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Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders.

July 3, 2015 By Manish Butte

Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders.

Ther Adv Neurol Disord. 2015 Jul;8(4):153-159

Authors: Yoon MS, Gold R, Kerasnoudis A

Abstract
OBJECTIVE: Intravenous immunoglobulin administration has long been used in the treatment of autoimmune neuromuscular disorders. Immunoglobulins may be administered by intramuscular, intravenous or subcutaneous routes.
METHODS: This is a report on the long-term clinical follow up of six patients with inflammatory neuromuscular disorders, that is, three chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy (MMN), one inclusion body myositis (IBM) and one myasthenia gravis (MG), treated with subcutaneous immunoglobulins for a mean of 3.25 years.
RESULTS: One MMN and two CIDP patients received a weekly dose of subcutaneous immunoglobulins equivalent to intravenous immunoglobulin. One CIDP patient received a 50% dose reduction, the IBM patient received a 30% reduction and the MG patient a 20% reduction. The lower dose chosen in the majority of patients was based not only on clinical effects, but also on studies of primary immunodeficiency syndromes. One patient with CIDP showed clinical fluctuation, which was successfully treated with an adaptation of the dose of subcutaneous immunoglobulins, while the remaining patients with neuromuscular disorders had a stable clinical course for 2 years. No serious side effects were observed.
CONCLUSIONS: Our results suggest that subcutaneous immunoglobulins can be an attractive alternative therapy in autoimmune neuromuscular disorders.

PMID: 26136842 [PubMed – as supplied by publisher]

Lymphoma-Like Syndrome: 4 Case Reports About Atypical Presentation of Primary Cytomegalovirus Infection in Immunocompetent Children.

July 2, 2015 By Manish Butte

Lymphoma-Like Syndrome: 4 Case Reports About Atypical Presentation of Primary Cytomegalovirus Infection in Immunocompetent Children.

Medicine (Baltimore). 2015 Jul;94(26):e855

Authors: Vigué MG, Tuaillon E, Makinson A, Bullen GM, Foulongne V, Segondy M, Perre PV, Jeziorski E

Abstract
In immunocompetent persons, primary cytomegalovirus (CMV) infection is self-limited infection. Lymphoma-like syndromes have been sometimes described in adults but have not been described for children.Lymphoma-like syndromes (protracted fever, alteration of the general status, and clinical lymphoproliferative syndrome) were retrospectively recorded in children attending our hospital from 1999 to 2008 for primary CMV infection. Patients with immunodeficiency, coinfection (Epstein-Barr virus, toxoplasmosis, or mycobacterial), or biological criteria of mononucleosis-like syndrome were excluded.We report 4 cases of lymphoma-like syndrome. The median duration of fever was 21.5 days (range 15-27). Tonsillitis and hepatitis are most of the time missing. A probable malignant diagnosis was raised in 3 cases. Clinical outcome was protracted (15-35 days) but favorable.To our knowledge, our study is the first pediatric case series of lymphoma-like syndrome. This clinical presentation is a source of delayed diagnosis due to diagnosis pitfall.

PMID: 26131836 [PubMed – as supplied by publisher]

Mutation analyses and prenatal diagnosis in families of X-linked severe combined immunodeficiency caused by IL2Rγ gene novel mutation.

July 1, 2015 By Manish Butte

Mutation analyses and prenatal diagnosis in families of X-linked severe combined immunodeficiency caused by IL2Rγ gene novel mutation.

Genet Mol Res. 2015;14(2):6164-6172

Authors: Bai QL, Liu N, Kong XD, Xu XJ, Zhao ZH

Abstract
We investigated the feasibility of interleukin-2 recep-tor gamma (IL2Rγ) gene based on gene mutation analysis and pre-natal diagnosis of X-linked severe combined immunodeficiency (X-SCID). Blood samples of patients and their parents of X-SCID (family 1) and X-SCID (family 2) were collected. IL2Rγ gene sequences of the 2 families were analyzed using bi-directional direct sequencing by polymerase chain reaction. DNA sequence changes in the IL2Rγ gene exon region and shear zone were also analyzed. We also sequenced the IL2Rγ gene in 100 healthy individuals. Prenatal genetic diagnoses for a high-risk fetus in family 1 were performed by chorionic villus sampling after determining each family’s genotypes. The suspect fe-male in family 1 underwent carrier detection. Two novel mutations of IL2Rγ gene were identified, including c.361-363delGAG (p.E121del) in the patient and his mother in family 1, and c.510-511insGAACT (p.W173X) heterozygous mutation in the proband’s mother in family 2. These mutations were absent in the 100 controls. Prenatal diagnosis of early pregnancy in the female fetus of family 1 was performed; the fetus was heterozygous, which was confirmed at postnatal follow-up. The suspect female in family 1 showed no mutation in carrier detection. The novel p.E121del and p.W173X mutations in IL2Rγ may have been the primary causes of disease in 2 families with X-SCID. In couples with an X-SCID reproductive history, prenatal gene mutation analysis of IL2Rγ can effectively prevent the birth of children with X-SCID and carrier detection for suspected females.

