To the Editor:
Primary biliary cirrhosis remains a fascinating field of research, and its possible causes have been intensively studied in the past years. Selmi and colleagues [
[1]
] provide in their review an update on recent developments in PBC, and based on their own contributions they explain that an environmental insult intervening on a genetic susceptible background precipitates PBC through molecular mimicry. However, in recent years new ideas and models have been developed that may challenge the current paradigm of autoimmunity in general and justify another view of the initiation of PBC. Schwartz and Ziv [[2]
], for instance, present the concept of immunity to self as a maintenance mechanism to protect the integrity of tissue function. Following Matzinger’s “danger model” [[3]
], autoimmunity evoked in response to a danger signal is a by-product of a necessary immune response and as such it can be useful, neutral or harmful.Based on these sound immunological findings, the introduction of the model of “balanced autoimmune surveillance activity” may help to explain some “inconvenient truths” [
[4]
] in PBC. Protective and organ-specific autoantibodies may be involved in its pathogenesis. An important argument that AMA fit into this concept is the fact that there is a common evolutionary origin of mitochondria. Because mitochondria are of endosymbiotic origin their proteins represent a transition from prokaryocyte foreign to essential self molecules. AMA can be, therefore, defined as natural autoantibodies of a polyreactive nature. An important feature of natural antibodies is that they contribute to maintenance of immune homeostasis and exert many functions such as clearance of apoptotic cells or selection of immune repertoire [[5]
]. Thus, the exposure of a mitochondrial antigen such as PDC-E2 in PBC is rather supposed to initiate first at early stages an innate and not an adaptive immune response.To get better insight into the AMA-related pathogenesis of PBC one can look at the two co-occurring diseases, Sjögren’s syndrome and scleroderma that express both diagnostic and functional active anti-receptor antibodies. In patients with scleroderma different types of organ specific antibodies are associated with different clinical manifestations such as oesophageal and gastrointestinal dysmotility and tissue fibrosis [
6
, 7
]. Furthermore, there is convincing evidence that the glandular hypofunction in Sjögren’s syndrome is attributed to the antagonistic action of antibodies to the muscarinic acetylcholine receptor M 3 [[8]
].Since proliferating bile ducts acquire all phenotypes of neuroendocrine cells [
[9]
] it seems very likely that cholangiocyte-specific anti-receptor antibodies are also induced in patients with PBC. Indeed, one even might define PBC as a neuroendocrine autoimmune disease.The concept of the maintenance function of innate immune system would be also applicable to the different courses of PBC. This means that under normal non pathological conditions, the immune system supports the structural and functional integrity of cholangiocytes. In contrast, overactivation of the self specific immune activities would underlie the loss of bile duct maintenance leading to the eruption of autoimmune disease. Reflecting this kind of surveillance function asymptomatic, symptomatic and progressive courses become easily understandable.
Macroautophagy induction has to be also considered as a pathway in innate and adaptive immunity [
[10]
] since apoptotic stimuli target mitochondria for degradation by autophagy. Danger signals may also activate the caspase cascade via the pro- and anti-apoptotic Bcl-2 family [[11]
]. Certainly, the question about the nature of the so called danger signals cannot be answered. Following Plotz’s view [] one could argue that the xenobiotic modified PDC-E2 antigen is especially chemoattractive for immature dendritic cells and will be readily exposed to cells of the innate and adaptive immune system. The process of apoptosis influences the presentation of the different intracellular antigens. Integrity of cholangiocytes may, therefore, depend upon the balance of protective (proliferative) and destructive (apoptotic) mechanisms. Thus, natural occurring autoantibodies may stimulate or inhibit apoptosis by interfering with Bcl-2 proteins or with the large family of transmembrane receptors. This theoretical concept is convincingly backed up by recent findings that UDCA can prevent apoptosis by reducing the apoptotic threshold through modulation of the classical mitochondrial pathway [[13]
].References
- The unfinished business of primary biliary cirrhosis.J Hepatol. 2008; 49: 451-460
- Immunity to self and self-maintenance: a unified theory of brain pathology.Trends Immunol. 2008; 29: 211-219
- The danger model: a renewed sense of self.Science. 2002; 296: 301-305
- The causes of primary biliary cirrhosis: convenient and inconvenient truths.Hepatology. 2008; 47: 737-745
- A possible new bridge between innate and adaptive immunity: are the anti-mitochondrial citrate synthetase autoantibodies components of the natural antibody network?.Mol Immunol. 2006; 43: 1761-1768
- Antibody-mediated gastrointestinal dysmotility in scleroderma.Gastroenterology. 2002; 123: 1144-1150
- Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.N Engl J Med. 2006; 354: 2667-2676
- Demonstration of autoantibody binding to muscarinic acetylcholine receptors in the salivary gland in primary Sjögren’s syndrome.Clin Immunol. 2008; 128: 269-279
- Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431
- Macrophagy versus mitochondrlal autophagy: a question of fate?.Cell Death Diff. 2005; 12: 1484-1489
- Pharmacological manipulation of Bcl-2 family members to control death.J Clin Invest. 2005; 115: 2648-2655
- The autoantibody repertoire: searching for order.Nat Rev. 2003; 73: 73-78
- p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis.J Biol Chem. 2007; 2282: 34250-34259
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Published online: December 11, 2008
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