Research

Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings.

Orphanet J Rare Dis. 2019 Feb 28;14(1):61

Authors: Galli J, Pinelli L, Micheletti S, Palumbo G, Notarangelo LD, Lougaris V, Dotta L, Fazzi E, Badolato R

Abstract
BACKGROUND: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing.
RESULTS: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6).
CONCLUSIONS: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.

PMID: 30819232 [PubMed – in process]

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Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations.

J Med Genet. 2019 Feb 28;:

Authors: van Os NJH, Chessa L, Weemaes CMR, van Deuren M, Fiévet A, van Gaalen J, Mahlaoui N, Roeleveld N, Schrader C, Schindler D, Taylor AMR, Van de Warrenburg BPC, Dörk T, Willemsen MAAP

Abstract
BACKGROUND: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations.
METHODS: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes.
RESULTS: This study included 35 patients who were homozygous or compound heterozygous for the ATM c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the ATM c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with ATM c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with ATM c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for ATM c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the ATM c.8147T>C mutant protein and only at a low level in some patients with ATM c.3576G>A.
CONCLUSION: Compared with classic A-T, the presence of ATM c.3576G>A results in a milder classic phenotype. Patients with ATM c.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.

PMID: 30819809 [PubMed – as supplied by publisher]

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Diagnosing feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) infection: an update for clinicians.

Aust Vet J. 2019 Mar;97(3):47-55

Authors: Westman ME, Malik R, Norris JM

Abstract
With the commercial release in Australia in 2004 of a vaccine against feline immunodeficiency virus (FIV; Fel-O-Vax FIV®), the landscape for FIV diagnostics shifted substantially. Point-of-care (PoC) antibody detection kits, which had been the mainstay for diagnosing FIV infection since the early 1990s, were no longer considered accurate to use in FIV-vaccinated cats, because of the production of vaccine-induced antibodies that were considered indistinguishable from those produced in natural FIV infections. Consequently, attention shifted to alternative diagnostic methods such as nucleic acid detection. However, over the past 5 years we have published a series of studies emphasising that FIV PoC test kits vary in their methodology, resulting in differing accuracy in FIV-vaccinated cats. Importantly, we demonstrated that two commercially available FIV antibody test kits (Witness™ and Anigen Rapid™) were able to accurately distinguish between FIV-vaccinated and FIV-infected cats, concluding that testing with either kit offers an alternative to PCR testing. This review summarises pertinent findings from our work published in a variety of peer-reviewed research journals to inform veterinarians (particularly veterinarians in Australia, New Zealand and Japan, where the FIV vaccine is currently commercially available) about how the approach to the diagnosis of FIV infection has shifted. Included in this review is our work investigating the performance of three commercially available FIV PoC test kits in FIV-vaccinated cats and our recommendations for the diagnosis of FIV infection; the effect of primary FIV vaccination (three FIV vaccines, 4 weeks apart) on PoC test kit performance; our recommendations regarding annual testing of FIV-vaccinated cats to detect ‘vaccine breakthroughs’; and the potential off-label use of saliva for the diagnosis of FIV infection using some FIV PoC test kits. We also investigated the accuracy of the same three brands of test kits for feline leukaemia virus (FeLV) diagnosis, using both blood and saliva as diagnostic specimens. Based on these results, we discuss our recommendations for confirmatory testing when veterinarians are presented with a positive FeLV PoC test kit result. Finally, we conclude with our results from the largest and most recent FIV and FeLV seroprevalence study conducted in Australia to date.

PMID: 30809813 [PubMed – in process]

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Primary Immunodeficiency and Cancer Predisposition Revisited: Embedding Two Closely Related Concepts Into an Integrative Conceptual Framework.

Front Immunol. 2018;9:3136

Authors: Haas OA

Abstract
Common understanding suggests that the normal function of a “healthy” immune system safe-guards and protects against the development of malignancies, whereas a genetically impaired one might increase the likelihood of their manifestation. This view is primarily based on and apparently supported by an increased incidence of such diseases in patients with specific forms of immunodeficiencies that are caused by high penetrant gene defects. As I will review and discuss herein, such constellations merely represent the tip of an iceberg. The overall situation is by far more varied and complex, especially if one takes into account the growing difficulties to define what actually constitutes an immunodeficiency and what defines a cancer predisposition. The enormous advances in genome sequencing, in bioinformatic analyses and in the functional in vitro and in vivo assessment of novel findings together with the availability of large databases provide us with a wealth of information that steadily increases the number of sequence variants that concur with clinically more or less recognizable immunological problems and their consequences. Since many of the newly identified hard-core defects are exceedingly rare, their tumor predisposing effect is difficult to ascertain. The analyses of large data sets, on the other hand, continuously supply us with low penetrant variants that, at least in statistical terms, are clearly tumor predisposing, although their specific relevance for the respective carriers still needs to be carefully assessed on an individual basis. Finally, defects and variants that affect the same gene families and pathways in both a constitutional and somatic setting underscore the fact that immunodeficiencies and cancer predisposition can be viewed as two closely related errors of development. Depending on the particular genetic and/or environmental context as well as the respective stage of development, the same changes can have either a neutral, predisposing and, in some instances, even a protective effect. To understand the interaction between the immune system, be it “normal” or “deficient” and tumor predisposition and development on a systemic level, one therefore needs to focus on the structure and dynamic functional organization of the entire immune system rather than on its isolated individual components alone.

