The genetic basis of severe combined immunodeficiency and its variants

The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Application of Clinical Genetics 08/2012; 5:67-80. DOI: 10.2147/TACG.S18693
Source: PubMed


Severe combined immunodeficiency (SCID) syndromes are characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplant. SCID comprises genotypically and phenotypically heterogeneous conditions, of which the genetic basis for approximately 85% of the underlying immunologic defects have been recently elucidated. A major obstacle in deciphering the pathogenesis of SCID syndromes is that different mutations in a single gene may give rise to distinct clinical conditions and that a similar clinical phenotype can result from mutations in different genes. Mutation analysis is now an important component of the complete evaluation of a patient with SCID since it has a dramatic impact on many aspects of this potentially life-threatening disease such as genetic counseling, prenatal diagnosis, modalities of treatment, and, eventually, prognosis. Dr Robert Good, one of the founders of modern immunology, described the SCID syndrome as "experiments of nature." By understanding the cellular and genetic basis of these immunodeficiency diseases and, eventually, normal immunity, we optimize the "bedside to research laboratory and back again" approach to medicine.

  • Source
    • "An umbrella term used to cover many austere T-cell primary immunodeficiencies is severe combined immunodeficiency (SCID). The illness is termed severe because it is fatal and is described as combined because although it is often directly T lymphocytes which are affected, B lymphocytes cannot adequately function without the help of T cells and thus both cellmediated and humoural immunity are lost (Tasher and Dalal, 2012). SCID is considered a paediatric emergency with patients appearing well at birth but after a few months, following the subsequent loss of maternal antibody, often present with diarrhoea , sepsis, otitis and an overall failure to thrive (Kelly et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Severe combined immunodeficiency (SCID) has many phenotypes, including those which result in the formation of T cells but render them incapable of an optimal level of proliferation following stimulation by an antigen. Phytohaemagglutinin (PHA) is a mitogen commonly used to assess T-cell proliferation, although anti-CD2/CD3/CD28-coated beads may provide a more physiological trigger. Some patients and healthy controls display poor T-cell proliferation (<45%) in response to PHA, but may be capable of an increased percentage proliferation when stimulated by another mitogen. This study aimed to develop an anti-CD2/CD3/CD28 bead-based T-cell proliferation assay and to compare T-cell proliferation generated by two mitogens both in healthy controls and in poor responders to PHA. A bead-based T-cell proliferation assay was optimized and validated. Peripheral blood mononuclear cells (PBMCs) were extracted from whole blood samples of 10 healthy controls and 3 poor PHA responders. PBMCs were incubated with carboxyfluorescin diacetate succinimidyl ester and three separate stimulants: PHA, Beads only and Beads plus IL-2. Flow cytometry was performed on Day 6, following fluorochrome staining with CD3 PerCP and CD4 APC, to identify CD4+ T cells. No significant difference was found between the results generated by PHA- or Bead stimulation in 10 healthy controls. A strong positive correlation was observed between the use of the Beads alone and the addition of IL-2. A varied response to the Beads was produced among the poor PHA responders. It has been concluded that the bead-based assay will be run alongside every PHA test in the Oxford Immunology diagnostic laboratory. The step to add IL-2 on Day 3 will not be included as this did not significantly impact T-cell proliferation. The Bead assay provides a more physiological addition to the current PHA test and may be useful in assessing T-cell proliferation in those patients who respond poorly to PHA. However, some individuals who respond poorly to PHA may also respond poorly to the anti-CD2/CD3/CD28 Beads.
    Preview · Article · Dec 2014 · Bioscience Horizons
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite its critical role in supplying naïve T cells to the circulation, the thymus is particularly sensitive to immune injury, such as that caused by cytoreductive chemo- or radiation therapy, shock, infection and graft versus host disease (GVHD). Crucially, insufficient thymic recovery has been directly correlated with increased risk of opportunistic infections and poor clinical outcomes in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prolonged immune deficiency is particularly pronounced in older patients whose thymi are already significantly impaired due to age-related thymic involution. Previous preclinical studies have revealed several strategies that can enhance thymic function and immune reconstitution after transplant, including sex steroid ablation (SSA), growth factors (growth hormone, GH, keratinocyte growth factor, KGF, insulin-like growth factor 1, IGF-1, interleukin-7, IL-7) and ex vivo generated precursor T cells (preT). In addition, recent studies have shown that other approaches, such as interleukein-22 (IL-22) and nutritional changes, may represent additional candidates to enhance thymic regeneration. In this review we provide updates on these strategies and comment on their potential to be translated into clinical therapies.
    No preview · Article · Oct 2013 · Immunology letters
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic counselors bring unique and important expertise to health care teams that serve patients with genetic conditions treated by hematopoietic stem cell transplantation (HSCT). Genetic counselors are master’s-trained allied health care professionals who work in collaboration with physicians to guide patients through the complexities of heritable conditions and emerging technologies, including through the diagnostic, HSCT treatment, and post-HSCT processes. This article will review the history of HSCT for genetic conditions, the role of the genetic counselor throughout the HSCT process, and the evolving and expanding role of genetic counselors in current and future stem cell therapies.
    No preview · Article · Jun 2014
Show more