Recent advancement in understanding primary immunodeficiencies

The International Union of Immunological Societies [IUIS] published an updated classification in 2011 of primary immunodeficiency diseases [PID] as part of their on-going work to collate and disseminate PID research findings reported worldwide.  This month, Parvaneh et al. provide a compendium of reports that have been published since the 2011 update (J Allergy Clin Immunol 2013; 131(2):314-323). 

Following the 2011 IUIS classification, newly published reports are summarized under combined immunodeficiences, syndromes with associated immunodeficiencies, predominant antibody defects, immune dysregulation, congenital phagocytic defects, defects of innate immunity, and autoinflammatory disorders.  Some highlights are provided below.

TCRα gene mutation/TCRαβ T cell depletion: Two patients from unrelated Pakistani families were identified after presenting with infection susceptibility, autoimmunity, T cell proliferation dysfunction, but normal antibody responses.  Both patients’ T cells were missing surface expression of TCRαβ, though CD3+ cells expressed TCRgd.  A homozygous mutation in the T cell receptor alpha constant [TRAC] gene was found in both patients.  Both patients were treated successfully with sibling bone marrow transplants. 

WIP deficiency/Wiskott-Aldrich Syndrome-like phenotype:Wiskott-Aldrich protein [WASP] binds with WASP-interacting protein [WIP] to form a stable complex.  A Morrocan infant presented with symptoms suggesting WAS, such as recurrent infections, eczema, and T cell lymphopenia.  Sequencing demonstrated normal WASP sequence and expression, though WASP was undetectable in the patient’s cells.  Additional analyses determined that WIP was absent as well and that a homozygous nonsense mutation was present in the WIPF1 gene, coding for WIP.  The patient was treated with unrelated cord blood transplantation at 4½ months and was reported to be thriving at 21 months. 

Parvaneh et al. conclude noting that reports of novel primary immunodeficiencies are increasing. There is no formal evidence that the incidence of PID has increased; however, improved treatment, allowing long-term survival may have increased the pool of mutant alleles in the general population.  The growing number of reportsofnew PIDs probably reflects several factors including:1) the increasing awareness of practicing physicians regarding the clinical and laboratory manifestations of PID; 2) improved networking (or collaboration) within the international PID community; 3) new immunological techniques to analyze leukocyte subsets and function; and finally 4) usage of next generation sequencing (whole exome sequencing) which has had a major impact on the field.  The authors emphasize the importance of this expansion in knowledge, not only to improve the patients’ outcomes, but also to contribute to the general understanding of these immune diseases.