Functional autoantibodies in primary biliary cirrhosis

Abstract

In their recent interesting article on primary biliary cirrhosis (PBC), Carlo Selmi and Eric Gershwin discuss how a mimicking microorganism or self proteins modified by xenobiotics can trigger anti-mitochondrial antibodies (AMA) that react with the pyruvate dehydrogenase complex (PDC-E2) on the luminal surface of the bile duct cell membrane. Bile duct destruction is thought to be induced by autoreactive T cells and “possibly AMA” [1xThe role of environmental factors in primary biliary cirrhosis. Selmi, C. and Gershwin, M.E. Trends Immunol. 2009; 30: 415–420Abstract | Full Text | Full Text PDF | PubMed | Scopus (52)See all References[1]. As I have articulated previously [2xAutoimmunity in primary biliary cirrhosis: an alternative view at initiation and function of anti-mitochondrial autoantibodies. Berg, P.A. J. Hepatol. 2009; 50: 827–830Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all References[2], I have a somewhat differing view to the PDC-E2-related concept of PBC immunopathogenesis. Here I will try to defend further some of my arguments that the innate immune system is constantly involved in the inflammatory biliary process, and that not only the PDC-E2- related autoimmune response, but rather other functionally active autoantibodies might also be involved in the pathogenesis of PBC.The reaction to mitochondrial antigens might also be seen as an expression of innate autoimmunity because of the endosymbiotic evolutionary origin of mitochondria [3xNaturally occurring auto-antibodies in homeostasis and disease. Lutz, H.U. et al. Trends Immunol. 2009; 30: 43–51Abstract | Full Text | Full Text PDF | PubMed | Scopus (69)See all References[3]. Manifestations such as the increase of IgM but not IgG during the whole clinical course of PBC may be related to the continuous stimulation of cells of the innate immune system by environmental factors. Thus the role of adaptive immunity may be less important than thought initially. Low or high levels of danger/alarm signals, such as endogenous self-antigens or molecular mimicry might affect the specificity of the innate immune response and the degree to which autoreactive T cells, natural killer cells or natural (auto) antibodies (Nabs/NAAbs) will regulate apoptosis and tissue repair in the affected cholangiocytes [4xA calculated response: control of inflammation by the innate immune system. Barton, G.M. J. Clin. Invest. 2008; 118: 413–420Crossref | PubMed | Scopus (158)See all References[4]. Thus, the evoked immunity to mitochondrial antigens can be beneficial, harmful, or neutral.From clinical observations, a protective role for AMA seems to me more likely. The clinical course of PBC varies widely from one patient to another, and active courses can also occur in AMA negative PBC patients. Interesting are recent findings that patients with overt autoimmune hepatitis who test positive for anti-PDC-E2 autoantibodies yet show no clinical or histological evidence for PBC, despite the continued detection of AMA over a period of up to 27 years [5xLong-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. O’Brien, C. et al. Hepatology. 2008; 48: 550–556Crossref | PubMed | Scopus (68)See all References[5]. The absence of PBC was explained by the action of immunosuppressive therapy necessary in these patients. However, immunosuppression is ineffective in PBC patients, in contrast to ursodeoxycholic acid (UDCA) that can protect PBC patients from a progressive disease course [6xThe effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Corpechot, C. et al. Gastroenterology. 2005; 128: 297–303Abstract | Full Text | Full Text PDF | PubMed | Scopus (212)See all References[6].A further important aspect is the notion that each organ has its own specific self-reactive cells and its own threshold for activation of the innate immune system [7xImmunity to self and self-maintenance: a unified theory of brain pathologies. Schwartz, M. and Ziv, Y. Trends Immunol. 2008; 29: 211–219Abstract | Full Text | Full Text PDF | PubMed | Scopus (44)See all References[7]. Thus, the induction of the inflammatory program could result in organ dysfunction, i.e. in a disturbed communication between tissue-derived signals and the effector class of the innate immune system. This process may then result in an impaired balance between proliferation and apoptosis of cholangiocytes, the hallmark of cholangiopathy that is controlled by proteins and membrane receptors governing the pro- and anti-apoptotic program within the biliary tract system (Figure 1Figure 1a and b ). Thus, proteins of the Bcl-2 family as well as proteins of the neuroendocrine system can interfere with the homeostasis of cholangiocytes. The release of a neurotransmitter such as acetylcholine by the vagal nerve directly stimulates the growth of bile duct epithelial cells shown to express the muscarinic acetylcholine receptor type 3 (mAChR3) (Figure 1Figure 1b). Bcl-2, in concert with the muscarinic acetylcholine receptor, mAChR3, can prevent cell death by inactivating the pro-apoptotic proteins Bax and Bak [8xApoptosis in the development and maintenance of the immune system. Opferman, J.T. and Korsmeyer, S.J. Nat. Immunol. 