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Researchers have found a method to repair the gene mutation causing agammaglobulinemia, an immunodeficiency disease that almost exclusively affects boys and in which the body lacks the ability to produce immunoglobulins (gamma globulin). The disease is characterized by recurring bacterial infections, mainly in the respiratory system, and persons who suffer from the illness currently need life-long gamma globulin treatment. 
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Alfredo Corell's insight:
Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) accord-ing to national and supranational registries. They are still considered rare and even of less clinicalimportance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and gen-eral practitioners but is also due to the fact that only few centers worldwide provide a comprehensivelaboratory complement analysis. To enable early identification, our aim is to present warning signs forcomplement deficiencies and recommendations for diagnostic approach. The genetic deficiency of anyearly component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune dis-eases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), arehighly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE)results in episodic angioedema, which in a considerable number of patients with identical symptomsalso occurs in factor XII mutations. New clinical entities are now reported indicating disease associa-tion with partial complement defects or even certain polymorphisms (factor H, MBL, MASPs). Mutationsaffecting the regulators factor H, factor I, or CD46 and of C3 and factor B leading to severe dysregulationof the alternative pathway have been associated with renal disorders, such as atypical hemolytic uremicsyndrome (aHUS) and – less frequent – with membranoproliferative glomerulonephritis (MPGN). Wesuggest a multi-stage diagnostic protocol starting based on the recognition of so called warning signswhich should aid pediatricians and adult physicians in a timely identification followed by a step-wisecomplement analysis to characterize the defect at functional, protein and molecular level.© 2014 Published by Elsevier
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Find information on Common Variable Immune Deficiency (CVID), including definition, diagnosis, treatment, and expectations for patients.
Alfredo Corell's insight:
An atypically adult with CVID recently published on "The Lancet" The Lancet, Volume 383, Issue 9920, Page 926, 8 March 2014 doi:10.1016/S0140-6736(14)60415-3Cite or Link Using DOI Common variable immunodeficiency syndrome in an adult Dr Laura S Lourdes MD a , Karen C Daily DO b
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The PedPAD study: Boys predominate in the hypogammaglobulinemi
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PLOS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF SCIENCE. Reports of well-performed scientific studies from all disciplines freely available to the whole world.
About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype.
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This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host–microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism.
The altered landscape of the human skin microbiome in patients with primary immunodeficienciesJulia Oh1, Alexandra F. Freeman2, NISC Comparative Sequencing Program3, Morgan Park3, Robert Sokolic1, Fabio Candotti1,Steven M. Holland2, Julia A. Segre1,5,6 and Heidi H. Kong4,5,6Article published online before print. Article, supplemental material, and publication date are athttp://www.genome.org/cgi/doi/10.1101/gr.159467.113.
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Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.
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Clinical Predictors of Primary Immunodeficiency Diseases in Children http://t.co/17g2Tf800Y
The 10 warning signs and IDR score do not aid in an early diagnosis of severe PID. Educational campaigns should target pediatricians aiming to increase PID awareness and to address family history of PID, parental consanguinity, and previous sibling death as key predictors of PID in communities with a high prevalence of consanguineous marriages.
Read more at http://ivancevichmd.blogspot.com/2013/03/clinical-predictors-of-primary.html#2P4aD3dUs488evRy.99
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Opinion from JAMA — Newborn Screening for Severe Combined Immunodeficiency — Progress and Challenges (RT @JAMA_current: #Newborn Screening for Severe Combined #Immunodeficiency http://t.co/opTP3izQBP...
September 30, 2014, marks the 50th anniversary of the Children’s Bureau recommendation for “the screening of all newborn infants for PKU [phenylketonuria] on a routine basis.”1 By 1968, 43 states had made screening for PKU mandatory.1 As a result of technological advances, newborn screening in the United States has been extended to as many as 37 core conditions in some states.2 As reported by Kwan and colleagues3 in this issue of JAMA, newborn screening for severe combined immunodeficiency (SCID) has been undertaken in 23 states and the Navajo Nation, beginning in Wisconsin in January 2008. The authors present data on more than 3 million newborns screened with a T-cell receptor excision circle (TREC) assay followed by confirmatory flow cytometry from 11 of these programs (10 states and the Navajo Nation).
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RT @Primary_Immune: Patients with Primary #Immunodeficiency in Pediatric ICUs: Risk, Outcomes & Mortality http://t.co/5M6TDf3cXt … #immun…
This is the first study regarding the outcome and mortality-related risk factors for PID patients requiring PICU admission. We suggest that PICU management is as important as early diagnosis and treatment for these patients. Prediction of those at risk for poorer outcome might be beneficial for accurate intensive care management and survival.
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Blood
Epstein Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.
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Open Access UCL Research: Actin cytoskeletal defects in immunodeficiency. http://t.co/GUckDlnylL
Link to Immunological Reviews pdf: http://discovery.ucl.ac.uk/1417386/1/imr12114.pdf
The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.
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Australian scientists have described an exquisitely balanced interplay of four molecules that trigger and govern antibody production in immune cells.
As well as being an important basic science discovery, it helps explain why people with mutations in any one of the associated genes cannot fight infection effectively, and develop rare and crippling immunodeficiency disorders.
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Over the past decade, scientists have made incredible strides in the field of HIV research, but a cure for the human immunodeficiency virus has still eluded scientists.
These findings mean that scientists have many more proviruses to kill in order to fully cure an individual of HIV. However, Siliciano hopes his research will dissuade patients from entering into clinical trials testing a “shock and kill” approach to curing the virus, which involves activating many of the body’s T cells to force the proviruses to activate. Since the size of the provirus reservoir is so large, Siliciano said this technique could lead to major damage in the body.
The paper in "Cell": http://www.cell.com/abstract/S0092-8674(13)01157-4 ;
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Lymphocyte receptor diversity is generated by recombining variable, diversity, and joining (VDJ) gene segments of the immunoglobulin and T-cell receptor (TCR) loci. V(D)J recombination requires DNA breakage, a process mediated by recombination-activating gene (RAG) 1 and 2. RAG deficiency was initially described in patients with the T−B− severe combined immunodeficiency (SCID) phenotype1; however, the spectrum of the disease has expanded to include Omenn syndrome, cytomegalovirus infection with γδ T-cell expansion, combined immunodeficiency with granuloma, and isolated CD4+ lymphopenia.2, 3, 4, 5, 6 The pleomorphic manifestations of RAG deficiency are partially explained by residual RAG activity, with null mutations producing an SCID phenotype and hypomorphic mutations presenting more variably.2, 7 Although autoimmunity is a known feature of aberrant RAG function, it has never been described as the primary manifestation of the disease in an infant. We describe a novel presentation of RAG deficiency characterized by the presence of B cells and early-onset autoimmunity.
published online 26 July 2013.
will help medical students understand the RAG is a useful enzyme
X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton’s tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2′-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro–B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
GO TO THE JOURNAL OF CLINICAL INVESTIGATION MANUSCRIPT:
http://www.jci.org/articles/view/76175