News at Medicine - October 2010 - New study identifies a possible cause of a specific type of immunodeficiency disease

New study identifies a possible cause of a specific type of immunodeficiency disease
October 20, 2010
Dr. Mani Larijani, BioMedical Sciences, is the senior author on a new study that has found for the first time that a specific type of immunodeficiency disease is caused by defective repair of DNA damage.

The study, titled “Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations,” was published on line Oct. 12 in Immunogenetics and is in press for print.  It was a multi-centre study involving Memorial, York University, University of Toronto and Karolinska institute in Sweden. 

Dr. Larijani explained the common variable immunodeficiency disease (CVID) is the most frequently diagnosed primary immunodeficiency, characterized by a variety of clinical symptoms, such as recurrent infections and lymphoproliferative cancers.  Due to the wide variability of symptoms amongst patients, molecular causes of the disease had previously remained unknown, although general phenotypic aberrations in the immune response such as specific perturbations in populations of B and T lymphocytes had been reported. 

Dr. Larijani’s research focus is on DNA damaging processes which are involved in the generation of the immune response.  He explained that these processes are actually a double-edged sword due to mutations and chromosomal translocations that lead to the transformation of normal lymphocytes into lymphoma/leukemias. 

He said that some CVID patients often suffer from deficiencies in a specific arm of the immune response which requires induction of DNA damage and subsequent error-prone repair of said damage in lymphocytes.

“Coupled with the fact that these patients exhibit higher frequencies of lymphoproliferative cancers which also have also been shown to result from defective repair of DNA damage, we saw a common thread and thus asked whether these patients suffered from abnormal DNA damage repair,” he explained.  “We analyzed the sequences of genes that we know undergo damage in lymphocytes from patients and healthy individuals and found that indeed our results were remarkably consistent with defects in a very specific type of DNA-damage repair process.” 

Dr. Larijani said that every cell in our body undergoes endogenous DNA damage such as those occurring as a result of mistakes during replication of its genome, as well as DNA damage caused by external sources such as those induced in skin cells as a result of UV irradiation.  “Thus, all cells have an arsenal of many complex and redundant pathways to detect and repair DNA damage.  Defects in many of these processes have hallmark signatures, and we picked up the signature of one of these defects in a sub-set of CVID patients.”

Dr. Larijani said this study was possible due to the collective expertise of all the authors involved, ranging from clinical understanding of the disease to obtaining DNA sequences from patients and healthy individuals, sequence analysis using the latest bioinformatics software and an understanding of the intricacies of the biochemical mechanisms of specific cellular pathways involved in DNA repair. “Our future goal is to further characterize the exact molecule(s) in this specific DNA repair process which mediate the disease-causing defect.”

View the entire article here.