Manish Butte

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TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.

J Immunol. 2014 Oct 1;193(7):3736-45

Authors: Tomlinson G, Chimalapati S, Pollard T, Lapp T, Cohen J, Camberlein E, Stafford S, Periselneris J, Aldridge C, Vollmer W, Picard C, Casanova JL, Noursadeghi M, Brown J

Abstract
Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host-pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB-regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2-associated responses were preserved. Experiments using leukocytes from IL-1R-associated kinase-4-deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R-associated kinase-4-mediated inflammatory responses to S. pneumoniae.

PMID: 25172490 [PubMed – indexed for MEDLINE]

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Newborn screening for SCID: where are we now?

Expert Rev Clin Immunol. 2014 Nov 12;:1-9

Authors: Buelow BJ, Routes JM, Verbsky JW

Abstract
Newborn screening (NBS) for severe T-cell lymphopenia/severe combined immunodeficiency using the T-cell receptor excision circle assay continues to expand in the USA and worldwide. Here, we will review why severe combined immunodeficiency is an excellent case for NBS, the outcomes of the first 6 years of screening, and dilemmas surrounding screening and management of infants detected by NBS. We will also discuss the future of NBS for primary immunodeficiencies.

PMID: 25387596 [PubMed – as supplied by publisher]

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A novel immunodeficiency syndrome associated with partial trisomy 19p13.

J Med Genet. 2014 Apr;51(4):254-63

Authors: Seidel MG, Duerr C, Woutsas S, Schwerin-Nagel A, Sadeghi K, Neesen J, Uhrig S, Santos-Valente E, Pickl WF, Schwinger W, Urban C, Boztug K, Förster-Waldl E

Abstract
BACKGROUND: Subtelomeric deletions and duplications may cause syndromic disorders that include features of immunodeficiency. To date, no phenotype of immunological pathology has been linked to partial trisomy 19. We report here on two unrelated male patients showing clinical and laboratory signs of immunodeficiency exhibiting a duplication involving Chromosome 19p13.
METHODS: Both patients underwent a detailed clinical examination. Extended laboratory investigations for immune function, FISH and array comparative genome hybridization (CGH) analyses were performed.
RESULTS: The reported patients were born prematurely with intrauterine growth retardation and share clinical features including neurological impairment, facial dysmorphy and urogenital malformations. Array CGH analyses of both patients showed a largely overlapping terminal duplication affecting Chromosome 19p13. In both affected individuals, the clinical course was marked by recurrent severe infections. Signs of humoral immunodeficiency were detected, including selective antibody deficiency against polysaccharide antigens in patient 1 and reduced IgG1, IgG3 subclass levels and IgM deficiency in patient 2. Class-switched B memory cells were almost absent in both patients. Normal numbers of T cells, B cells and natural killer cells were observed in both boys. Lymphocytic proliferation showed no consistent functional pathology, however, function of granulocytes and monocytes as assessed by oxidative burst test was moderately reduced. Moreover, natural killer cytotoxicity was reduced in both patients. Immunoglobulin substitution resulted in a decreased number and severity of infections and improved thriving in both patients.
CONCLUSIONS: Partial trisomy 19p13 represents a syndromic disorder associating organ malformation and hitherto unrecognised immunodeficiency.

PMID: 24431329 [PubMed – indexed for MEDLINE]

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Current treatment options with immunoglobulin G for the individualisation of care in patients with primary immunodeficiency disease.

Clin Exp Immunol. 2014 Nov 10;

Authors: Jolles S, Orange JS, Gardulf A, Stein MR, Shapiro R, Borte M, Berger M

Abstract
Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin G (IgG) to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualised to provide optimal medical and quality of life outcomes in infants, children, adults and the elderly. Frequency, dose, route of administration, home or infusion-centre administration, and the use of self- or health-professional administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient’s treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self-infusion regimens, however, require independence and self-reliance, good compliance on the part of the patient/parent, and confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self-administer or a lack of self-reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health-related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed.

PMID: 25384609 [PubMed – as supplied by publisher]

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Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.

Pediatr Blood Cancer. 2014 Nov 8;

Authors: Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI

Abstract
BACKGROUND: Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness.
PROCEDURE: Children <15 years old presenting with HLH 1987-2006 in Sweden were identified through the national mortality registry as well as by nation-wide inquiries to all pediatric centers. HLH was diagnosed according to the HLH-2004 diagnostic guidelines (in case of missing data of at least three of the eight diagnostic criteria, fulfillment of four was sufficient for inclusion). We defined primary HLH as patients presenting with HLH requiring transplantation or dying of disease.
RESULTS: Remarkably, the minimal annual incidence rate of primary HLH remained 0.12 per 100,000 children, equating to 1.8 per 100,000 live births. Notably, an increased overall survival was observed in 1997-2006, relative to the period 1987-1996. During the subsequent 5-year period, 2007-2011, the incidence of genetically and/or functionally verified primary HLH was 0.15 per 100,000 children per year, suggesting that new assays may aid the identification of patients with primary HLH.
CONCLUSION: The annual incidence of primary HLH in Sweden is 0.12-0.15 per 100,000 children per year. Pediatr Blood Cancer 2014;9999: 1-7. © 2014 Wiley Periodicals, Inc.

PMID: 25382070 [PubMed – as supplied by publisher]

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Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation.