2003; 4: 410–415Crossref | PubMed | Scopus (322)See all References[8]. Budd and colleagues [9xSignalling of the M3-muscarinic receptor to the anti-apoptotic pathway. Budd, D.C. et al. Biochem. J. 2004; 381: 43–49Crossref | PubMed | Scopus (29)See all References[9] showed recently that the muscarinic receptor family members (M) that are coupled to Gq11 proteins (e.g. M1, M3, M5), but not those coupled to G1 proteins (e.g. M2, M4), can protect cells from apoptosis following DNA damage. Bcl-2 can be detected in bile ductules but not in large and septal bile ducts, and is reduced in bile duct lesions of patients with PBC [10xExpression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis. Iwata, M. et al. Hum. Pathol. 2000; 31: 179–184Abstract | Full Text PDF | PubMedSee all References[10]. These findings underline the important role of a tissue specific apoptotic process in exposed bile ducts.Figure 1A speculative model for the interaction of natural autoantibodies with either proteins of the Bcl-2 family or the neuroendocrine receptor system at the level of proliferating cholangiocytes. (a) The “BH3 only” proteins are associated with the endoplasmic reticulum and initiate the intrinsic apoptotic mitochondrial pathway in response to cellular danger signals or other death stimuli. BH3 only proteins directly engage pro-apoptotic proteins Bax/Bak once they have overwhelmed their pro-survival homologues Bcl2 and BCXL Permeability of the outer mitochondrial membrane is controlled by the Bcl-2 family. Activation of the pro-apoptotic Bcl-2 members (Bax, Bak) induces mitochondrial swelling, disruption of the membrane and exposure of outer membrane antigens as well as intermembrane space antigens. In contrast, the anti-apoptotic Bcl-2 and BclXL act to prevent permeabilisation. (b) The main immunogenic region (MIR) of AChRs is on the top of their extracellular surface. Thus, a high density of functional autoantibodies can be easily bound to the extracellular region of mAChR thereby interacting with cholangiocyte proliferation. Cross-linking of two MIR might activate receptors. Thus, one could envisage that functional natural (auto) antibodies could act in concert with proteins of the Bcl-2 family or with ligands of the autonomous nervous system to provide or inhibit tissue repair and tissue integrity.View Large Image | Download PowerPoint SlideFocusing on the function of innate immune reactivity with respect to the balanced process of inflammation within small cholangiocytes, one may hypothesize that additional natural autoantibodies besides AMA/anti-PDC-E2 might control death and repair of cholangiocytes by interfering with receptors or proteins involved in the apoptotic program (Figure 1Figure 1a, b). From our preliminary data, there is evidence that anti-mAChR3 antibodies can be detected in patient sera (unpublished observations). Interestingly, similar functional autoantibodies have been found also in scleroderma and Sjogren syndrome, two diseases that co-occur with PBC (see references in [2xAutoimmunity in primary biliary cirrhosis: an alternative view at initiation and function of anti-mitochondrial autoantibodies. Berg, P.A. J. Hepatol. 2009; 50: 827–830Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all References[2]). Recent findings also indicate that the therapeutic effect of UDCA may be related to its action to prevent the increase of the pro-apoptotic Bax protein levels induced by p53 [11xp53 is a key molecular target or ursodeoxycholic acid in regulating apoptosis. Amaral, J.D. et al. J. Biol. Chem. 2007; 282: 34250–34259Crossref | PubMed | Scopus (42)See all References[11].In conclusion, I propose that innate immunity, tissue-specific factors as well as a genetically susceptible background can all influence the balance of proliferation and apoptosis in small bile ducts exposed to an overload of danger/alarm signals. Probably, different types of functional autoantibodies against proteins of the apoptotic pathway may control the clinical course, and determine the final outcome of PBC.