PMID: 26125817 [PubMed – as supplied by publisher]

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

July 1, 2015 By Manish Butte

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

Front Pediatr. 2015;3:54

Authors: Lyons JJ, Milner JD, Rosenzweig SD

Abstract
Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.

PMID: 26125015 [PubMed]

Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

July 1, 2015 By Manish Butte

Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

Clin Immunol. 2015 Jun 26;

Authors: van Schouwenburg PA, Davenport EE, Kienzler AK, Marwah I, Wright B, Lucas M, Malinauskas T, Martin HC, WGS500 Consortium, Lockstone HE, Cazier JB, Chapel HM, Knight JC, Patel SY

Abstract
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are a highly variable disease and a genetic cause has been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. By using an extensive analysis strategy we found variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. Pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm a polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together out data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

PMID: 26122175 [PubMed – as supplied by publisher]

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

July 1, 2015 By Manish Butte

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

Brain. 2015 Jun 29;

Authors: Shahni R, Cale CM, Anderson G, Osellame LD, Hambleton S, Jacques TS, Wedatilake Y, Taanman JW, Chan E, Qasim W, Plagnol V, Chalasani A, Duchen MR, Gilmour KC, Rahman S

Abstract
Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.

PMID: 26122121 [PubMed – as supplied by publisher]

CD21(-/low) B cells: A snapshot of a unique B-cell subset in health and disease.

June 30, 2015 By Manish Butte

CD21(-/low) B cells: A snapshot of a unique B-cell subset in health and disease.

Scand J Immunol. 2015 Jun 28;

Authors: Thorarinsdottir K, Camponeschi A, Gjertsson I, Mårtensson IL

Abstract
B cells represent one of the cellular components of the immune system that protects the individual from invading pathogens. In response to the invader, these cells differentiate into plasma cells and produce large amounts of antibodies that bind to and eliminate the pathogen. A hallmark of autoimmune diseases is the production of autoantibodies i.e. antibodies that recognize self. Those that are considered pathogenic can damage tissues and organs, either by direct binding or when deposited as immune complexes. For decades B cells have been considered to play a major role in autoimmune diseases by antibody production. However, as pathogenic autoantibodies appear to derive mainly from T-cell dependent responses, T cells have been the focus for many years. The successful treatment of patients with autoimmune diseases with either B-cell depletion therapy (rituximab) or inhibition of B-cell survival (belimumab), suggested that not only the autoantibodies but also other B-cell features are important. This has caused a surge of interest in B cells and their biology resulting in the identification of various subsets e.g. regulatory B cells, several memory B-cell subsets etc. Also in other conditions such as chronic viral infections and primary immunodeficiency several B-cell subsets with unique characteristics have been identified. In this review, we will discuss one of these subsets, a subset that is expanded in conditions characterized by chronic immune stimulation. This B-cell subset lacks, or expresses low, surface levels of the complement receptor 2 (CD21) and has therefore been termed CD21(-/low) B cells. This article is protected by copyright. All rights reserved.

PMID: 26119182 [PubMed – as supplied by publisher]

[FREQUENCY OF IMMUNOGLOBULIN E DEFICIENCY AMONG PATIENTS WITH IMMUNODEPENDENT DISORDERS].

June 30, 2015 By Manish Butte

[FREQUENCY OF IMMUNOGLOBULIN E DEFICIENCY AMONG PATIENTS WITH IMMUNODEPENDENT DISORDERS].

