Differential Expression of HLA-DQ-α/β In Multiple Sclerosis Patients Who Are Non-Responsive To Treatment With Interferon-β

Manuel Comabella, M.D.

Institut de Recerca

Funded in September, 2006: $100000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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The Immuno-Genetics of Successful vs. Failed Responses to Multiple Sclerosis Treatment

This study will explore the role of a genetic factor in determining whether or not multiple sclerosis (MS) patients respond to current immune-based therapies. 

In autoimmune MS, the body’s immune cells mistakenly attack the “myelin” sheath.  This sheath insulates nerve cell axons (communication cables) and ushers electrical communication signals from one nerve cell to another in the brain and spinal cord.  Myelin damage is not repaired. One potential cause of repeated myelin damage may be that errant (autoimmune) T cells are not effectively controlled. Alternatively, or in addition, faulty immunity may occur at the site of myelin inflammation, perpetuating tissue damage.  Three recently approved biologic products (Betaseron®, Rebif® and Avenex®), all of which contain Interferon-beta (IFN-β), work well in some MS patients, but not in others.  These biologics are thought to dampen the immune system’s production of autoimmune inflammation and reduce inflammation that has occurred in myelin.  

The investigators compared the gene profiles of “good” and “bad” MS-patient responders to IFN-β treatment.  They found that the proteins produced by HLA-DQ genes are produced in greater amounts in good responders compared to bad responders. The researchers now will determine whether a specific form of a the HLA-DQ gene is related to this difference in response to IFN-β drugs, studying blood from 20 good responding and 20 poor responding MS patients. 

Significance:  This is a first step in efforts to determine whether variability in MS patients' responses to IFN-β drugs is related to a specific genetic factor. It could lead to a pre-treatment test to determine which MS patients are likely to derive benefit from current INF-β therapies.  The research also may lead to an understanding of how this gene is involved MS autoimmunity.

ABSTRACT

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Differential Expression of HLA-DQ-α/β In Multiple Sclerosis Patients Who Are Non-Responsive To Treatment With Interferon-B

We have recently studied biomarkers related to the response to interferon-ß (IFN-ß) treatment in patients with multiple sclerosis (MS). In a cohort of 55 clinically well-defined IFN good responders (GR) and bad responders (BR), we employed gene expression profiling of all known human genes by whole genome oligonucleotide microarrays. Prominent among the genes differentially expressed in GR versus BR at baseline and at various time points during treatment were both HLA-DQ-α and –DQ-ß, but no other polymorphic or non-polymorphic HLA-class I or –class II gene. IFN-GR demonstrated higher HLA-DQ expression at baseline and each subsequent time point. HLA-class II genes confer by far the largest part of the genetic risk for MS, and certain HLA-DR alleles and –DQ alleles, which are in close linkage disequilibrium, have been associated with the disease. However, it is at present not clear, how HLA-class II molecules contribute to the autoimmune process.

Studies of autoantigen-specific CD4+ T cell responses in MS suggest that HLA-DR molecules are more important as restriction elements of proinflammatory autoimmune T cells. Very few autoreactive T cells that are restricted by HLA-DQ have been described in MS, and data from a number of infectious diseases, but also from transplantation, allergic diseases, and autoimmune processes indicate that HLA-DQ may be more important for regulatory than effector T cell responses.

Since type I interferons, i.e. the different α-interferons and ß-interferon, are critical for anti-viral responses, we speculate that the differential expression of HLA-DQ-α/β in IFN-ß-treated non/poor-responding MS patients will provide important clues not only with regard to this particular treatment in MS, but also with respect to the role of HLA-DQ in controlling immune responsiveness and in the role of differential IFN-ß expression for the host response to viral agents in MS etiology or pathogenesis.

We will combine various methodologies, including flow cytometry, cellular immunology techniques, single nucleotide polymorphism mapping of the HLA region on chromosome 6p21, high resolution HLA typing, the isolation and functional testing of various immune populations, and viral stimulation assays to investigate the potential role of the differential HLA-DQ expression in IFN-GR and IFN-BR.

INVESTIGATOR BIOGRAPHIES

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Manuel Comabella, M.D.

Dr. Comabella trained in neurology at the Neurology Department of the Vall Hebron University Hospital in Barcelona, Spain, after attaining his M.D. Holding a post-doctoral fellowship, he spent 3 years at the Center for Neurologic Diseases at the Harvard Medical School in Boston. There he studied the immunological effects of drugs commonly used for treatment of multiple sclerosis (MS). At present, Dr. Comabella holds a senior research position and is leader of Neuroimmunology research in the laboratory of the Neuroimmunology Unit of Vall d’Hebron University Hospital and Research Institute.

Regarding specific research lines, he focuses on a combination of genetic and immunological studies in MS. He contributed to the data obtained from the Spanish cohort to the GAMES study—a large international effort to map genetic susceptibility loci of MS via whole genome microsatellite screens. Recently, he has initiated a project stemming from the GAMES consisting of saturating chromosomal areas by all known SNPs in order to fine map susceptibility genes. He is also interested in finding biomarkers of good or bad response to treatment of MS by means of a combination of 500,000 SNP arrays, whole genome gene expression profiling by microarrays and proteomics.