Autoantibodies in liver disease

Abstract

Autoantibodies are immunoglobulins that react against normal host proteins and may be natural or pathologic.1 Natural autoantibodies are germline responses that develop from genetically programmed clones of B cells and are typically present in low serum titers as isotypes of immunoglobulin M.2–5 Natural autoantibodies do not fix complement and usually have weak antigen-binding affinities, multiple reactivities, and no disease associations.6,7 They occur more commonly in women than in men,8 the repertoires remain stable with aging,9,10 and they may bind products of natural cell death or foreign antigens that resemble selfantigens.11,12 In this fashion, natural autoantibodies may prevent the emergence of autoreactive immunocytes and have a protective function.2,4,6,11,12 Pathologic autoantibodies are produced by antigenspecific B-cell activation and subsequent clonal expansion of dedicated plasma cells.1,2 These autoantibodies typically are present in high serum titers as isotypes of immunoglobulin G. Pathologic autoantibodies fix complement, have high antigen-binding affinities, inhibit autoantigen activity in vitro, and have disease associations.2,6 They are rarely pathogenic, but their presence in serum does imply the existence of an antigen-driven immunopathic process. This process may be crucial for disease expression, a consequence of other cytodestructive mechanisms, or coincidental with the main disorder. Natural and pathologic autoantibodies can be distinguished from each other by class-specific attributes (Table 1). The presence of low-titer autoantibodies in the absence of hypergammaglobulinemia or a compatible clinical liver disease usually indicates the presence of natural autoantibodies. Any component of the liver cell can trigger the production of pathologic autoantibodies, and reactivities have been described against nuclear, microsomal, cytosolic, and mitochondrial proteins.13 Expression of the antigen on the surface of professional antigen-presenting cells is the principal mechanism for activation of B cells, and antigen presentation to CD4 T-helper cells is restricted by the class II molecules of the major histocompatibility complex.14–16 Intracellular antigens can be expressed on the surface of the liver cell membrane, and the hepatocyte can present autoantigens that generate autoantibodies.17,18 Mechanisms for pathologic autoantibody production include the discovery of self-antigens that had been poorly recognized or sequestered during ontogeny (cryptic or sequestered epitopes) or the generation of new antigens by the degradation of viruses, xenobiotics, and chemicals within the hepatocyte (neoepitopes).19,20 Selfantigens can be targeted by an exuberant immune response to an infectious agent (superantigen effect), and nonspecific mediators of inflammation, including cytokines, chemotactic substances, macrophages, and natural killer cells, can extend the immune response (bystander effects). Epitopes within the same antigen or between different antigens can become involved (epitope spread); autologous antigens can combine with infectious or environmental agents (adjuvant effects); or foreign antigens can mimic self-antigens (molecular mimicry).19,20 Autoantibodies may lack disease specificity or pathogenic importance, and bystander effects, adjuvant effects, and molecular mimicry may explain in part the occurrence of autoantibodies in nonautoimmune diseases. Importantly, autoantibodies are not found in all forms of hepatocellular injury and are not simply the trappings of liver cell destruction. Autoantibody titers do not correlate closely with the severity of liver cell damage, and changes in autoantibody expression do not reflect disease behavior.21