Research

The importance of vaccination and immunoglobulin treatment for patients with primary immunodeficiency diseases (PIDs) – World PI Week April 22-29, 2015.

Eur J Immunol. 2015 May;45(5):1285-6

Authors: Reda SM, Cant AJ

PMID: 25952627 [PubMed – in process]

Powered by WPeMatico

[Pulmonary complications in pediatric patients with primary immunodeficiency].

Gac Med Mex. 2015 Mar-Apr;151(2):157-163

Authors: Membrila-Mondragón J, Staines-Boone AT, Sánchez-Sánchez LM, Ruiz-Pedraza MD

Abstract
Introducción: Las IDP son enfermedades que comprenden alteraciones del sistema inmunitario. Las manifestaciones clínicas se caracterizan por presentar infecciones respiratorias de repetición, las cuales pueden complicarse con bronquiectasias, engrosamiento peribronquial, abscesos, bulas y fibrosis pulmonar. El objetivo de este estudio fue determinar las complicaciones pulmonares en pacientes pediátricos según su tipo de IDP. Resultados: Se incluyeron 65 pacientes: 28 con inmunodeficiencias humorales, 4 con inmunodeficiencias celulares, 13 con síndromes bien definidos y 20 con defectos fagocíticos. Los pacientes con inmunodeficiencias celulares iniciaron la sintomatología a edades tempranas: se diagnosticaron antes del año de edad (p = 0.01). Los pacientes con inmunodeficiencias humorales tuvieron cuadros respiratorios más frecuentes y tempranos (p = 0.01). Las enfermedades respiratorias más frecuentes fueron otitis media aguda supurada (OMAS), sinusitis y neumonías, más frecuentes en las inmunodeficiencias humorales y los defectos fagocíticos. Las complicaciones pulmonares más frecuentes fueron bronquiectasias, daño intersticial y fibrosis pulmonar, sin diferencia estadística entre el tipo de IDP. Las pruebas de función pulmonar (PFP) mostraron mayor alteración en los pacientes con defectos fagocíticos, pero sin diferencia estadística (p = 0.28). La presencia de complicaciones pulmonares no mostró diferencias al comparar según el tipo de inmunodeficiencia, excepto la agammaglobulinemia (p = 0.02). Conclusiones: Las inmunodeficiencias celulares se diagnostican de forma más temprana, ya que el inicio de los síntomas ocurre antes del año de edad. Las inmunodeficiencias humorales presentan mayor número de infecciones respiratorias altas y bajas, así como mayor riesgo de complicaciones pulmonares, especialmente de agammaglobulinemia.

PMID: 25946525 [PubMed – as supplied by publisher]

Powered by WPeMatico

Altrered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype.

Clin Immunol. 2015 May 1;

Authors: Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, Piscianz E, Bianco A, Girardelli M, Baronio M, Loganes C, Fasth A, Salvini F, Trizzino A, Moratto D, Facchetti F, Giliani S, Plebani A, Tommasini A

Abstract
PIK3R1 monoallelic mutations were recently reported in eight patients to be responsible for the APDS-like syndrome, a rare form of primary immunodeficiency presenting with a Hyper-IgM like phenotype. This study reports on four novel patients carrying PIK3R1 mutations with early, not previously reported, alterations in peripheral B cell maturation and describes the novel findings of the tonsillar architecture in PIK3R1 mutated disorder, that resembles AID deficiency, offering novel insight on the role of PIK3R1 in the human germinal center reaction. Furthermore, this study offers insight on the prevalence of the PIK3R1 mutation among HIGM-like patients. Finally, the comparison of the available clinical features from the reported patients to date shows that poor growth is an underestimated frequent feature of this disorder.

PMID: 25939554 [PubMed – as supplied by publisher]

Powered by WPeMatico

STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.

J Exp Med. 2015 May 4;

Authors: Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Arkwright PD, Peake J, Wong M, Adelstein S, Smart JM, French MA, Fulcher DA, Picard C, Bustamante J, Boisson-Dupuis S, Gray P, Stepensky P, Warnatz K, Freeman AF, Rossjohn J, McCluskey J, Holland SM, Casanova JL, Uzel G, Ma CS, Tangye SG, Deenick EK

Abstract
Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.

PMID: 25941256 [PubMed – as supplied by publisher]

Powered by WPeMatico

History and current status of newborn screening for severe combined immunodeficiency.

