Advancing immunology and primary immunodeficiencies in the genomic era: The importance of being collaborative

We celebrate the day of Immunology with an interview with Sergio Rosenzweig, Deputy Chief of the Immunology Service at the Clinical Center, NIH and the Co-Director of the Primary Immunodeficiency Clinic, NIAID, NIH and Associate Editor for Frontiers in Immunology and for Frontiers in Pediatrics.

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After more than 20 years of experience as pediatrician and researcher in the field of primary immunodeficiencies, Dr Rosenzweig has no doubt: the best is yet to come.

 “It is a fascinating time to be practicing medicine: if you take into consideration that the first genome was sequenced in 2003 and just six years later, in 2009, the first patient that diagnosed using next-generation sequencing, with a test cost reduction of 1 million times (from approximately 1billion dollars to 1 thousand dollars, that is just amazing” he said.

Through omics technologies, the field of primary immunodeficiencies field is evolving at an exponential rate “We discover, on average, more than one new gene associated with primary immunodeficiencies per month”, he explained, “and this is teaching us so much: we thought we knew about those diseases, but now we are completely rethinking the way we study them.”

 

Can you tell us a bit more about primary immunodeficiencies and what is their impact in the population?

Primary immunodeficiencies are genetic disorders that primarily affect the immune system and confer susceptibility to infections, immune dysregulation, autoimmunity and cancer. As for the it is somewhat debated. Some claim that primary immunodeficiencies occur 1 in 1200 newborns, while others say 1 in 20000. I guess the real incidence is likely somewhere in the middle: in general we say 1 in 10000 newborns. We do have precise numbers for one specific type of immunodeficiency, Severe Combined Immunodeficiency (SCID), because now we are screening newborns for it in the US and we know that the incidence is 1 in 58000 newborns.

In particular for SCID, early diagnosis have had an impressive beneficial impact in patient’s outcome. SCID patients need to be immune-reconstituted in order to survive. In other words, without a new/healthy immune system, this disease is lethal. One of the treatments of choice for SCID is hematopoietic stem cell transplant also known as bone marrow transplant, a procedure that allows for the complete reconstitution of the immune system. The earlier these patients are transplanted, the better the outcome. If patients are transplanted within the first three and a half months of life (which is the average time for patients to get infections), the percentage of survival is 95%. For such severe disease, being able to cure 95% of these patients is an amazing achievement. If patients are transplanted later the success rate changes significantly. With newborn screening for SCID we are diagnosing patients who are completely asymptomatic, this give us the possibility not only to intervene earlier but also to change completely the future for these children.

In you recent paper “Loss of B Cells in Patients with Heterozygous Mutations in IKAROS” published in the New England Journal of Medicine you used whole-exome sequencing and array-based comparative genomic hybridization to show the link between mutations in the transcription factor IKAROS and the loss of B cells. How have the new “Omics” technologies changed the investigation and diagnosis of immune system disorders?

What we call unbiased genetic diagnostic approach has strikingly modified the way we practice medicine. The challenge with this kind of approach is not anymore the lack of data, but rather, the excess of data. 6 billion nucleotides, 3 billion base pairs, 180000 exons, 20000 genes, 3.5 million possible changes per genome: the difficult part is to make sense out of all this information. Which of these changes are associated with a given disease? Linking genetic changes to clinical phenotypes and validating their biologic effect is where most of our time is spent.

Within the unbiased genetic diagnostic approach there are different methods available. The more accessible is targeted next-generation sequencing: we select a number of disease causing genes associated with the phenotype of interest (in our case, primary immunodeficiencies) and we screen the DNA of the patients for changes in these genes. The next level is whole-exome sequencing, where we screen all the exons of all the genes present in the genome. Currently we are moving to whole-genome sequencing: we have to consider indeed that exons are just 1% of all of our genetic information and 15 % of the mutations that cause diseases are scattered along all the other parts of the genome.

The omics approach helps a lot, it was a quality change in terms of diagnosis. However physical examination, asking questions and tailoring the study to your patients is still a critical step in order to get you the right answer. Just to make an extreme example: if you have a patient with Down syndrome and you do whole-exome sequencing without checking the number of gene copies (also known as copy number variation) you will probably find no difference compared to a person without Down syndrome. We can use the more sophisticated tests, but if we do not adequately examine or interrogate our patients you we will miss a lot of useful information while performing a lot of unnecessary and expensive tests in the way.

So whole-genome approach is a fantastic tool but it has to be tailored to the patient and combined with the clinical knowledge and all the other tools that we already have in order to make it really useful.

You were at the Clinical Immunology Society meeting two weeks ago, what for you was the most notable breakthrough presented at the meeting?

During the meeting we learnt about several new genes that are associated with various primary immunodeficiencies, from combined immunodeficiencies to neutropenia and fungal infection susceptibility. The speed by which this field is evolving, as a result of omics technologies, is incredible and it is difficult to keep up. That is also why these meetings are so important: they are not just a way to learn about new discoveries, but we network together and we plan our future investigations there.  It is about sharing experiences and building new collaborations for future discoveries and improved patient care.

The use of new technologies for primary immune deficiencies is also the subject of the Research Topic “Exploiting New Technologies for Immune System Evaluation in Primary Immune Deficiencies” you hosted in Frontiers in Immunology. Can you tell us a bit more about your experience as Topic Editor for Frontiers?

It was very helpful because it allowed me to expand my scientific horizons. Because the friendly and fast way Frontiers works, it was a true collaborative experience. The collection of articles covered various aspects of how these new omics technologies are helping the primary immunodeficiencies community to evolve.

It was not just a scientific experience, it was a learning experience. It was a community experience on how we share data and how we can take advantage of having a friendly and collegial community.

Aida Paniccia, PhD
Journal Operations Specialist
Frontiers in Immunology
immunology@frontiersin.org

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