Neuroendocrine tumours can form in any part of the gastrointestinal tract. The most common types are the ECL cell tumours of the oxyntic mucosa of the stomach, G cell tumours of the duodenum, argentaffin, EC cell tumours of the small intestine and L cell tumours of the large bowel. The only well-defined clinical syndromes associated with hormone hypersecretion are ZES, resulting from duodenal gastrinomas, and carcinoid syndrome, caused by malignant argentaffin tumours. Genetic predisposition has been demonstrated for some tumour types, e.g. duodenal gastrinoma in MEN 1 and duodenal somatostatin cell tumours in MEN 2. Other factors predisposing to the genesis of these lesions include circulating hormone levels and the maintenance of chronic inflammatory states. As with most neuroendocrine tumours, malignant potential is difficult to assess on the basis of histology alone and prognostic evaluation depends more on size and evidence of local invasion and/or distant metastases.

Gastrointestinal motility and sensory perception are altered in a variety of mucosal inflammatory conditions of the gut, ranging from peptic esophagitis to ulcerative colitis. Studies in animal models now clearly indicate a causal relationship between the presence of mucosal inflammation and altered sensory-motor function. In many instances, these changes occur in the absence of any discernible encroachment of the deeper neuromuscular layers by the inflammatory infiltrate, which remains largely within the lamina propria. Accordingly, attention has focused on local sources of mediators, and recent studies indicate that smooth muscle cells and enteroglia are sources of and targets for cytokines such as interleukin 1 beta and interleukin 6. In several instances, neuromuscular dysfunction persists after mucosal inflammation has subsided; this state may be maintained by locally produced mediators. Studies also show the ability of enteric muscle to modulate lymphocyte function via major histocompatibility complex II-restricted antigen presentation. Clinical observation and experimental data also suggest that nerves modulate intestinal inflammation via local release of proinflammatory neuropeptides (substance P) and via the activation of extensive circuits that may involve the brain. Taken together, these findings provide plausible explanations for a variety of clinical scenarios ranging from inflammatory bowel disease to pseudo-obstruction syndromes and subgroups of functional bowel disorders.

Recent advances in molecular biology, in particular X-ray crystallography of the purified antigens A2 and DR1 and development of PCR-based HLA genotyping techniques, has revolutionized our understanding of immunogenetics and cellular immunology. The application of molecular immunogenetics has refined our understanding of HLA-encoded susceptibility and resistance to both autoimmune and chronic viral liver disease. Recent studies of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) have identified substitutions of specific amino acid residues in the HLA DR beta-polypeptide (AIH and PSC) and DP beta-polypeptide (PBC) which may determine susceptibility to and resistance from disease. Although these models of HLA-encoded susceptibility in PSC and PBC are currently controversial, the model for AIH, based on lysine residue at DR beta 71 has recently been confirmed in an independent series. Data on chronic viral liver disease are less abundant, but a number of interesting observations are beginning to emerge. In the Gambia, resistance to chronic hepatitis B infection has been associated with the HLA DRB1*1302 allele, and in studies of patients with chronic hepatitis C virus infection DQA1*03 and DQB1*05 have been identified as a possible protective factors. Clarifying these HLA associations is not simply an academic pursuit; in addition to providing useful clues to the pathogenesis of these diseases, HLA associations may be important indicators of prognosis. In AIH, patients with the DRB1*0301-DRB3*0101 haplotype appear to have more severe disease than those with DRB1*0401, while in PSC, DRB3*0101 is associated with early onset of disease and DRB1*0401 may be a marker of more rapid disease progression. To date, our knowledge of immunogenetic susceptibility in liver disease is incomplete and further work is needed.

Autoantibodies directed against cytochromes P450 or UDP-glucuronosyl-transferases (UGTs) are detected in hepatitis of different aetiology: drug-induced hepatitis autoimmune hepatitis type 2, hepatitis associated with the autoimmune polyglandular syndrome type 1 (APS1) and virus-induced autoimmunity. Autoantibodies directed against cytochrome P450 2C9 are induced by tienilic acid, and anti-P450 1A2 autoantibodies by dihydralazine. Potential mechanisms involved may be metabolic activation of the drugs by cytochromes P450, adduct formation and circumvention of T cell tolerance. In contrast, little is known about the aetiology of autoimmune hepatitis type 2. This disease is characterized by marked female predominance, hypergammaglobulinaemia, circulating autoantibodies and benefit from immunosuppression. Patients with HLA B8, DR3 or DR4 are over-represented. The major target of autoimmunity in this disease is cytochrome P450 2D6. The autoantibodies were shown to be directed against at four short linear epitopes. In addition, about 10% of the patient sera form an additional autoantibody that detects a conformational epitope on UGTs of family 1. The phenomenon of virus-associated autoimmunity is found in chronic infections with hepatitis C and D. In chronic hepatitis C the major target of the autoantibodies again is cytochrome P450 2D6. Some linear and a high proportion of conformational epitopes are recognized. The LKM3 autoantibody is found in 13% of patients with chronic hepatitis D. The target proteins are UGTs of family 1 and, in some sera also, low titres of anto-antibodies directed against UGTs of family 2 are found. The epitopes detected are conformational. In contrast to the patients suffering from autoimmune hepatitis, patients with hepatitis as part of the autoimmune polyglandular syndrome type 1 recognize cytochrome P450 1A2. Interestingly, in APS1 patients also, autoantibodies directed against cytochromes P450 c21, P450 scc and P450 c17a may be detected; these autoantibodies are associated with adrenal and ovarian failure.

