Page 1058 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Inflammatory Hepatobiliary Diseases

Carlo Selmi, Michael P. Manns, M. Eric Gershwin

Inflammatory hepatobiliary disease generically refers to chronic Environmental factors have also been linked to AIH develop-
autoimmune diseases associated with predominant hepatic or ment. Specifically, infections such as hepatitis C virus (HCV) may
biliary clinical manifestations, with no evidence of infectious trigger a process of molecular mimicry leading to exaggerated
disease. Based on specific cellular targets, we can distinguish immune responses against self-components with structural
autoimmune hepatitis (AIH) targeting hepatocytes from primary homology. In support of this hypothesis, it has been demonstrated
biliary cholangitis (PBC) (also known as primary biliary cirrhosis) that HCV shares high amino-acid sequence homology with the
and primary sclerosing cholangitis (PSC), both of which target autoantigenic target of antiliver/kidney microsomal-1 (LKM-1)
the biliary tract. Cirrhosis is the common evolution of inflam- autoantibodies, and that 10% of HCV patients are seropositive for
matory hepatobiliary diseases, regardless of the target tissue, anti-LKM-1. Nonviral environmental factors include medications,
eventually leading to liver failure. However, pathogenesis and in particular antibiotics (nitrofurantoin and minocycline), statins,
therapeutics may vary in between the spectrum of inflammatory and anti-tumor necrosis factor (TNF)-α agents (adalimumab and
1,2
hepatobiliary diseases. This chapter describes the main char- infliximab). However, the disease is slightly different from classical
acteristics of AIH, PBC, and PSC, with particular attention to AIH and usually does not require long-term immunosuppressive
clinical manifestations, pathogenesis, autoantibodies, and thera- treatment. 2
peutic options. From an immunological standpoint, liver damage is likely
orchestrated by CD4 lymphocytes, which can differentiate into
AUTOIMMUNE HEPATITIS T-helper cell-1 (Th1), Th2, and Th17 cells (Chapter 16). These
effector cells initiate a cascade of immune reactions largely
Epidemiology determined by the cytokines they produce: (i) Th1 cells secrete
Autoimmune hepatitis (AIH) is a severe liver disease affecting mainly interleukin (IL)-2 and interferon (IFN)-γ; IFN-γ is
almost all age groups worldwide. Although an accurate estimate considered the main orchestrator of tissue damage since it not
of its incidence is not available, it is believed be around 1 per only stimulates CD8 cells but also enhances the expression of
100 000 person-years, supposedly with higher incidence in HLA class I, induces the expression of HLA class II molecules
3
Scandinavia. AIH preferentially affects females, with a male:female on hepatocytes, and activates monocytes/macrophages, which
ratio of 1 : 4 and a two-peak incidence during adolescence as in turn release IL-1 and TNF-α; (ii) Th2 cells produce IL-4,
well as in the age range 30–45 years. 2 IL-10, and IL-13, cytokines that induce the maturation of B cells
into plasma cells, with consequent production of autoantibodies;
Pathogenesis (iii) Th17 cells, which arise in the presence of transforming
AIH is a chronic inflammatory disease of unknown etiology growth factor (TGF)-β and IL-6 and produce IL-17, IL-22, TNF-α,
7
resulting from the immune-mediated destruction of hepatocytes and the chemokine CCL- 20. Th17 cells, which are crucial in
secondary to a breakdown of immune tolerance against liver PBC, are being evaluated also in AIH, as an increased number
4
tissues. Both genetics and environmental factors contribute to of Th17 cells has been reported in the peripheral blood and liver
the development of the disease. Genetics certainly represents a of patients with AIH compared with healthy controls. 8
strong risk factor for the development of AIH, as susceptibility
to AIH is strongly influenced by the large and highly polymorphic Clinical Features and Diagnosis
human leukocyte antigen (HLA) region, which contains several AIH is a complex disease with various manifestations, predomi-
5
genes related to the adaptive immune system (Chapter 5). AIH nantly in the liver, but it is not limited to this organ. The onset
has been associated with polymorphisms in the genes encoding is most frequently insidious, whereas 20–30% of patients present
the HLA class II DRB1 alleles, which have also been confirmed with an acute icteric hepatitis, which is consistently associated
in genome-wide association studies (GWAS). In particular, with peripheral hypergammaglobulinemia. Two types of AIH
expression of HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are distinguished primarily based on the autoantibody patterns:
confers susceptibility to AIH-1 in European and North American i.e., AIH type 1, with antinuclear and/or antismooth muscle
populations, whereas the DRB1*04:05 and DRB1*04:04 alleles antibodies; and AIH type 2, with antiliver/kidney/microsomal
6
are linked to AIH susceptibility in Japan, Argentina, and Mexico. type 1 antibody and/or antiliver cytosol type 1 antibody. Type
Interestingly, DRB1*13:02 and DQB1*03:01 alleles were found 1 AIH (AIH-1) can affect people of any age and sex, and it is
2
to be protective. Moreover, certain HLA alleles have been associ- associated with expression of HLA-DRB1*03:01. AIH-1 patients
ated with AIH clinical manifestations, response to treatment, are more likely to be male, to present with high immunoglobulin
and prognosis. G (IgG) levels, and to be positive for antinuclear antibodies/
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