Current Molecular Medicine 2009, 9, 45-51 45 1566-5240/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Innate Immunity and Primary Biliary Cirrhosis Carlo Selmi 1 , Ana Lleo 2,3 , Simone Pasini 1 , Massimo Zuin 2 and M. Eric Gershwin* ,3 1 Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, University of Milan, Italy; 2 Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Italy; 3 Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA Abstract: There has been a rapid growth in our understanding of the molecular bases of primary biliary cirr- hosis (PBC). These efforts were initiated when the immunodominant mitochondrial autoantigen was cloned and sequenced. Using the recombinant cloned antigen as a tool, research has focused on the effector mecha- nisms of disease and the uniqueness of the primary target tissue, the intrahepatic bile ducts. Most recently, there have been experimental data suggesting that innate immunity changes may be critical to the initiation and perpetuation of the autoimmune injury, as in the case of the enhanced response of monocytes and memo- ry B cells to infectious stimulation and environmental mimics. These observations are important as they help fill in the many gaps which remain on the most difficult subject of autoimmunity, etiology. Indeed, based on the available data, several experimental models of PBC have been developed. These models illustrate and sug- gest that PBC can be initiated by several mechanisms, all of which lead to loss of tolerance to the mitochon- drial antigens. However, once this adaptive response develops, it appears that much of the subsequent pat- hology is exacerbated by innate responses. We suggest that future therapeutic efforts in PBC will depend hea- vily on understanding the nature of this innate immune responses and methodology to blunt their cytotoxicity. Keywords: Autoimmune cholangitis, apoptosis, monocyte, memory B cells, NK cells. INTRODUCTION Autoimmune diseases are multifactorial processes involving the dysregulation of both the adaptive and the innate systems, with genetic and environmental factors interplaying to determine disease susceptibility and progression. Primary biliary cirrhosis (PBC) is a repre- sentative, organ-specific autoimmune disease with a striking female predominance. Its features include high titers of serum antimitochondrial autoantibodies (AMA), high plasma levels of immunoglobulin M (IgM) [1-5], and an histologically-proven immune mediated destruc- tion of the small and medium size intrahepatic bile ducts [6]. Understanding the etiology of PBC remains a challenge. However, recent studies have provided new insights into the events leading to the breakdown of self-tolerance and the development of PBC. The adaptive immune system has been the primary subject of study in autoimmunity and is composed of highly specialized, systemic cells and processes that evolved to provide amplification of the immune respon- se. Indeed, the study of adaptive immunity has led to important contributions in several fields [7-11]. It is highly specific and confers memory to the host. Accor- dingly, the adaptive immune response is characterized by an exquisite specificity for distinct molecules and by the ability to recognize and react to a large number of microbial and non-microbial substances. The major components of this type of immune response are B and *Address correspondence to this author at the Division of Rheumato- logy, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA; Tel: 530-752- 2884; Fax: 530-752-4669; E-mail: megershwin@ucdavis.edu T cells. On the other hand, the innate immune system comprises the cells and mechanisms that defend the host from infections in a non-specific manner; it recog- nizes and reacts to pathogens in a generic way, but unlike the adaptive immune system, its response does not confer long-lasting or protective immunity to the host. Indeed, innate immunity is considered as the ear- ly line of defense against pathogens and is specific for a limited number of structures common to groups of similar micro-organisms. For a long time, the innate and acquired compartments have been considered as mutually exclusive and independent, yet during the past years several lines of evidence have proven ot- herwise [12], particularly in the field of autoimmunity [13, 14]. The adaptive immune responses observed in PBC, including the development of autoantibodies and auto- reactive T cells, have been extensively studied. The features of the innate response in PBC have been overlooked until recently when several studies have shed promising light on this field. This review illustrates the available evidence regarding the role of innate im- munity in PBC and discusses their potential implica- tions and limitations. LIVER IMMUNOLOGY AT A GLANCE The liver is exposed to both arterial and portal ve- nous blood, which is rich in mainly harmless food- derived antigens or microbial products, being actively involved in their clearance [15]. The liver, therefore, needs to avoid activation of the immune system in the presence of nonpathogenic molecules (including food components) and micro-organisms (such as the gut