More than 500 million people world-wide suffer from viral hepatitis which can be caused by a variety of distinct infectious agents. The spectrum of disease, which ranges from acute self-limited hepatitis to liver cirrhosis, not only reflects the different biological properties and pathogenicity of the hepatitis viruses, but is also the result of the specific interaction between each virus and the immune system of the infected host. The immune response plays a crucial role in the elimination of the infecting virus as well as in disease pathogenesis and is described in detail for acute and chronic hepatitis B and C virus infection. Acute hepatitis B virus infection is characterized by a vigorous, polyclonal cytotoxic T lymphocyte response against HBV that is not readily detectable in patients with chronic hepatitis B, suggesting that resolution of disease is mediated by the HBV-specific CTL response in these patients. Because traces of virus as well as HBV-specific CTL can persist for decades after clinical recovery, continuous priming of new CTL by minute traces of virus is thought to protect from reactivation of disease. In contrast, the hepatitis C virus causes chronic liver disease despite a polyclonal and multispecific immune response, suggesting that distinct immunological and viral mechanisms determine the different clinical outcome of HBV and HCV infection. Their implications for the development of immunomodulatory vaccines to cure patients with chronic viral hepatitis are discussed.

Our understanding of the immunopathology of PBC has dramatically changed with the application of molecular biology techniques in clinical medicine. This has allowed, not only the possibility of characterizing mitochondrial autoantigens fully at the molecular level, but also the identification of specific sites on these molecules that are targetted by autoreactive B and T cells. In addition, the expression of cloned antigens has facilitated the development of the most reliable assays currently available for the detection of mitochondrial autoantibodies. The assessment of the pathogenic capacity of autoreactive T cells, as well as the characterization the PDC-E2 'look alike' molecule expressed on the cell membrane of PBC biliary epithelial cells, remain the major unsolved issues in this disease. Ideally, the continuous effort from both basic and clinical scientist in understanding the pathogenic mechanisms of PBC will lead to more specific, effective, and safer modalities of treatment.

Despite the progress made in understanding the mechanisms of allergic disease, the pathophysiology and clinical significance of intestinal allergic reactions is largely unclear. The intestinal mucosa is pre-destined for allergic reactions against food proteins and other antigens, and a number of studies indicate that allergic reactions occur in the GI tract. However, only a few epidemiological data are available, and the mechanisms are poorly understood. Intestinal allergic reactions may be different to classical IgE-mediated reactions because patients with intestinal allergy often have negative skin tests and low levels of serum IgE. There is increasing evidence that, as with the findings in the skin and lung, mast cells and eosinophils play a central role in mediating intestinal allergic reactions. Furthermore, both types of cell are found to be activated in a number of other GI inflammatory diseases such as inflammatory bowel disease, celiac disease and eosinophilic gastroenteritis. However, the relationship between these pathologies and intestinal allergy is largely unclear. A major clinical problem is the lack of appropriate means for confirming the diagnosis of intestinal allergy. However, new test systems have been developed--such as the measurement of eosinophil mediators in stool samples or endoscopic provocation tests performed locally at the intestinal mucosa, which may improve the possibility of identifying afflicted patients on an objective basis. Since symptoms of intestinal allergic reactions are variable and non-specific, the diagnosis requires the use of multiple tests and the exclusion of other pathologies such as infectious disease or non-immunological intolerance reactions. The preferred therapeutic option is avoidance of the allergens of relevance; however, this approach can be realized only in some patients, whereas others require additional treatment, for example, with oral cromoglycate or corticosteroids. Although we do not yet know to what extent intestinal allergic reactions may be an aetiological factor in GI diseases, such reactions should be considered in the differential diagnosis of unclear intestinal inflammation and irritable bowel syndrome.

