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It all began in 1963 when two American pediatricians, Fred Rosen and James Bougas, reported the case of a 37-year-old woman suffering from recurrent infections and severe bronchiectasis - dilatation of the bronchi - for 10 years.
A disease of the immune system
It was not until 1975 that the analysis of the clinical and biological characteristics of 37 family members over three generations was published. Abnormalities in the immune response, the system that is supposed to protect us from infection, were identified in 12 family members, although only three of them had recurrent infections. In addition, 10 family members had high levels of IgM immunoglobulins, the antibodies produced by the body in response to infection, and seven had low levels of IgG, IgA or both.
This analysis based on immunohistochemistry over three generations suggested that the antibody deficiency had an autosomal dominant mode of inheritance, meaning that only one of the genes, either maternally or paternally inherited, needed to be mutated for the disease to occur. In 1979, this type of disease was named "hyper IgM syndrome" (HIGM) SYNDROME.
60 years to discover the genetic origin
"By combining the data from the 1975 study with more recent information, we showed that 15 members of the family suffered from recurrent respiratory infections - usually in late childhood or early adulthood," notes Sven Kracker, CNRS research director in the human lymphohematopoiesis laboratory headed by Isabelle André at the Imagine Institute.
His laboratory then decided to sequence the entire exome, i.e. all the parts of the genome expressed to produce proteins, of one of the members of this family suffering from hyper IgM syndrome.
Sequencing initially revealed the presence of a mutation in this individual, which was then found in six other family members who all suffered from recurrent infections. Five of these seven individuals had the hyper IgM syndrome. This is a so-called nonsense mutation of R190X," describes Sven Kracker. The replacement of a single letter of the genetic code prevents the complete transcription of the gene into protein. This results in the production of a truncated protein that cannot perform its assigned functions and, in addition, interacts with the normal protein present, which alters the functioning of part of the immune system and prevents it from fully performing its functions. In 2005, Anne Durandy, Inserm Research Director Emeritus and member of the laboratory had already described the deleterious effect of this mutation ".
Since 1963 when Rosen and Bougas used the available immunochemical methods to characterize what was called "dysgammaglobulinemia", technological advances have continued to better characterize this pathology. In the 1970's, advances in immunology made it possible to identify which types of white blood cells, T or B lymphocytes, were involved. Then it was the turn of genetics to shed light on this rare disease and to find its genetic origin, opening the way to a possible search for a treatment. From a more general point of view, all primary immune deficiencies have benefited from this succession of advances, since to date, more than 400 genes have been implicated in this family of diseases, and this number is increasing exponentially every year.
Nevertheless, much remains to be discovered in order to understand the 350 distinct primary immune deficiencies counted to date, and thus to improve the management of the several hundred children born each year with this disease and the thousands of people concerned in France alone.
