An introduction to Research | Current research funded by CLDF | Role of HLA and immunoregulatory genes in childhood autoimmune liver disease: a family study

Role of HLA and immunoregulatory genes in childhood autoimmune liver disease: a family study

Dr Yun MA - King’s College Hospital, London

Autoimmune diseases are caused by the body’s defence mechanism, the immune system, malfunctioning and attacking part of itself. 

There are two types of autoimmune liver disease (AILD): autoimmune hepatitis (AIH type 1 and 2) and autoimmune sclerosing cholangitis (ASC), both of which probably belong to the same disease group. AILD represents 15% of the liver disorders seen in specialised paediatric liver centres and is the most common diagnosis in children with liver disease between the ages 10-16.

It is a severe form of childhood liver disease and the majority of the children present cirrhotic liver when they are diagnosed. 75% of cases of AILD in children are in girls.  The condition can occur from the age of 6 months, is rare before 6 years and is most common between 10 and 30 years. The main treatment is by medicines which make the immune system less active, mainly steroids.  These drugs are powerful but toxic and have major side effects.  In addition, the symptoms of AILD seriously affect not only the child’s health but also their quality of life. 

It is not fully understood why the immune system malfunctions in this way but it is known that 1) there is a genetically inherited tendency to develop autoimmune disorders; 2) an impairment of negative immune regulatory mechanisms and 3) some unknown factors trigger the malfunction of the immune system which then attacks the patient’s own organs, such as a viral infection, which may have happened a long time previously, even years, before the liver disease manifests itself. 

The project
We do not know the nature of the genetic predisposition to AILD.  If we did, we would have a better understanding of what happens to cause the body’s immune system tolerant to own tissues to break down and develop AILD. 

Previous work by the King’s College Hospital team has identified that certain cells, such as CD4+CD25+ T cells, involved in regulating autoimmunity in the body are numerically and functionally impaired and that patients who possess particular HLA genes are predisposed to the development of AILD or a serious course of the disease.  This project seeks to investigate the link between the particular genes which cause predisposition and the immune response.  In particular the team hopes to identify the genetic factors involved in disease susceptibility, severity and prognosis.  The ultimate goal, and beyond the scope of this project, is to provide information useful in designing more effective treatments which are more specific and less toxic. 

The project will recruit and study 90 patients with AILD and their first degree relatives (parents and siblings); 30 patients will have AIH type 1, 30, with AIH type 2 and 30 with autoimmune sclerosing cholangitis.  Using blood samples from the patient and families and utilising modern molecular based techniques, the project will seek to identify the characteristics of a genetic predisposition to childhood autoimmune liver disease by studying links between clinical signs of disease, autoimmune responses and specific genes which have been implicated with autoimmune liver disease.  Ethical permission has been granted. 

King’s College Hospital, London has an internationally established reputation in research into autoimmune liver disease and this research team has contributed greatly to knowledge in the field.  Dr Yun Ma has established a collaboration with Dr Peter Donaldson at the University of Newcastle.  Dr Donaldson is an authority in molecular genetics of AILD and has agreed to collaborate in the interpretation of any genetic factors which may be discovered.  The scientific advisers at Children’s Liver Disease Foundation recommend this project for funding. 

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