The gastrointestinal lymphocytic system can be divided in two functional compartments, the organized lymphoid tissue, for example, the Peyer's patches, and the lymphocytes located diffusely in the mucosa, the lamina propria lymphocytes (LPL), and the intra-epithelial lymphocytes (IEL). Antigens enter the Peyer's patches as the afferent part of the GALT via specialized epithelial cells called M cells. After the initiation of the immune response by antigen processing and presentation to B and T cells in Peyer's patches, primed lymphocytes leave the mucosa via the thoracic duct. Finally they migrate back to the mucosa where they exert effector functions. Adhesion molecules, including integrins, especially alpha 4 beta 7 and alpha E beta 7 (HML-1) are involved in these homing and adhesion processes. LPL and LEL differ from peripheral blood lymphocytes in their expression of adhesion molecules and other surface and activation markers. Additionally, they exhibit functional features different from those of other lymphocyte compartments. In the mucosal immune system, plasma cells mainly secrete IgA, which is part of the specialized humoral defence in the gut.

The intestinal mucosa is the largest surface area in the body which is continually exposed to an enormous amount of food antigens, viruses, bacteria, parasites or the by-products of these organisms. In such an antigen-loaded environment, specialized defence mechanisms must exist. There is clear evidence that the function of lymphocytes in the intestinal mucosa (IELs or LPLs) is different from that of lymphocytes of the peripheral blood, lymph node or spleen (these are antigen-free organs). The basic processes of these reactions are not completely understood. The role of differential antigen handling and presentation, and the non-random distribution of responsibilities between the professional and non-professional APC in this regard, have not been characterized. Thus, much remains to be learned about the basic mechanisms of antigen uptake, processing and presentation in the intestine which are necessary to induce an immune response. Diversity in APC function is a natural requirement for the maintenance of homeostasis in the intestine. Subpopulations of professional and non-professional APC may have been programmed to function in such a way that non-professional APCs may play a dominant role. It is anticipated that in vivo model systems will be developed and that eventually a clearer understanding will be gained in this rapidly evolving field.

Rapid re-sealing of the intestinal epithelial barrier is initially accomplished by migration of viable epithelial cells from the wound edge into the denuded area ('restitution') and only later by cell proliferation. Whereas proliferation of intestinal epithelial cells has been studied intensively, much less is known about the pivotal initial phase of cell migration. Restitution appears to be modulated by peptide growth factors/cytokines, extracellular matrix molecules, and luminally secreted products of mucus-producing cells (schematically summarized in Figure 1). Recent work has demonstrated that various cytokines (TGF-beta 1, TGF-alpha, EGF, IL-1 beta, IFN-gamma, basic FGF, KGF and HGF) present in the intestinal mucosa enhance intestinal epithelial restitution, presumably by mediating its effects through the basolateral pole of the epithelial monolayer. In addition to their effects on cell adhesion, differentiation, and spatial organization, the extracellular matrix molecules on which intestinal epithelial cells reside also have the potential to stimulate intestinal epithelial cell migration. The basement membrane components fibronectin and collagen type IV may be especially important. Finally, trefoil factors, a recently identified family of peptides which are secreted onto the luminal surface where they form the visco-elastic mucus layer through interaction with mucin glycoproteins, also promote the important process of restitution through a pathway distinct from that used by factors acting at the basolateral cell surface.

Electrical rhythmicity in gastrointestinal muscles has been studied for a century, but the pacemakers driving this phenomenon have been elusive. Anatomic studies suggest that interstitial cells of Cajal (ICC) may be pacemakers and conductors of electrical activity. ICC may also mediate neurotransmission from enteric neurons. Functional evaluations of ICC include the following. (1) Electrophysiology experiments on dissected muscle strips show that slow waves originate from specific sites. These pacemaker areas are populated by networks of ICC that make gap junctions with smooth muscle cells. Removal of pacemaker regions interferes with slow wave generation and propagation. (2) Chemicals that label ICC histochemically can damage ICC and abolish rhythmicity. (3) isolated ICC are spontaneously active, and several voltage-dependent ion channels, including a low-threshold Ca2+ conductance, are expressed. (4) ICC are innervated by enteric neurons, and they respond to neurotransmitters. ICC may produce nitric oxide and amplify inhibitory neurotransmission. (5) Some classes of ICC fall to develop in animals with mutations in c-kit or stem cell factor, the ligand for c-Kit receptors. Without ICC, electrical slow waves are absent. Many questions remain about the function of ICC, but modern technologies should now facilitate rapid progress toward determining the role of these cells in normal physiology and pathological conditions.

The current status of liver transplantation (OLTx) for chronic viral hepatitis is reviewed. The major issues addressed include the rate of recurrence of disease, its severity and natural history, and the potential for therapy. These issues vary markedly for each type of viral hepatitis. The development of new antiviral agents for clinical use may change the current restriction on liver transplantation for hepatitis B virus (HBV)-related liver disease such that it begins to challenge hepatitis C virus (HCV) as the principal indication for OLTx world-wide.

The data presented indicate that viral agents (namely, HBV and HCV) are major environmental aetiological factors for human primary liver cancer. It is important to elucidate the molecular mechanisms further because HCC is one of the few examples of virus-related human cancers. In addition, the available evidence points to the possibility of at least partial prevention of the tumour by large-scale vaccination.