T-cell receptor and B-cell receptor repertoire analysis in patients with immune-mediated liver disease

Background: Primary biliary cirrhosis (PBC), primary sclerosing cholangitis
(PSC) and IgG4-associated cholangitis (IAC) are disabling diseases of the
biliary tract. Their etiology is incompletely understood, but it is generally
accepted that deregulation of the immune system contributes to these
conditions. Treatment options are focussed on the inhibition of the progressive
destruction of the biliary tract and the consequences of chronic cholestasis
including fibrosis, cirrhosis, and the risk of hepatobiliary malignancy, by
decreasing bile toxicity, by improving secretory function of hepatocytes and
cholangiocytes, and by reducing local damage caused by chronic inflammatory
activity. However, these strategies often lead to incomplete responses. Novel
therapies are, therefore, needed to more effectively protect these patients
against biliary fibrosis, cirrhosis, malignancy and the need for liver
transplantation.

T cells and B cells with their unique receptors, respectively the T-cell
receptor (TCR) and B-cell receptor (BCR), are major components in the normal
adaptive immune response. However, they are also implicated in the pathogenesis
of systemic auto-immune diseases such as rheumatoid arthritis (RA),
spondylarthropathies (SpA) and systemic lupus erythematosus (SLE). In
small-scale analyses of T cell repertoires of patients with primary biliary
cirrhosis clonal expansion was reported, but these results should be verified
as patient numbers were limited.

When B- and T-cells become activated, they undergo clonal expansion, producing
multiple cells with identical TCRs or BCRs on the cell surface. Previously it
has been hypothesized that clonally expanded T-cells or B-cells or so-called
disease specific clones are present and possibly causative in auto-immune
diseases. Specific targeting of such clones may eradicate antigen-driven immune
responses, providing a novel therapeutic strategy to control these diseases.
To identify and quantify specific clones, a microarray based technique was
developed in the Department of Clinical Immunology and Reumatology that is able
to screen the complete TCR and BCR repertoire for dominant clones or for
quantitative changes in this repertoire.

Objective: Primary objectives: To screen TCR/BCR repertoires in patients with
primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and
IgG4-associated cholangitis (IAC).
Secondary objectives: To determine the influence of disease activity and
treatment on the repertoire.

Study design: Explorative study. The work will include patient recruitment and
collection of blood samples. Lymphocyte DNA will be isolated from tissue by
laser capture microdissection if liver biopsy specimens are available. The TCR
and BCR repertoire will be analysed for specific clones using a novel
microarray sequencing technology that was validated for repertoire screening in
rheumatoid arthritis patients.

Burden:
Patients will visit the Investigator a total of 5 times during 10 years.

Risks:
The risks associated with participation in this study are those associated with
the performance of a vena punction. These risks include hematoma, protracted
bleeding and flebitis.