Lik Sprava. 2014 Jul-Aug;(7-8):3-9

Authors:

Abstract
Isolated IgE deficiency is one of the most common primary immunodeficiency, which is still underestimated cause of health disorders of modern man. Recent genetic studies report that the cause of the IgE deficiency is immune dysregulation caused by polymorphisms of the gene, which is responsible for the synthesis of activation-induced cytidinedeaminase (AICDA). The Institute of Immunology and Allergology at Bogomolets NMU during the years 2012-2014 were examined 5298 patients with a range of different diseases, which could be suspected violations of immunity. All patients were conducted comprehensive immunological study, and 4476 of them were examined for content of total serum IgE. The criterion for the selection of patients for follow-up began serum IgE < 10 kIU/l. Serum immunoglobulin E was determined by ELISA. Serum IgE < 10 IU/ml was detected in 342 patients (7%). Average reduction in the study group made up (5.30 ± 1.31) IU/ml. Partial deficiency (5-10 kIU/l) was detected in 212 patients (4%), while the total–130 (3%). For follow-up, we are clinically selected group of patients with deficiency of IgE (n = 60) and control group (n = 30). All patients were distributed as per clinical syndromes, and the frequency of their manifestations: sinopulmonary syndrome (63%), gastrointestinal syndrome (13%), autoimmune manifestations (10%), allergic reactions (7%) and chronic fatigue syndrome (7%). The levels of serum IgG, IgA, IgM in the study group were within the age norm (IgG = 1160.00 mg/dl ± 2.88 mg/dl, IgA = 138 g/l ± 37 mg/dl, IgM = 114 mg/dl ± 30 mg/dl). However, only a small proportion of patients was observed decrease in other classes of immunoglobulins in 8 patients with IgG < 700 mg/dL in 16 patients with IgA < 90 mg/dl and 6 patients with decreased serum IgM < 90 mg/dl. These patients were examined the levels of serum IgG subclasses and sIgA levels in saliva. Significant violations by cellular immunity in determining lymphocyte subpopulations by flow cytometry using monoclonal antibodies also were found. Phagocytic indices were also no significant abnormalities. An important aspect of clinical deficiency of immunoglobulin E is its association with diseases of bacterial origin (H. influenza, M. catarrhalis, Str. pneumoniae), indicating a protective role of these antibodies in the mucosa of the respiratory tract. Thus, isolated IgE deficiency is associated with sustained decrease in serum concentrations of immunoglobulin E (< 10 kIU/l) in patients with normal immune status of other indicators that require dispensary and treatment. The results of their study indicate a high incidence of the IgE-deficiency among the population and its high incidence among the humoral defects.

PMID: 26118074 [PubMed – in process]

Stem cell transplantation for primary immunodeficiencies: the European experience.

June 30, 2015 By Manish Butte

Stem cell transplantation for primary immunodeficiencies: the European experience.

Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):516-20

Authors: Cavazzana M, Touzot F, Moshous D, Neven B, Blanche S, Fischer A

Abstract
PURPOSE OF REVIEW: Primary immunodeficiencies (PIDs) constitute a heterogeneous group of inherited disorders affecting the development and/or function of the immune system. This review focuses on the recent advances in hematopoietic stem cell transplantation (HSCT) for PIDs, as it remains the only potentially curative option for many of these diseases.
RECENT FINDINGS: We report on the most recent HSCT European results and suggest some opportunities for better treatment of certain PIDs. Progress on gene therapy is also discussed, as it emerges as an interesting option for PIDs management.
SUMMARY: Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies – such as gene therapy – emerge as an interesting option for some PIDs.

PMID: 25304229 [PubMed – indexed for MEDLINE]

Dual-Tropic CXCR6/CCR5 Simian Immunodeficiency Virus Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in SIV Natural versus Pathogenic Hosts.

June 26, 2015 By Manish Butte

Dual-Tropic CXCR6/CCR5 Simian Immunodeficiency Virus Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in SIV Natural versus Pathogenic Hosts.

J Virol. 2015 Jun 24;

Authors: Elliott ST, Wetzel KS, Francella N, Bryan S, Romero DC, Riddick NE, Shaheen F, Vanderford T, Derdeyn CA, Silvestri G, Paiardini M, Collman RG

Abstract
Natural host sooty mangabeys (SM) infected with SIV exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4+ T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which has been linked to low expression of the canonical SIV entry receptor CCR5 on CD4+ T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by in SM in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIVsmm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIVinfection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4+ T cell subset targeting compared with non-natural hosts, enabling SIV to maintain high level replication without leading to widespread CD4(+) T cell loss.
IMPORTANCE: Natural hosts of SIV such as sooty mangabeys sustain high viral load but do not develop disease, while non-natural hosts like rhesus macaques develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5 suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that, in sooty mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may re-direct the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of non-essential cells and limit infection of critical cells in natural hosts, and thus contribute to benign outcome of infection.

PMID: 26109719 [PubMed – as supplied by publisher]