PMID: 30809233 [PubMed – in process]

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Measuring quality of life of primary antibody deficiency patients using a disease-specific health-related quality of life questionnaire for common variable immunodeficiency (CVID_QoL).

J Patient Rep Outcomes. 2019 Feb 26;3(1):15

Authors: Andersen JB, Midttun K, Feragen KJB

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) and other primary antibody deficiencies (PAD) are a heterogeneous group of > 300 congenital disorders affecting the immune system. Until recently, efforts to measure health-related quality of life (QoL) in PAD patients have utilised generic QoL tools and disease-specific tools for other conditions. Still, the full impact of the disease is probably not understood. We evaluated the performance of the CVID_QoL, a novel disease-specific QoL instrument for adults with CVID, on Norwegian PAD patients and compared the results to those of the generic WHOQOL-BREF.
METHODS: Respondents were recruited through the Norwegian Centre for Rare Disorders’ patient database. Included patients fulfilled the following criteria (all three): 1.) Age ≥18 years, 2.) a PAD diagnosis, 3.) currently on immunoglobulin therapy. The CVID_QoL is a 32-item questionnaire. Global CVID_QoL scores were compared between Norwegian PAD patients and Italian CVID patients.
RESULTS: In total, 83 PAD patients filled out the CVID_QoL, 63% had CVID, 76% were females. 32 patients filled out the WHOQOL-BREF. Feasibility was high (<1% missing). Internal consistency for the emotional- (Cronbach's α-value = 0.91) and relational functioning (α =  0.77) subscales was high, but questionable for the gastrointestinal and skin symptoms subscale (α =  0.66). Convergent validity varied from weak to strong (range 0.3-0.8). Floor and ceiling effects were present.
CONCLUSIONS: Although many disease-specific characteristics are probably shared with CVID and other PAD, the CVID_QoL captures some, but not all, dimensions of PAD patients’ QoL. More evaluations of the CVID_QoL’s performance in different contexts are needed.

PMID: 30806830 [PubMed]

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Pathophysiology, causes and genetics.

Respirology. 2019 Feb 25;:

Authors: Bush A, Floto RA

Abstract
Bronchiectasis has historically been considered to be irreversible dilatation of the airways, but with modern imaging techniques it has been proposed that ‘irreversible’ be dropped from the definition. The upper limit of normal for the ratio of airway to arterial development increases with age, and a developmental perspective is essential. Bronchiectasis (and persistent bacterial bronchitis, PBB) is a descriptive term and not a diagnosis, and should be the start not the end of the patient’s diagnostic journey. PBB, characterized by airway infection and neutrophilic inflammation but without significant airway dilatation may be a precursor of bronchiectasis, and there are many commonalities in the microbiology and the pathology, which are reviewed in this article. A high index of suspicion is essential, and a history of chronic wet or productive cough for more than 4-8 weeks should prompt investigation. There are numerous underlying causes of bronchiectasis, although in many cases no cause is found. Causes include post-infectious, especially after tuberculosis, adenoviral or pertussis infection; aspiration syndromes; defects in host defence, which may solely affect the airways (cystic fibrosis, not considered in this review, and primary ciliary dyskinesia); and primary ciliary dyskinesia or be systemic, such as common variable immunodeficiency; genetic syndromes; and anatomical defects such as intraluminal airway obstruction (e.g. foreign body), intramural obstruction (e.g. complete cartilage rings) and external airway compression (e.g. by tuberculous lymph nodes). Identification of the underlying cause is important, because some of these conditions have specific treatments and others genetic implications for the family.

PMID: 30801930 [PubMed – as supplied by publisher]

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The First Cohort of Iranian Patients with Hyper Immunoglobulin E Syndrome: A Long-Term Follow-up and Genetic Analysis.

