Research

Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia.

Clin Immunol. 2017 Jul 10;:

Authors: Geier CB, Piller A, Eibl MM, Ciznar P, Ilencikova D, Wolf HM

Abstract
Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulins levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.

PMID: 28705765 [PubMed – as supplied by publisher]

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Kunkel Lecture: Fundamental immunodeficiency and its correction.

J Exp Med. 2017 Jul 12;:

Authors: Nathan C

Abstract
“Fundamental immunodeficiency” is the inability of the encoded immune system to protect an otherwise healthy host from every infection that could threaten its life. In contrast to primary immunodeficiencies, fundamental immunodeficiency is not rare but nearly universal. It results not from variation in a given host gene but from the rate and extent of variation in the genes of other organisms. The remedy for fundamental immunodeficiency is “adopted immunity,” not to be confused with adaptive or adoptive immunity. Adopted immunity arises from four critical societal contributions to the survival of the human species: sanitation, nutrition, vaccines, and antimicrobial agents. Immunologists have a great deal to contribute to the development of vaccines and antimicrobial agents, but they have focused chiefly on vaccines, and vaccinology is thriving. In contrast, the effect of antimicrobial agents in adopted immunity, although fundamental, is fragile and failing. Immunologists can aid the development of sorely needed antimicrobial agents, and the study of antimicrobial agents can help immunologists discover targets and mechanisms of host immunity.

PMID: 28701368 [PubMed – as supplied by publisher]

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Early and Late Complications in Patients with Allogeneic Transplantation of Hematopoietic Stem Cell – Case Report.

Open Access Maced J Med Sci. 2017 Jun 15;5(3):340-343

Authors: Trajkovska I, Georgievski B, Cevreska L, Gacovski A, Hasan T, Nedeska-Minova N

Abstract
BACKGROUND: Allogeneic hematopoietic stem cells transplantation (HSCT) is a curative intervention in patients with haematological malignant and non-malignant diseases, immunodeficiency, autoimmune, and other genetic diseases. Early complications are complications that are occurring in the first 100 days, while complications arising after the 100th day of transplantation belong to late complications.
CASE REPORT: Forty-nine years old patient with AML treated with allogeneic HSCT from HLA-identical (sister) donor. Ascertained and display of early (acute Graft versus host disease (GvHD) and late complications (chronic GVHD, infections, cataract, secondary malignancy with MS deposits) are made, that emerged after the patient transplantation.
CONCLUSION: Rapidly growing population of patients that undergo allogeneic HSCT creates an obligation to educate patients and physicians about observed late complications that occur after this therapy.

PMID: 28698754 [PubMed – in process]

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Primary Immunodeficiency Diseases in Highly Consanguineous Populations from Middle East and North Africa: Epidemiology, Diagnosis, and Care.

Front Immunol. 2017;8:678

Authors: Al-Mousa H, Al-Saud B

Abstract
Middle East and North Africa region (MENA) populations are of different ethnic origins. Consanguineous marriages are common practice with an overall incidence ranging between 20 and 50%. Primary immunodeficiency diseases (PIDs) are a group of heterogeneous genetic disorders caused by defects in the immune system that predisposes patients to recurrent infections, autoimmune diseases, and malignancies. PIDs are more common in areas with high rates of consanguineous marriage since most have an autosomal recessive mode of inheritance. Studies of PIDs in the region had contributed into the discovery and the understanding of several novel immunodeficiency disorders. Few MENA countries have established national registries that helped in estimating the prevalence and defining common PID phenotypes. Available reports from those registries suggest a predominance of combined immunodeficiency disorders in comparison to antibody deficiencies seen in other populations. Access to a comprehensive clinical immunology management services is limited in most MENA countries. Few countries had established advanced clinical immunology service, capable to provide extensive genetic testing and stem cell transplantation for various immunodeficiency disorders. Newborn screening for PIDs is an essential need in this population considering the high incidence of illness and can be implemented and incorporated into existing newborn screening programs in some MENA countries. Increased awareness, subspecialty training in clinical immunology, and establishing collaborating research centers are necessary to improve patient care. In this review, we highlight some of the available epidemiological data, challenges in establishing diagnosis, and available therapy for PID patients in the region.

PMID: 28694805 [PubMed – in process]

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[Reduced-intensity conditioning haematopoietic stem cell transplantation in genetic diseases: Experience of the Spanish Working Group for Bone Marrow Transplantation in Children].

