Inborn Errors of Immunity Committee (IEI) - Activities

 

IUIS Expert Committee on Inborn Errors of Immunity – Newsletter Report, June 2018

This is my first newsletter in the capacity as Chair of the IUIS Expert Committee on Inborn Errors of Immunity (previously Primary Immunodeficiencies). I joined this committee in 2015, at a time when Prof Bobby Gaspar (Great Ormond St Hospital, London, UK) was Chair. Bobby was succeeded by Prof Kate Sullivan (Children’s Hospital of Philadelphia, USA) in 2016, and it was with great excitement (and some trepidation) that I was invited to succeed Kate earlier this year. I have greatly enjoyed being on this committee and really appreciated the excellent leadership of both Kate and Bobby, from whom I have learnt a great deal – I know that I have large shoes to fill.

 

I thought I would take this opportunity to introduce myself to IUIS. Unlike many previous chairs (and even members) of our committee, I am not a clinician – however, I have always had a great passion for human immunology. Like the careers of many individuals, numerous serendipitous events lead me to study primary immunodeficiencies – as such, I have been working in this field for nearly 20 years now, firstly focusing on a single inborn error of immunity (SH2D1A, which is mutated in X-linked lymphoproliferative disease) but now we study a very broad range of primary immunodeficiencies to understand the requirements for generating effective immune responses in humans but also to elucidate mechanisms of disease in affected individuals. I have been fortunate to collaborate with, and benefit from the generosity and collegiality of, many former and current members of the IUIS Expert Committee on Inborn Errors of Immunity. Thus, being invited to join this committee was very humbling and rewarding, and becoming the Chair represents a great opportunity for me to continue the outstanding work the committee and previous Chairs have done for over the past 3 decades.

The IUIS Expert Committee on Inborn Errors of Immunity committee is tasked with maintaining a list of immunologic disorders. The rate of discovery of genetic variants underlying immune dysregulatory conditions – infection, autoimmunity, allergy, malignancy – continues remarkable. his has been facilitated by the access to and affordability of next generation sequencing (NGS) technologies and platforms that enable unbiased and rapid detection of genetic variants in affected individuals and the ability to establish causation and contribution of these variants to disease pathogenesis. The explosion in discovery of inborn errors responsible for novel immunological diseases of the immune system is illustrated in the graph below. This depicts the annual accumulated number of genes identified that, when mutated, cause disease. In 2011, ~200 gene defects had been identified, and this was almost exclusively through targeted/traditional approaches such as linkage analyses, homozygosity mapping, and sequencing candidate genes. Today, >350 gene defects have been discovered, with the vast majority of these being resolved by NGS approaches, such as whole exome and whole genome sequencing. In the last 18 months alone, >50 gene defects have been discovered – with more and more centers routinely performing NGS, and even incorporating this into the work up of patients with atypical clinical presentations, this number and rate of discovery will only increase in the weeks, months and years ahead.

 

The reason I am emphasizing this is because one of the major goals of the committee is to judiciously assess the reporting of novel variants and maintain a detailed and current list of primary immune dysregulatory conditions. The most recent update was published in January in the Journal of Clinical Immunology – this is a key resource for the fields of clinical and basic immunology, evidenced by this publication being dowloaded >5000 times. As this list of gene defects is routinely used as a reference to categorise and predict the pathogenicity of variants identified in patients by NGS, it is imperative for us as a committee to remain abreast of reportings of all genetic defects attributed to causing immunological diseases. Due to the rapid rate of publication of novel gene defects, we are thus committed to providing an update to the list of gene defects every 6 months – this update is available on the IUIS website

 

Upcoming activity for the IUIS Expert Committee and its members on Inborn Errors of Immunity includes:

  • a meeting held as part of the 18th Biennial Meeting of the European Society of Immunodeficiencies in October 2018;
  • the major biennial meeting in February 2019 where content of the next published update of the genetic and phenotypic classification of Inborn Errors of Immunity will be ratified.
  • working with the Clinical immunology committee to support educational activities
  • educational initiatives, with several members of the committee attending as teaching faculty at the LASID (Latin American Society of Immunodeficiencies) Summer School, to be held in Medellin, Columbia in August 2018
  • attendance at the Jeffrey Modell Foundation Primary Immunodeficiency meeting, to be held in New York in September 2018, providing opportunities
  • liaise with IUIS to ensure participation of our committee members, as well as an appropriate symposium session on Inborn errors of immunity, at the IUIS meeting to be held in Beijing in 2019.

Prof Stuart Tangye
Garvan Institute of Medical Research, NSW, Australia


Last meeting

During its last meeting in February 2017, the committee began the work of updating the list of disorders.  Historically, the list has been published as a journal article and that will be forthcoming.  However, in acknowledgement of digital sources offered by IUIS and the need for a more nimble approach, this list is now available for direct download on the IUIS web site. This list can be used to design sequencing panels, ICD code lists and diagnostic algorithms.  The download list also allows sorting by gene name and inheritance when opened using a database application such as Excel.

 

Current activities

  • To review national and international guidelines for the diagnosis and or management of immune deficiencies by expert groups on request. Liaison – Luigi Notarangelo
  • To assist with the revision of diagnostic criteria for primary immunodeficiencies with the IUIS Clinical Immunology committee and the European Society for Immune Deficiencies. Liaison – Mary Ellen Conley
  • To produce a simplified version of the IEI Classification Tables for the general public. Liaison – Aziz Bousfiha
  • To assist Orphanet and the World Health Organisation in the revision of the International Classification of Diseases (ICD) codes for the primary immune deficiencies, version 11, due to be published in 2015. Liaison – Mimi Tang
  • To ensure the continued inclusion of therapeutic immunoglobulin in the World Health Organisation Essential Medicines Lists. Liaison – Jose Franco
  • To encourage, with the International Patient Organisation for Primary Immunodeficiencies, the implementation of the recommendations from the IUIS IEI position paper on the Safety and Availability of Immunoglobulin (1999) including: the avoidance of blood donation by individuals who have received blood or blood products in the past; recording of all batch numbers for tracing in the event of any pathogen transmission; to attempt (with the patient organisations) to obtain ante-mortem permission for post-mortem examination in all patients with primary immune deficiencies in countries in which post-mortem examinations are permitted; to consider advice on the routine immunisations needed for patients with primary immune deficiencies. Liaison – Jose Franco

 

Previous activities

  • Report on classification of IEIs published biennially since 1973. Latest version (2009) is available online
  • Availability of immunoglobulin – Successful application to WHO Essential Medicines List 2007 and WHO Essential Medicines List for Children 2008
  • Safety of immunoglobulin therapies – Position paper published in Clinical and Experimental Immunology in 1999


Relationship with IUIS

The IEI committee liaises with the following IUIS committees:

  • IUIS Committee on Clinical Immunology - particularly in relation to diagnostic criteria and availability of new therapies – Liaison -Mary Ellen Conley
  • IUIS Committee on Education - advertisement of schools for young investigators run by European Society for Immune Deficiencies (winter, spring and summer schools), US Clinical Immunology Society, Latin American Group for Immune Deficiencies and the S Asia Pacific group; facilitation of exchange of students from different regions; to encourage new groups such as the Federation of African Immunological Societies to establish similar educational opportunities for IEIs
  • IUIS Committee on Quality Assessment and Standardization – particularly in relation to QA for diagnostic procedures in IEIs, such as test immunization responses.

Sponsors

We are grateful to the following for their support, without which the committee would not be able to meet these responsibilities:
Baxter Healthcare, Octapharma, Grifols, Talecris and CSL-Behring.

 
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