Pediatr Allergy Immunol. 2019 Feb 23;:

Authors: Tavassoli M, Abolhassani H, Yazdani R, Ghadami M, Azizi G, Abdolrahim Poor Heravi S, Moeini Shad T, Kokabee M, Movahedi M, Abdshahzadeh H, Gharagozlou M, Rezaei N, Esmaeilzadeh H, Aleyasin S, Aghamohammadi A

Abstract
BACKGROUND: Hyper IgE syndromes (HIES) are distinct disease characterized by recurrent cutaneous and lung infections, eczema and elevated serum IgE level.
METHODS: In this study, clinical manifestations, immunologic findings and genetic studies of all patients with HIES in the Iranian national registry database were evaluated.
RESULTS: 129 HIES patients with median age of 14.0 (9.0-24.0) years were followed for a total of 307.8 patient-years. Genetic studies showed heterozygous STAT3 mutations in 19 patients and homozygous DOCK8 mutation in 16 patients. The mean of National Institutes of Health score in STAT3 deficient patients was higher than patients with DOCK8 mutation (p= 0.001). It was shown that the presence of pneumatocele and hematologic complication were significantly frequent in STAT3 deficient cases compared to patients with DOCK8 deficiency (p=0.001 and p=0.002, respectively). Moreover, the median IgE serum levels were higher in patients with STAT3 gene mutation than patients with DOCK8 gene mutation (p=0.02). The eosinophils’ count was enhanced in patients with DOCK8 deficiency than patients with STAT3 gene defects (p=0.02).
CONCLUSION: Specific molecular study of STAT3 and DOCK8 mutations in patients with HIES clinical phenotype could help the physician to definitively characterize the disease. Since HIES showed the highest rate of unsolved combined immunodeficiency investigation of other genetic and environmental factors could also help in understanding the mechanism of remaining patients as well as providing strategy into therapeutic modalities. This article is protected by copyright. All rights reserved.

PMID: 30801830 [PubMed – as supplied by publisher]

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Current clinical practice and challenges in the management of secondary immunodeficiency in hematological malignancies.

Eur J Haematol. 2019 Feb 22;:

Authors: Na IK, Buckland M, Agostini C, Edgar JDM, Friman V, Michallet M, Sánchez-Ramón S, Scheibenbogen C, Quinti I

Abstract
OBJECTIVE: Despite long-standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency (SID) due to B-cell lymphoproliferative diseases are limited. Here we examine the correlation between approved IgRT indications, treatment recommendations and clinical practice in SID.
METHODS: An international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted.
RESULTS: Serum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia and 69% with non-Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the USA, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT and used subcutaneous immunoglobulin more frequently than physicians overall.
CONCLUSIONS: The management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines. This article is protected by copyright. All rights reserved.

PMID: 30801785 [PubMed – as supplied by publisher]

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Recent advances in understanding RAG deficiencies.

F1000Res. 2019;8:

Authors: Gennery A

Abstract
Recombination-activating genes ( RAG) 1 and RAG2 initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in RAG1/ RAG2 cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in RAG genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, which confers a less-severe clinical phenotype. Many of the non-SCID phenotypes are associated with autoimmunity. New findings into the effect of mutations in RAG1/2 on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context.

PMID: 30800289 [PubMed – in process]

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The level of myeloid-derived suppressor cells positively correlates with regulatory T cells in the blood of children with transient hypogammaglobulinaemia of infancy.

Cent Eur J Immunol. 2018;43(4):413-420

Authors: Siemińska I, Rutkowska-Zapała M, Bukowska-Strakova K, Gruca A, Szaflarska A, Kobylarz K, Siedlar M, Baran J

Abstract
Introduction: Transient hypogammaglobulinaemia of infancy (THI) is a primary immunodeficiency characterised by low levels of immunoglobulin G (often with concomitant decrease of IgA and sometimes also of IgM) with still unknown exact reason. A delayed normalisation of the immunoglobulin level in THI may be associated with a transiently elevated number of regulatory T cells (Treg). Although in cancer and chronic inflammation it was shown that the level of Treg cells can be increased by myeloid-derived suppressor cells (MDSCs), until now no studies have been performed in the context of the role of MDSCs in THI and their correlation with Treg cells. Consequently, we aimed to determine the occurrence of MDSCs in the peripheral blood of children with THI and correlate their level with the level of Treg cells.
Material and methods: Flow cytometry analyses of Mo-MDSCs and Gr-MDSCs, characterised as HLA-DR-CD11b+CD15-CD14+ and HLA-DR-CD11b+CD15+CD14-, respectively, and Treg (CD4+CD25+Foxp3+) cells were performed.
Results: The proportion of Mo-MDSCs and Gr-MDSCs was significantly higher in the group of THI patients with elevated level of Treg cells (from the 95% confidence interval level of healthy controls). The cells with Mo-MDSC and Gr-MDSC characteristics positively correlated with the level of Treg cells. Moreover, children with a higher proportion of circulating Treg cells, and thereby higher level of MDSCs, showed delayed normalisation of IgG level and recovery.
Conclusions: These findings show for the first time that MDSCs may be involved in the pathomechanism of THI, probably acting through the induction of Treg cells.

PMID: 30799989 [PubMed]

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