An Pediatr (Barc). 2017 Jul 07;:

Authors: López-Granados L, Torrent M, Sastre A, Gonzalez-Vicent M, Díaz de Heredia C, Argilés B, Pascual A, Pérez-Hurtado JM, Sisinni L, Diaz MÁ, Elorza I, Dasí MA, Badell I

Abstract
INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) involves implanting cellular elements capable of generating a new and healthy haematopoietic system. Reduced intensity conditioning (RIC) consists of an immunosuppressive treatment to facilitate a progressive implant with lower morbidity. This type of conditioning can also lead to myelosuppression, which is potentially reversible over time. Reduced intensity conditioning enables HSCT to be performed on patients with genetic diseases for whom added comorbidity is undesirable due to the high doses of chemotherapy that accompanies conventional myeloablative regimens.
PATIENTS AND METHODS: An analysis was performed on the outcomes of 68 paediatric patients with genetic diseases who underwent HSCT with RIC between 2005 and 2013 in the of Paediatric Haematopoietic Stem Cell Transplantation Units that are part of the Spanish Working Group for Bone Marrow Transplantation in Children. A multicentre study was conducted including 68 patients, of whom 43 had Primary Immunodeficiency, 21 with congenital haematological diseases, and 4 with metabolic diseases.
RESULTS: Fifty (73.5%) of the 68 patients were still alive. The Overall Survival (OS) at nine years was 0.74. Twenty-three (33.8%) had some event during the course of the HSCT, with an event-free survival rate of 0.66. The OS in patients with haematological diseases was 0.81, being 0.7 in primary immunodeficiencies, and 0.4 in metabolic diseases. No significant difference was observed between the 3 groups of diseases. As regards the source of haematopoietic progenitors, there was an OS rate of 0.74 in patients transplanted with peripheral blood, 0.70 with bone marrow, and 0.70 and with cord blood, with no statistically significant differences.
CONCLUSIONS: Favourable results have been obtained in HSCT with reduced intensity conditioning in genetic diseases. It should be noted that the risks and benefits of the RIC in patients with metabolic diseases need to be assessed on an individual basis.

PMID: 28694008 [PubMed – as supplied by publisher]

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Oral manifestations of selective IgA-deficiency: review and case-report.

J Biol Regul Homeost Agents. 2017 Apr-Jun;31(2 Suppl 1):113-117

Authors: Azzi L, Croveri F, Vinci R, Maurino V, Boggio A, Mantegazza D, Farronato D, Tagliabue A, Silvestre-Rangil J, Tettamanti L

Abstract
Immunoglobulin A deficiency is the most common primary immunodeficiency defined as decreased serum level of IgA (less than 7 mg/dl) in the presence of normal levels of other immunoglobulin isotypes. Most individuals with IgA deficiency are asymptomatic and identified coincidentally. However, some patients may present with recurrent infections, allergic disorders and autoimmune manifestations, such as diabetes mellitus, Graves disease and celiac disease. The international literature has not produced any kind of review yet about intra-oral manifestations of selective IgA-deficiency. L.S., a 7-year-old Caucasian girl, was examined at our hospital. After she had undergone a professional dental cleaning, a symmetric, bilateral ulcerative gingivitis developed nearby the upper second primary molars. The gingival ulcers were persistent and did not disappear in the following 3 weeks. In the meantime, the young patient reported the presence of gastrointestinal symptoms. IgA serum level was 4.5 mg/dl, while the other isotypes levels were in the common range. The diagnosis of selective IgA-deficiency was formulated and the girl underwent further examination for the specific IgG autoantibodies in celiac disease, which were not present. Consequently, a full prevention program was planned. This case report emphasizes the role of the paediatric dentist in the early detection of systemic disorder, such as the immunological diseases. The oral cavity often reveals to be the first site of manifestation of important systemic diseases. Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency and is defined as a decrease in serum IgA levels in the presence of normal levels of other immunoglobulin isotypes (1). Serum IgA deficiency was first described in children with ataxia-telangiectasia (2) and has since been identified in other patients, including normal patients. The prevalence of IgA deficiency ranges from 1:223 to 1:1000 in community studies and from 1:400 to 1:3000 in healthy blood donors (3).

PMID: 28691461 [PubMed – in process]

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[Clinical and immunological profile of 15 Moroccan patients with Hyper IgM syndrome].

Pan Afr Med J. 2017;26:212

Authors: Ouair H, Benhsaien I, Jeddane L, El Bakkouri J, Elhafidi N, Rada N, Najib J, Ailal F, Alj HS, Bousfiha AA

Abstract
Hyper IgM syndrome is a well known genetic (primary) immunodeficiency disorder which was first described in 1961. It is caused by B lymphocyte deficiency characterized by normal or elevated serum IgM levels and low or zero levels of IgG, IgA, IgE resulting from isotype-switching deficiency. Clinical manifestations are dominated by recurrent infections, especially involving the digestive tube of the ENT sphere and the lungs. This syndrome is caused by B-cell immunoglobulin class switch deficiency and decreased capacity to induce proliferation of T lymphocytes. The net result of these deficiencies is reflected in increased susceptibility to Pneumocystis jiroveci, Cryptosporidium spp and other intracellular organisms as well as high rate of bacterial and viral infections. This study aimed to illustrate the importance of understanding the pathophysiological mechanisms associated with this increased susceptibility to infections in order to allow a better diagnosis and therapy in patients with Hyper IgM syndrome (HIM).

