Cause Of Primary Immunodeficiency Research Articles

Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα).

Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κB–inducing kinase and impairs lymphotoxin-β–driven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.

A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction.

BackgroundFour patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected.Methods and resultsThe four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease‐causing variants were identified in known primary immunodeficiency genes or in other disease‐related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T‐cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T‐cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ ‐synthesis in CD4+ T cells and NK cells.ConclusionsWe report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐,DOCK8‐,GATA2‐,MAGT1‐,MCM4‐,STK4‐,RHOH‐,TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype.

The First Report of a Pregnancy in a Patient with Purine Nucleoside Phosphorylase Deficiency

ABSTRACTBackground: The cause of primary immunodeficiency has expanded to nearly 200 distinct disorders. An improved understanding of these disorders has resulted in decreased morbidity and mortality with reciprocal improved life expectancy. Obstetricians should have knowledge of primary immunodeficiency, as more women with these disorders will reach reproductive age. Case: 21-year-old G1P0 with purine nucleoside phosphorylase (PNP) deficiency delivered a viable infant vaginally at 37 weeks. Although the patient's diagnosis and pregnancy placed her at increased risk for infection, she remained asymptomatic and infection-free throughout pregnancy. Conclusion: The management of pregnancy complicated by PNP deficiency requires strict immune surveillance and regimented immunoglobulin replacement.

7th International Immunoglobulin Conference: Immunodeficiencies.

Awareness of the challenges involved in diagnosing and treating a heterogeneous group of immunodeficiency disorders is growing. The improvements in neonatal screening offer new methods to ensure that primary immunodeficiencies (PIDs) are diagnosed as early as possible, enabling accurate treatment and the prevention of life-threatening infections and other complications. Additionally, the need to individualize patient therapy in order to optimize both clinical outcomes and quality-of-life is obvious and is exemplified by the ability to switch between intravenous and subcutaneous immunoglobulin administration offering flexible treatment regimens. However, further research is crucial in order to determine the optimal treatment for secondary immunodeficiencies, and to gain greater understanding of the underlying causes of PIDs, including common variable immunodeficiency. The information relating to the growth of patient registries is encouraging, with approximately 25 000 patients with PIDs included in the two registries discussed. Registries such as this are vital for future research, as well as providing an educational resource.

Gene hunting in the genomic era: Approaches to diagnostic dilemmas in patients with primary immunodeficiencies

There are more than 180 different genetic causes of primary immunodeficiencies identified to date. Approaches for identifying causative mutations can be broadly classified into 3 strategies: (1) educated guesses based on known signaling pathways essential for immune cell development and function, (2) similarity of clinical phenotypes to mouse models, and (3) unbiased genetic approaches. Next-generation DNA sequencing permits efficient sequencing of whole genomes or exomes but also requires strategies for filtering vast amounts of data. Recent studies have identified ways to solve difficult cases, such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in noncoding regions. This review focuses on recently identified primary immunodeficiencies to illustrate the strategies, technologies, and potential pitfalls in finding novel causes of these diseases.

Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies

This review discusses the strengths and challenges of using whole genome sequencing (WGS)/whole exome sequencing (WES) for identifying novel genetic causes of primary immunodeficiencies. WGS permits comprehensive sequencing of introns and exons, whereas WES allows deeper sequencing of exonic regions at a lower cost. Due to the large number of genetic variants found in each genome, it is necessary to use filtering approaches to distinguish deleterious from benign variants. WES has been used successfully to identify novel genetic causes of primary immunodeficiency. Complex structural variations and non-Mendelian disorders remain challenges for WGS/WES. WGS/WES is a powerful screening tool with great potential to identify genetic causes of primary immunodeficiencies for research and clinical applications. To use WGS/WES effectively, it is necessary to understand how to filter the sequencing data and to realize its limitations as well as its strengths.

102 Bronchiectasis

BackgroundThe common variable Immunodeficiency (CVID) is the second cause of primary immunodeficiency. The bronchiectasis are the most frequent structural pulmonary alterations in CVID, which have been principally described in pediatric population, finding the presence of the same ones in 50% of the cases, nevertheless exists inssuficient information about the location and characteristics as type and distribution of the bronchiectasis; in adult population, less information exists still on this matter. High resolution CT scan is valuable for detection of bronchiectasis and may alter treatment of these patients.ObjectiveThe purpose of this study was to determine the presence of bronchiectasis, their characteristics and most frequent location using a high resolution CT scan in adults with diagnosis of CVID.MethodsThis was a cohort study whit 15 adult subjects whit the diagnosis of CVID, who underwent a chest high-resolution computed tomography scan, previous signature of a letter of informed consent and with the approval of the committee of ethics and investigation (F-2011-3601-21).ResultsWe studied all the subjects (n = 15) whit CVID, finding the presence of bronquiectasias in 73% of the subjects with CVID, 82% was a women and 8% males. The most frequent location was in the left lung in 46% of the cases and 45 bilateral %, with only 9% of location in right lung. These were more frequent in the lower lobe in 42, 17% in top lobe and l6% diffuse, the rest of them were brought like diffuse, bibasal or parahiliar. In one patient we found the presence of a left apical cavitation and only one was brought by presence of pulmonary diffuse fibrosis.ConclusionsThere was realized a search of bronchiectasis and their characteristics in subjects with CVID disorders, the incidence of bronchiectasis is higher in our poblation (82%) than in the rest (50% described in other pubiclations). The most affected lung was the left in the lower lobe. The most frequent type of bronchiectasis was the cystic form.

X-linked severe combined immunodeficiency.

Severe combined immunodeficiency is one of the most common causes of primary immunodeficiencies in humans. Molecular biological techniques have allowed new, therapeutically useful treatments for these diseases to be introduced into clinical practice. This review will focus on the molecular basis and new treatments for X-linked severe combined immunodeficiency.

Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency.

Adenosine deaminase (ADA) deficiency was the first known cause of primary immunodeficiency. Over the past 25 years the basis for immune deficiency has largely been established. Now it appears that ADA deficiency may also cause hepatic toxicity, raising new questions about its pathogenesis. The ADA gene has been sequenced and the ADA three-dimensional structure solved. The relationship between genotype and phenotype is being analysed, and ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy.