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Germline CBM-opathies: From immunodeficiency to atopy.

J Allergy Clin Immunol. 2019 May;143(5):1661-1673

Authors: Lu HY, Biggs CM, Blanchard-Rohner G, Fung SY, Sharma M, Turvey SE

Abstract
Caspase recruitment domain (CARD) protein-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9, CARD11, CARD14, BCL10, and MALT1.

PMID: 31060714 [PubMed – in process]

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Comparison of Clinical and Immunological Features and Mortality in Common Variable Immunodeficiency and Agammaglobulinemia Patients.

Immunol Lett. 2019 May 03;:

Authors: Bagheri Y, Vosughi A, Azizi G, Yazdani R, Kiaee F, Hafezi N, Alimorad S, Khoshmirsafa M, Seif F, Hassanpour G, Abolhassani H, Aghamohammadi A

Abstract
Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children’s Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.

PMID: 31059734 [PubMed – as supplied by publisher]

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Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency.

Front Pediatr. 2019;7:122

Authors: Dorna MB, Barbosa PFA, Rangel-Santos A, Csomos K, Ujhazi B, Dasso JF, Thwaites D, Boyes J, Savic S, Walter JE

Abstract
Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.

PMID: 31058115 [PubMed]

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A Systematic Review on Predisposition to Lymphoid (B and T cell) Neoplasias in Patients With Primary Immunodeficiencies and Immune Dysregulatory Disorders (Inborn Errors of Immunity).

Front Immunol. 2019;10:777

Authors: Riaz IB, Faridi W, Patnaik MM, Abraham RS

Abstract
Primary immunodeficiencies and immune dysregulatory disorders (PIDDs; now referred to as inborn errors in immunity) are rare disorders with a prevalence of 41. 4 or 50.5 per 100,000 persons (1). The incidence of malignancy in PIDD patents is the second-highest cause of death in children as well as adults, after infection, and is higher in certain PIDDs compared to others. We performed a systematic review of the literature to identify reports of B cell and T cell neoplasias in PIDDs and clustered them based on their classification in the IUIS schema. As would be expected, higher susceptibility to malignancies are typically reported in patients with Common Variable Immunodeficiency (CVID), combined immunodeficiencies affecting cellular immunity, in particular, DNA repair defects, or in the context of impaired immune regulatory control. There is not much evidence of increased risk for cancer in patients with innate immune defects, indicating that not all types of infection or genetic susceptibility predispose equally to cancer risk. Viral infections, in particular EBV, HHV and HPV, have been shown to increase susceptibility to developing cancer, but also patients with defects in immune regulation, such as Autoimmune Lymphoproliferative Syndrome (ALPS), activated p110delta syndrome (APDS type 1) and IL-10 receptor deficiency among others have a higher incidence of neoplastic disease, particularly lymphomas. In fact, lymphomas account for two-thirds of all malignancies reported in PIDD patients (2), with either a combined immunodeficiency or DNA repair defect predominating as the underlying immune defect in one registry, or antibody deficiencies in another (3). The vast majority of lymphomas reported in the context of PIDDs are B cell lymphomas, though T cell lymphomas have been reported in a few studies, and tend to largely be associated with chromosomal breakage disorders (4) or Cartilage Hair Hypoplasia (5). There appears to be a much higher prevalence of T cell lymphomas in patients with secondary immunodeficiencies (6), though this could reflect treatment bias. We reviewed the literature and summarized the reports of B and T cell lymphoma in PIDD patients to survey the current state of knowledge in this area.

PMID: 31057537 [PubMed – in process]

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Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency.

Front Immunol. 2019;10:568

Authors: Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, Schubert D, Warnatz K, Grimbacher B

Abstract
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.

PMID: 31057532 [PubMed – in process]

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Preparation, structural identification and intervention on immunodeficiency mice of enzymatic peptides from Mauremys mutica and Cuora trifasciata.

J Ethnopharmacol. 2019 Apr 28;:111920

Authors: Lv YB, Zhou Q, Fan Y, Zhang JL

Abstract
ETHNOPHARMACOLOGY RELEVANCY: Mauremys mutica (Asian yellow pond turtle, YPT) and Cuora trifasciata (Chinese three-striped box turtle, TBT) are traditional Chinese medicine. They possess many biological characteristics, such as immune enhancement, anti-inflammatory, anti-cancer effects. They have long been used as folk anti-cancer drugs in central and southern China. However, there was no studies to compare the immune enhancement effect of YPT and TBT, nor to identify the structures of YPT peptides and TBT peptides.
AIMS OF THE STUDY: The aim of this study was to evaluate the protective efficacy of YPT and TBT on immunodeficient mice and to compare the primary structures of YPT peptides and TBT peptides.
MATERIALS AND METHODS: The protein extracts were extracted using boiling water, and peptides were obtained by hydrolyzing protein extract with alkaline protease. Cyclophosphamide (CTX) was used to induce immunodeficiency in mice. The immune enhancement effect was evaluated by measuring body weight gain curve, thymus index, spleen index, serum SOD activity and GSH-Px activity. Primary structure of peptides identified by HPLC-ESI-MS/MS.
RESULTS: The protein extracts and peptides of the YPT and TBT had certain recovery effects on immunodeficient mice. YPT peptides has the best effect on the recovery of damaged immune organs in mice. In the identification of the primary structure of the polypeptide, YPT and TBT have some similar peptide segments, but there are also many differences. This may be the reason why they have the same function and different effects, which lays the foundation for the follow-up mechanism researches.
CONCLUSIONS: Two kinds of healthy turtle protein extracts and peptides had certain recovery effects on immune injury in mice. YPT peptides possessed the best effect on the recovery of immunodeficiency.

