Severe Combined Immunodeficiency Publications (7557)


Severe Combined Immunodeficiency Publications

Arch. Immunol. Ther. Exp. (Warsz.)
Arch Immunol Ther Exp (Warsz) 2017 Jan 12. Epub 2017 Jan 12.
Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663, Krakow, Poland.
J. Biol. Chem.
J Biol Chem 2017 Jan 12. Epub 2017 Jan 12.
Institute for Transfusion Medicine, University of Ulm, Germany.

The nuclease ARTEMIS is essential for the development of B and T lymphocytes. It is required for opening DNA hairpins generated during antigen receptor gene assembly from variable (V), diversity (D) and joining (J) subgenic elements (V(D)J recombination). As a member of the non-homologous end joining pathway it is also involved in repairing a subset of pathological DNA double-strand breaks. Read More

Loss of ARTEMIS function therefore results in radiosensitive severe combined immunodeficiency (RS-SCID). The hairpin-opening activity is dependent on the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which can bind to and phosphorylate ARTEMIS. The ARTEMIS C-terminus is dispensable for cellular V(D)J recombination and in vitro nuclease assays with C-terminally truncated ARTEMIS show DNA PKcs-independent hairpin-opening activity. Therefore it has been postulated that ARTEMIS is regulated via autoinhibition by its C-terminus. To obtain evidence for the autoinhibition model, we performed co-immunoprecipitation experiments with combinations of ARTEMIS mutants. We show that an N-terminal fragment comprising the catalytic domain can interact both with itself and with a C-terminal fragment. Amino acid exchanges N456A+S457A+E458Q in the C-terminus of full-length ARTEMIS resulted in unmasking of the N-terminus and in increased ARTEMIS activity in cellular V(D)J recombination assays. Mutations in ARTEMIS-deficient patients impaired the interaction with the C-terminus and also affected protein stability. The interaction between the N- and C-terminal domains was not DNA-PKcs dependent and phosphomimetic mutations in the C-terminal domain did not result in unmasking of the catalytic domain. Our experiments provide strong evidence that a physical interaction between the C-terminal and catalytic domains mediates ARTEMIS autoinhibition.

Gene repair of CD34(+) hematopoietic stem and progenitor cells (HSPCs) may avoid problems associated with gene therapy, such as vector-related mutagenesis and dysregulated transgene expression. We used CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated 9) to repair a mutation in the CYBB gene of CD34(+) HSPCs from patients with the immunodeficiency disorder X-linked chronic granulomatous disease (X-CGD). Sequence-confirmed repair of >20% of HSPCs from X-CGD patients restored the function of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide radical production in myeloid cells differentiated from these progenitor cells in vitro. Read More

Transplant of gene-repaired X-CGD HSPCs into NOD (nonobese diabetic) SCID (severe combined immunodeficient) γc(-/-) mice resulted in efficient engraftment and production of functional mature human myeloid and lymphoid cells for up to 5 months. Whole-exome sequencing detected no indels outside of the CYBB gene after gene correction. CRISPR-mediated gene editing of HSPCs may be applicable to other CGD mutations and other monogenic disorders of the hematopoietic system.

Orphanet J Rare Dis
Orphanet J Rare Dis 2017 Jan 11;12(1). Epub 2017 Jan 11.
Developmental Immunology Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Read More

Diagnosis relies on testing for FOXN1 mutations, which allows genetic counselling and guides therapeutic management. Options for treating the underlying immune deficiency include HLA-matched genoidentical haematopoietic cell transplantation containing mature donor T-cells or thymus tissue transplantation. Experience from other severe combined immune deficiency syndromes suggests that early diagnosis, supportive care and definitive management result in better patient outcomes. Without these the prognosis is poor due to early-onset life threatening infections.

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short- and long-term enzyme replacement therapy with PEG-ADA. Read More

These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency.


Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency usually diagnosed as autosomal recessive hyper IgE syndrome. We sought to reveal the varying manifestations in patients with a unique mutation in DOCK8 gene by a retrospective medical record review. Ten patients from five consanguineous families and three tribes were included. Read More

Seven patients were homozygous for the c.C5134A, p.S1711X mutation, and the remaining three patients were their siblings manifesting hyper IgE syndrome features without a genetic diagnosis. Prior to the genetic diagnosis, the clinical diagnosis was "hyper IgE syndrome" in six patients and "anti-pneumococcal antibody deficiency," "recurrent pneumonia with bronchiectasis," and "asthma with hypereosinophilic syndrome" each diagnosed once. One additional patient was diagnosed due to family history. The age of presentation varied from 1 to 16 months. Eczema was diagnosed in all patients, food allergies in three, and severe herpes keratitis or malignancy or autoimmunity in two patients. Elevated IgE was recorded in nine patients; however, in six patients, the initial serum IgE concentration was equal to or less than three times the normal concentration for age, and in these patients, the median age at IgE evaluation was 7.5 months compared with 21.5 months in patients with an initial IgE concentration above three times the normal concentration for age (P = 0.067). The spectrum of disease manifestations in patients with a unique mutation in DOCK8 is variable. The genotype-phenotype correlations may be modified by genetic and/or epigenetic modifiers beyond the monogenic effect. Younger patients tend to have lower IgE concentrations at the initial measurement of IgE.

Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3. Read More

5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.

Public Health
Public Health 2017 Jan 18;142:39-45. Epub 2016 Nov 18.
Centro Operativo AIDS, Istituto Superiore di Sanità, Rome, Italy.

Despite the wide accessibility to free human immunodeficiency virus (HIV) testing and combined antiretroviral therapy (cART), late HIV diagnosis remains common with severe consequences at individual and population level. This study aimed to describe trends of late HIV testing and to identify their determinants in the late cART era in Italy.
We conducted a population-based, nationwide analysis of the Italian National AIDS Registry data (AIDS - acquired immune deficiency syndrome) for the years 1999-2013. Read More

Late testers (LTs) were defined as people with AIDS (PWA) whose first HIV-positive test preceded AIDS diagnosis by 3 months or less. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were estimated to examine factors associated with being LTs. Joinpoint analysis was used to estimate annual percent changes (APCs) of LTs' proportion over time.
Among 20,753 adult PWA, 50.8% were LTs. Italian PWA showed a lower proportion of LTs than non-Italian PWA (46.5% vs 68.2%). Among Italian PWA, the odds of being LTs was higher in men than in women (OR = 2.62, 95% CI: 2.38-2.90); in the age groups below 35 years and over 49 years at diagnosis (OR = 1.24, 95% CI: 1.12-1.37 and OR = 1.51, 95% CI: 1.38-1.67, respectively) vs PWA aged 35-49 years; and in those infected through sexual contact as compared with injecting drug use (OR = 13.34, 95% CI: 12.06-14.76 for heterosexual contact and OR = 8.13, 95% CI: 7.30-9.06 for male-to-male sexual contact). The proportion of LTs increased over time among Italians, especially in the latest period (APC2006-2013 = 5.3, 95% CI: 3.8-6.9). The LTs' proportion resulted higher, though stable, among PWA aged ≥50 years. Conversely, an increasing trend was observed among PWA aged 18-34 years (APC = 5.3, 95% CI: 4.5-6.1). The LTs' proportion was persistently higher among PWA who acquired HIV infection through sexual contact, even if a marked increase among injecting drug users was observed after 2005 (APC = 11.4, 95% CI: 5.7-17.5).
The increasing trend of LTs' proportion in the late cART era highlights the need of new strategies tailored to groups who may not consider themselves to be at a high risk of infection. Active promotion of early testing and continuous education of infection, especially among young people, need to be implemented.