PMID: 28690727 [PubMed – in process]

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Flow cytometry-based diagnosis of primary immunodeficiency diseases.

Allergol Int. 2017 Jul 03;:

Authors: Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T

Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.

PMID: 28684198 [PubMed – as supplied by publisher]

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A multicentre, prospective, non-randomized, sequential, open-label trial to demonstrate the bioequivalence between intravenous immunoglobulin new generation (IGNG) and standard IV immunoglobulin (IVIG) in adult patients with primary immunodeficiency (PID).

Rev Med Interne. 2017 Jul 03;:

Authors: Viallard JF, Brion JP, Malphettes M, Durieu I, Gardembas M, Schleinitz N, Hoarau C, Lazaro E, Puget S

Abstract
OBJECTIVES: To demonstrate the bioequivalence between 2 intravenous immunoglobulin (IVIG) preparations, TEGELINE(®) and ClairYg(®), a ready-to-use 5% IVIG, in primary immunodeficiency (PID). Secondary objectives were to assess the efficacy, safety and pharmacokinetics of ClairYg(®).
METHODS: Twenty-two adult PID patients receiving stable doses of TEGELINE(®) (5% lyophilized IVIG) were switched to ClairYg(®) for 6 months. ClairYg(®) was administered under the same conditions as TEGELINE(®), either every 3 or 4 weeks. The primary endpoint was mean average total IgG trough level at steady state with ClairYg(®) versus TEGELINE(®). Clinical efficacy was also assessed in terms of infections and associated events.
RESULTS: Bioequivalence was established with a mean average total IgG trough level at steady state being 8.05g/L with TEGELINE(®) and 9.17g/L with ClairYg(®) (i.e. geometric mean for the difference between ClairYg(®) and TEGELINE(®) was 1.136; [90% CI: 1.092-1.181] P<0.001), within the pre-specified margin to establish bioequivalence (0.80-1.25). Total IgG trough levels remained clinically adequate (>4-6g/L) throughout the study. No patient was hospitalized for infection or had serious bacterial infections while receiving ClairYg(®). The median annualized infections rate per patient was similar for both products: 4.35 [0; 21.8] for TEGELINE(®) and 4.30 [0; 15.1] for ClairYg(®). Infections were less common with higher IgG trough levels (>8.16g/L). ClairYg(®) showed good safety, in particular good hepatic and renal tolerance, and did not induce hemolysis. ClairYg(®) pharmacokinetics profile was comparable to that of TEGELINE(®).
CONCLUSION: ClairYg(®) is safe and effective in the treatment of adult PID.

PMID: 28683953 [PubMed – as supplied by publisher]

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Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG / NEMO mutations.

Blood. 2017 Jul 05;:

Authors: Miot C, Imai K, Imai C, Mancini AJ, Kucuk ZY, Kawai T, Nishikomori R, Ito E, Pellier I, Dupuis Girod S, Rosain J, Sasaki S, Chandrakasan S, Pachlopnik Schmid J, Okano T, Colin E, Olaya-Vargas A, Yamazaki-Nakashimada M, Qasim W, Espinosa Padilla S, Jones A, Krol A, Cole N, Jolles S, Bleesing J, Vraetz T, Gennery AR, Abinun M, Güngör T, Costa-Carvalho B, Condino-Neto A, Veys P, Holland SM, Uzel G, Moshous D, Neven B, Blanche S, Ehl S, Döffinger R, Patel SY, Puel A, Bustamante J, Gelfand EW, Casanova JL, Orange JS, Picard C

Abstract
X-linked recessive ectodermal dysplasia (EDA) with immunodeficiency (XR-EDA-ID) is a rare primary immunodeficiency (PID) caused by hypomorphic mutations of the IKBKG gene encoding the NEMO protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and non-hematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests that it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n=7), HLA-matched unrelated donors (n=12), HLA-mismatched unrelated donors (n=8), and HLA-haplo-identical related donor (n=2). Engraftment was documented in 24 patients and GVHD in 13 patients. Up to 7 patients have died from 0.2 to 12 months post HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (4-108 months). Pre-existing mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly due to cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

PMID: 28679735 [PubMed – as supplied by publisher]

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