Case Reports Immunol. 2014;2014:136752

Authors: Cooper CJ, Said S, Hernandez GT

Abstract
Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL), eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess) with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL). Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

PMID: 25379309 [PubMed]

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Common variable immunodeficiency disorder – An uncommon cause for bronchiectasis.

Lung India. 2014 Oct;31(4):394-6

Authors: Panigrahi MK

Abstract
Bronchiectasis continues to be a common respiratory problem of varied etiology. Common variable immunodeficiency disorder (CVID) is an uncommon cause for bronchiectasis. However, the prevalence of bronchiectasis remains very high in patients with CVID. This remains largely an underdiagnosed entity as primary immunodeficiency is not suspected in adults as a cause of bronchiectasis and hence, serum immunoglobulin (Ig) levels are not measured routinely. In addition to bronchiectasis, patients with CVID usually present with various extrapulmonary symptoms. I report here a case of young man who presented with bronchiectasis and multisystem complains who was diagnosed as CVID.

PMID: 25378851 [PubMed]

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Nonalcoholic steatohepatitis in a patient with ataxia-telangiectasia.

Case Reports Hepatol. 2014;2014:761250

Authors: Caballero T, Caba-Molina M, Salmerón J, Gómez-Morales M

Abstract
Ataxia-telangiectasia (A-T) is a rare disease characterized by neurodegenerative alterations, telangiectasia, primary immunodeficiency, extreme sensitivity to radiation, and susceptibility to neoplasms. A-T patients have inactivation of ataxia-telangiectasia-mutated (ATM) protein, which controls DNA double-strand break repair and is involved in oxidative stress response, among other functions; dysfunctional control of reactive oxygen species may be responsible for many of the clinical manifestations of this disease. To the best of our knowledge, hepatic lesions of steatohepatitis have not previously been reported in A-T patients. The present study reports the case of a 22-year-old man diagnosed with A-T at the age of 6 years who was referred to our Digestive Disease Unit with a three-year history of hyperlipidemia and liver test alterations. Core liver biopsy showed similar lesions to those observed in nonalcoholic steatohepatitis. Immunohistochemical staining disclosed the absence of ATM protein in hepatocyte nuclei. We suggest that the liver injury may be mainly attributable to the oxidative stress associated with ATM protein deficiency, although other factors may have made a contribution. We propose the inclusion of A-T among the causes of nonalcoholic steatohepatitis, which may respond to antioxidant therapy.

PMID: 25374730 [PubMed]

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Reversal of Immunoglobulin A Deficiency in Children.

J Clin Immunol. 2014 Nov 5;

Authors: Lim CK, Dahle C, Elvin K, Andersson BA, Rönnelid J, Melén E, Bergström A, Truedsson L, Hammarström L

Abstract
PURPOSE: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD.
METHODS: Clinical laboratory records from 654 pediatric IgA deficient patients, 4-13 years of age, were retrieved from five university hospitals in Sweden. Follow up in the children where IgA serum levels had been routinely measured was subsequently performed. In addition, follow up of the IgA-levels was also performed at 4, 8 and 16 years of age in children who were IgA deficient at the age of 4 years in a Swedish population-based birth cohort study in Stockholm (BAMSE).
RESULTS: Nine out of 39 (23.1 %) children who were identified as IgAD at 4 years of age subsequently increased their serum IgA level above 0.07 g/L. The average age of reversal was 9.53 ± 2.91 years. In addition, 30 out of the 131 (22.9 %) children with serum IgAD when sampled between 5 and 9.99 years of age reversed their serum IgA level with time. The BAMSE follow up study showed a reversal of IgAD noted at 4 years of age in 8 out of 14 IgAD children at 16 years of age (5 at 8 years of age) where 4 were normalized their serum IgA levels while 4 still showed low serum levels of IgA, yet above the level defining IgAD. The results indicate that using 4 years of age, as a cut off for a diagnosis of IgAD may not be appropriate.
CONCLUSIONS: Our findings suggest that a diagnosis of IgAD should not be made before the early teens using 0.07 g/L of IgA in serum as a cut off.

PMID: 25370723 [PubMed – as supplied by publisher]

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Dramatic Improvement in the Multifocal Positron Emission Tomography Findings of a Young Adult with Chronic Granulomatous Disease Following Allogeneic Hematopoietic Stem Cell Transplantation.

J Clin Immunol. 2014 Nov 4;

Authors: Shigemura T, Nakazawa Y, Hirabayashi K, Kobayashi N, Sakashita K, Agematsu K, Koike K

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects of nicotinamide adenine dinucleotide phosphate oxidase. Catalase-positive bacteria and fungi are phagocytosed, but persist within phagocytes, resulting in granulomatous inflammation. Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, HSCT sometimes leads to fatal outcomes related to the exacerbation of persistent infectious or post-infectious inflammatory diseases, particularly in adolescent and young adult patients with a history of recurrent infections and/or multiple granulomas in organs. Here, we present the case of a young adult with X-linked CGD in whom multiple lesions were found in lungs and lymph nodes on both computed tomography and positron emission tomography (PET) scans before allogeneic HSCT, but all the lesions disappeared only on PET scan 5 months after HSCT. Monitoring the activity of multiple pre-existing lesions with PET scan may be beneficial to adolescent and young adult CGD-patients undergoing allogeneic HSCT.

PMID: 25367170 [PubMed – as supplied by publisher]

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