin or Freud’s complete adjuvant. Treatment of paraneoplastic cerebellar degeneration with intravenous immunoglobulin Paraneoplastic cerebellar degeneration (PCD) is a neuro-degenerative disease associated with autoantibodies against Purkinje cells of the cerebellum. The treatment options usually fail in most cases. Widdess-Walsh et al. (J Neuro-Oncol 2003;63:187) report a case of PCD treated with intravenous immunoglobulin (IVIg) and review additional similar cases. According to this review, most patients that were treated with IVIg and had a good response — were treated within 1 month of symptoms onset. However, patients who were treated 1–3 months post-symptoms onset had usually a stable disease course, whereas those treated after 3 months of symptoms onset did not benefit from IVIg as they had a poor outcome. The authors therefore recommend an early trial of high dose IVIg (2 gykg body weight) and intravenous methylprednisolone for any patients having PCD and positive autoantibodies. Epitope spreading following immunization with thyroglobulin peptide Thyroglobulin is the autoantigen targeted by autoantibodies in autoimmune diseases of the thyroid. It contains 3 20mer peptides bearing epitopes of autoantibodies associated with Graves’ disease. Thrasyvoulides and Lymberi (Clin Exp Immunol 2003;132:401) immunized rabbits with thyroglobulin, and these animals had reactivity against only one of the three peptides, TgP41. This peptide was also used for immunization, which was followed by a strong serological response against the immunizing peptide, but also against intact human and rabbit thyroglobulin. As evident from immunoadsorption and ELISA, immunization and TgP41 induced intramolecular B-cell epitope spreading, turning this peptide into a dominant immunogenic epitope of experimentally induced thyroglobulin-specific antibodies. BPI-ANCA and susceptibility to infections Patients having defects in the transporter associated with antigen presentation (TAP) have recurrent Gramnegative bacterial lung infections. Schulz et al. (Clin Exp Immunol 2003;133:252) report the presence of antineutrophil cytoplasmic autoantibodies against the bactericidalypermeability-increasing protein (ANCABPI) in 5 of 6 of these patients. BPI is a potent neutrophil antibiotic that neutralizes endotoxin efficiently. IgG from these patients could also inhibit the antimicrobial function of BPI in vitro. Inhibition of BPI by ANCA is a possible mechanism of how these autoantibodies may contribute to increases susceptibility to infections.