Semin Perinatol. 2015 Apr 30;

Authors: Kwan A, Puck JM

Abstract
The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T-cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions.

PMID: 25937517 [PubMed – as supplied by publisher]

Powered by WPeMatico

Corrigendum: Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome.

Front Pediatr. 2015;3:28

Authors: Rider NL, Boisson B, Jyonouchi S, Hanson EP, Rosenzweig SD, Casanova JL, Orange JS

Abstract
[This corrects the article on p. 2 in vol. 3, PMID: 25688341.].

PMID: 25932458 [PubMed – as supplied by publisher]

Powered by WPeMatico

Altered lymphopoiesis and immunodeficiency in miR-142 null mice.

Blood. 2015 Apr 30;

Authors: Kramer NJ, Wang WL, Reyes EY, Kumar B, Chen CC, Ramakrishna C, Cantin EM, Vonderfecht SL, Taganov KD, Chau N, Boldin MP

Abstract
MicroRNAs (miRNAs) are a class of powerful post-transcriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, while the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of BAFF receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.

PMID: 25931583 [PubMed – as supplied by publisher]

Powered by WPeMatico

Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation.

Clin Immunol. 2015 Apr 27;

Authors: Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, Gombert M, Hönscheid A, Saleh H, Shaag A, Borkhardt A, Grimbacher B, Warnatz K, Elpeleg O, Stepensky P

Abstract
Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care.

PMID: 25931386 [PubMed – as supplied by publisher]

Powered by WPeMatico

Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.

Oncotarget. 2015 Mar 14;

Authors: Compeer EB, Janssen W, van Royen-Kerkhof A, van Gijn M, van Montfrans JM, Boes M

Abstract
Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of B-cell receptors (BCR): transmembrane signaling through BCR-complexes to induce B-cell differentiation and proliferation, and BCR-mediated antigen internalization for class-II MHC-mediated presentation to acquire antigen-specific CD4+ T-cell help.We identified a variant (L3P) in the B-lymphoid tyrosine kinase (BLK) gene of 2 related CVID-patients, which was absent in healthy relatives. BLK belongs to the Src-kinases family and involved in BCR-signaling. Here, we sought to clarify BLK function in healthy human B-cells and its association to CVID.BLK expression was comparable in patient and healthy B-cells. Functional analysis of L3P-BLK showed reduced BCR crosslinking-induced Syk phosphorylation and proliferation, in both primary B-cells and B-LCLs. B-cells expressing L3P-BLK showed accelerated destruction of BCR-internalized antigen and reduced ability to elicit CD40L-expression on antigen-specific CD4+ T-cells.In conclusion, we found a novel BLK gene variant in CVID-patients that causes suppressed B-cell proliferation and reduced ability of B-cells to elicit antigen-specific CD4+ T-cell responses. Both these mechanisms may contribute to hypogammaglobulinemia in CVID-patients.

PMID: 25926555 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis.

Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):400-5

Authors: Field MS, Kamynina E, Watkins D, Rosenblatt DS, Stover PJ

Abstract
An inborn error of metabolism associated with mutations in the human methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene has been identified. The proband presented with SCID, megaloblastic anemia, and neurologic abnormalities, but the causal metabolic impairment is unknown. SCID has been associated with impaired purine nucleotide metabolism, whereas megaloblastic anemia has been associated with impaired de novo thymidylate (dTMP) biosynthesis. MTHFD1 functions to condense formate with tetrahydrofolate and serves as the primary entry point of single carbons into folate-dependent one-carbon metabolism in the cytosol. In this study, we examined the impact of MTHFD1 loss of function on folate-dependent purine, dTMP, and methionine biosynthesis in fibroblasts from the proband with MTHFD1 deficiency. The flux of formate incorporation into methionine and dTMP was decreased by 90% and 50%, respectively, whereas formate flux through de novo purine biosynthesis was unaffected. Patient fibroblasts exhibited enriched MTHFD1 in the nucleus, elevated uracil in DNA, lower rates of de novo dTMP synthesis, and increased salvage pathway dTMP biosynthesis relative to control fibroblasts. These results provide evidence that impaired nuclear de novo dTMP biosynthesis can lead to both megaloblastic anemia and SCID in MTHFD1 deficiency.

PMID: 25548164 [PubMed – indexed for MEDLINE]

Powered by WPeMatico