Primary Immune Disorders (PID)


This study focuses on genetic causes of severe immune disorders, also known as Primary ImmunoDeficiencies (PID), with the largest category being Common Variable ImmunoDeficiency (CVID), but also including those with “Extreme” Autoimmunity as well as general PID.

Immune homeostasis in healthy individuals is maintained by at least 30 different types of well characterised immune cells that interact with each other and soluble factors like cytokines, chemokines and interleukins. Genetic mutations can severely compromise the immune system’s ability to fight infection or maintain tolerance and prevent premature autoimmune manifestations.

These immune diseases are referred to as primary immunodeficiency (PID). These PIDs are generally of an inherited nature and are represented by broad categories of which common variable immunodeficiency (CVID) is the largest category. Together, these disorders may also include the “extreme phenotype” of premature and severe autoimmunity. These conditions are all chronic with significant impact on patient well-being and survival and those with CVID require life-long support with expensive blood-derived immunoglobulin concentrates whilst certain PID cases must be transplanted with donor blood stem cells at early age or cured by gene therapy (as exemplified by current trials of PID gene therapy at GOSH BRC). For PID in general about 200 genes are known to be causative, nonetheless more than 50% of the phenotypic severe immunodeficiencies cannot yet be explained and for CVID so far only 7 genes have been identified, but coding mutations in these only explain about 5-10% of cases. Modern genomics techniques, which include exome-sequencing (exo-seq), promise to identify the genetic causes of these conditions if of coding nature.

To date about 200 genes have been officially accepted by the International Union of Immunological Societies as being implicated with PIDs. In spite of the vast number of genes already identified by classic linkage and candidate gene studies, most patients and particularly those with CVID cannot be explained by mutations in the coding fraction of these genes. It is plausible to postulate that the remaining genes to be discovered will be numerous and dispersed across the genome. The classic pattern of inheritance for the majority of PIDs is autosomal recessive but there are several examples of X-linked “de novo” presentation in a pedigree. We assume a similar mode of inheritance for a considerable subset of the currently unresolved cases, but more complex genetic mechanisms may underlie the disease phenotype in a fraction of the 1000 cases we propose for sequencing.

Recruitment Criteria:

There are three sets of recruitment criteria for patients to enter the BioResource via PID.

CVID: Patients over 4 years of age: serum IgG below lower limits of normal for age and IgA below lower limits of normal for age, IgM may be low or normal; failure of production of specific antibodies as defined locally – or at least documented failure of specific antibody production to a minimum of 2 antigens (documented immunization or exposure); inclusion of a single CVID case per CVID family, although DNA samples from affected relatives are available for most index cases or will be otherwise collected).

“Extreme” autoimmunity: Patients with aggressive autoimmune disease with early age onset will be included for exo-seq. This will include patients with clinical features of immunodeficiency/chronic lymphoproliferation with autoimmunity but without mutations in classically associated genes. Cases of informative pedigrees will be prioritised.

PID: Recurrent (and/or unusual) microbial infections suggestive of severely defective innate or cell-mediated immunity. Patients have been extensively characterised through standardised cellular immunophenotyping and functional testing for lymphocytes and myeloid cells. Patients with mutations in the most likely candidate genes known to results in PID/CVID will be excluded.

Centres at which PID is currently recruiting:

Barts Health NHS Trust
Belfast Health and Social Care Trust
Birmingham Heartlands Hospital
Birmingham University NHS Trust
Cambridge University Hospitals NHS Foundation Trust
Cardiff & Vale University UHB

Epsom & St Helier University Hospitals NHS Trust
Frimley Park Hospital NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust, London
Heart of England NHS Foundation Trust
Hull & East Yorkshire NHS Foundation Trust
Imperial College Healthcare NHS Trust,
Leeds University Hospitals
NHS Greater Glasgow and Clyde
Northern Lincolnshire & Goole NHS Trust
Oxford University NHS Trust
Papworth Hospital NHS Trust, Cambridgeshire
Plymouth Hospitals NHS Trust
Royal Brompton & Harefield NHS Foundation Trust, London
Royal Free London NHS Foundation Trust, London
Salford Royal NHS Foundation Trust
Sandwell & West Birmingham Hospitals NHS Trust
Sheffield Teaching Hospitals NHS Foundation Trust

University College Hospital, London
University Hospitals of Leicester NHS Trust
University Hospitals of North Midlands NHS Trust

Professor Ken Smith, University of Cambridge
Professor Adrian Thrasher, Great Ormond Street Hospital
Professor Taco Kuijpers, Emma’s Children’s Hospital

If you feel your NHS site would be suitable to recruit for PID please get in contact with the PID Study Coordinator Matthew Brown