PMID: 31042594 [PubMed – as supplied by publisher]

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[The diagnostic challenge of primary immunodeficiencies in adults].

Rev Med Suisse. 2019 Apr 03;15(645):719-722

Authors: Jandus P

Abstract
Primary immunodeficiencies (PID) constitute a heterogeneous group of genetic disorders caused by defects in the development and/or function of the immune system resulting in an increased susceptibility to recurrent infections. In addition to a predisposition to infections, PID patients present an increased vulnerability to autoimmunity, lymphoproliferation, allergies and malignancies. Studies performed in the past decade revealed that the prevalence of PID in adults was largely underestimated. These have also demonstrated that the disease burden of PID is not less than in children. PID is more common than generally thought.

PMID: 30942969 [PubMed – in process]

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Graft Versus Host Disease Following HLA-Matched Sibling Donor Compared with Matched Related Donor for Hematopoietic Stem Cell Transplantation for the Treatment of Severe Combined Immunodeficiency Disease.

J Clin Immunol. 2019 Apr 30;:

Authors: Al-Saud B, Al-Saleem A, Al Rasheed B, Al-Ghonaium A, Al-Ahmari A, Al-Mousa H, Al-Seraihy A, Arnaout R, Al-Jefri A, Elshorbagi S, Elsayed N, Al-Dhekri H, Ayas M, Al-Muhsen S

Abstract
BACKGROUND: One of the limiting factors for successful hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD). The EBMT/ESID guidelines for HSCT in severe combined immunodeficiency (SCID) recommend no GVHD prophylaxis for a matched sibling donor (MSD).
OBJECTIVE: To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD).
METHODS: This retrospective cohort study compares MSD with MRD and the outcome of GVHD in all SCID patients who underwent HSCT between 1993 and 2013. All statistical analyses were done using IBM SPSS statistics software.
RESULTS: One hundred forty-five SCID patients underwent 152 HSCTs while 82 (54%) received GVHD prophylaxis. GVHD occurred in 48 patients (31.5%); 20/48 (42%) had GVHD prophylaxis compared to 28/48 (58%) that did not, P = 0.022. Acute GVHD occurred at a higher trend in MSD, 37/120 (30.8%), compared to MRD, 6/32 (18.8%), P = 0.17. We also analyzed the outcome according to the period of HSCT. The first period was 1993 to 2003, 48 HSCTs, 43 MSD, 5 MRD; all patients had GVHD prophylaxis, and there was no difference in GVHD. The second period was 2004 to 2013: of 104 HSCTs, 77 had MSD and 27 had MRD; GVHD prophylaxis was used in 22.1% of MSD and 63% of MRD, P = 0.000. GVHD was significantly higher in the MSD (40.2%) compared to MRD (18.5%) patients, P = 0.041.
CONCLUSION: GVHD prophylaxis in MSD transplant should be considered in SCID patients.

PMID: 31041574 [PubMed – as supplied by publisher]

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A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation.

J Exp Med. 2019 Apr 30;:

Authors: Fernandez IZ, Baxter RM, Garcia-Perez JE, Vendrame E, Ranganath T, Kong DS, Lundquist K, Nguyen T, Ogolla S, Black J, Galambos C, Gumbart JC, Dawany N, Kelsen JR, de Zoeten EF, Quinones R, Eissa H, Verneris MR, Sullivan KE, Rochford R, Blish CA, Kedl RM, Dutmer CM, Hsieh EWY

Abstract
The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells.

PMID: 31040184 [PubMed – as supplied by publisher]

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Spatial analysis of AIDS and the social determinants of health.

Rev Bras Epidemiol. 2019;22:e190032

Authors: Paiva SS, Pedrosa NL, Galvão MTG

Abstract
INTRODUCTION: The social determinants of health (SDH) are factors that can influence the distribution of rates for acquired immunodeficiency syndrome (AIDS) in a given region. The objective of this study was to analyze SDHs related to AIDS.
METHOD: Ecological study, using spatial analyses techniques. 7,896 disease case reports were analyzed over a period of 11 years. Subjects were 13 years or older and residents of the state of Ceará, in the northeast of Brazil. The area of analysis was the municipality, calculating both the average rate of AIDS and the Freeman-Tukey transformed average rate for measuring softening. We used the Simple Linear Regression Model to make the spatial correlation between AIDS detection rates and SDH. A Geographic Information Systems (GIS) was used to manipulate georeferenced data.
RESULTS: High rates of AIDS could be found in cities with better living conditions. Additionally, there was a significant relationship between primary health care coverage and lower rates of the disease in Ceará.
CONCLUSION: Socioeconomic indicators with statistically significant correlation to the distribution of AIDS should be targeted by strategies policies in the fight against the disease.

PMID: 31038613 [PubMed – in process]

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