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Absence of the Thymic Shadow in a Neonate Suspected of Primary Immunodeficiency: Not a Straightforward Clinical Sign of Immunodeficiency.

October 15, 2014 By Manish Butte

Absence of the Thymic Shadow in a Neonate Suspected of Primary Immunodeficiency: Not a Straightforward Clinical Sign of Immunodeficiency.

J Pediatr. 2014 Oct 10;

Authors: Nickels AS, Boyce T, Joshi A, Hagan J

PMID: 25311707 [PubMed – as supplied by publisher]

Corrigendum: Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency.

October 14, 2014 By Manish Butte

Corrigendum: Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency.

Front Immunol. 2014;5:460

Authors: Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML

Abstract
[This corrects the article on p. 162 in vol. 5, PMID: 24795713.].

PMID: 25309542 [PubMed – as supplied by publisher]

Comparison of diagnostic criteria for common variable immunodeficiency disorder.

October 14, 2014 By Manish Butte

Comparison of diagnostic criteria for common variable immunodeficiency disorder.

Front Immunol. 2014;5:415

Authors: Ameratunga R, Brewerton M, Slade C, Jordan A, Gillis D, Steele R, Koopmans W, Woon ST

Abstract
Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.

PMID: 25309532 [PubMed]

Utility of next generation sequencing in clinical primary immunodeficiencies.

October 14, 2014 By Manish Butte

Utility of next generation sequencing in clinical primary immunodeficiencies.

Curr Allergy Asthma Rep. 2014 Oct;14(10):468

Authors: Raje N, Soden S, Swanson D, Ciaccio CE, Kingsmore SF, Dinwiddie DL

Abstract
Primary immunodeficiencies (PIDs) are a group of genetically heterogeneous disorders that present with very similar symptoms, complicating definitive diagnosis. More than 240 genes have hitherto been associated with PIDs, of which more than 30 have been identified in the last 3 years. Next generation sequencing (NGS) of genomes or exomes of informative families has played a central role in the discovery of novel PID genes. Furthermore, NGS has the potential to transform clinical molecular testing for established PIDs, allowing all PID differential diagnoses to be tested at once, leading to increased diagnostic yield, while decreasing both the time and cost of obtaining a molecular diagnosis. Given that treatment of PID varies by disease gene, early achievement of a molecular diagnosis is likely to enhance treatment decisions and improve patient outcomes.

PMID: 25149170 [PubMed – indexed for MEDLINE]

Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis.

October 11, 2014 By Manish Butte

Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis.

Aust Dent J. 2014 Oct 10;

Authors: Horie N, Kawano R, Kaneko T, Shimoyama T

Abstract
Methotrexate (MTX) is the primary drug used in the management of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. MTX is a strong immunosuppressive agent and has been reported to cause iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). Stomatitis caused by MTX-related cytotoxicity may occur, but gingival MTX-related LPDs are rare. In this article we present a case of gingival MTX-related LPD in a 60-year-old man with RA. The local findings of the gingival ulceration and alveolar bone exposure were similar to those of bisphosphonate-related osteonecrosis of the jaw. However, he had never received bisphosphonate therapy. The biopsy specimen of the gingival lesion was diagnosed as diffuse large B-cell lymphoma with Epstein-Barr virus positivity. Immediate withdrawal of MTX resulted in marked remission of the LPD. This article is protected by copyright. All rights reserved.

PMID: 25302816 [PubMed – as supplied by publisher]

[Immune reconstitution inflammatory syndrome related with infliximab interruption in patient with Crohn's disease and active tuberculosis.]

October 10, 2014 By Manish Butte

[Immune reconstitution inflammatory syndrome related with infliximab interruption in patient with Crohn’s disease and active tuberculosis.]

Acta Reumatol Port. 2014 Oct 1;

Authors: Carvalho J, Gonçalves C, Duque L, Brito P, Poças J

Abstract
Tumor necrosis factor alpha inhibitors are associated with an increased risk of active tuberculosis. However, its interruption in this setting may trigger a paradoxical response to tuberculosis treatment, as an immune reconstitution inflammatory syndrome. We present the case of a 36-year-old patient, with Crohn’s disease, treated with infliximab for the last 8 years, who was admitted with miliary tuberculosis. A pan-susceptible Mycobacterium tuberculosis strain was isolated. Infliximab was interrupted and standard antituberculous therapy was started, as well as systemic corticotherapy, without any clinical or radiological improvement. After exclusion of other opportunistic infections and primary or acquired immunodeficiency, we considered the possibility of an immune reconstitution inflammatory syndrome triggered by infliximab interruption. Thus, infliximab was reintroduced after 2 months of antituberculous therapy and clinical and radiological improvement was observed.

PMID: 25298330 [PubMed – as supplied by publisher]

Diagnostic assays for chronic granulomatous disease and other neutrophil disorders.

October 10, 2014 By Manish Butte

Diagnostic assays for chronic granulomatous disease and other neutrophil disorders.

Methods Mol Biol. 2014;1124:517-35

Authors: Elloumi HZ, Holland SM

Abstract
Inasmuch as neutrophils are the primary cellular defense against bacterial and fungal infections, disorders that affect these white cells typically predispose individuals to severe and recurrent infections. Therefore, diagnosis of such disorders is an important first step in directing long-term treatment/care for the patient. Herein, we describe methods to identify chronic granulomatous disease, leukocyte adhesion deficiency, and neutropenia. The assays are relatively simple to perform and cost effective and can be performed with equipment available in most laboratories.

PMID: 24504972 [PubMed – indexed for MEDLINE]

Immunoglobulin replacement therapy for primary immunodeficiencies.

October 8, 2014 By Manish Butte

Immunoglobulin replacement therapy for primary immunodeficiencies.

Immunotherapy. 2014 Jul;6(7):853-869

Authors: Peter JG, Chapel H

Abstract
Exogenous antibody therapy to protect patients against infections and toxins is over 100 years old, yet progress continues to be made in the manufacture, administration and application of this type of immunotherapy, known as therapeutic human immunoglobulin. For the majority of patients with primary immunodeficiencies, immunoglobulin replacement is the only life-saving therapy and treatment is life-long, since the vast majority of primary immunodeficiency patients have primary antibody failure. Successful treatment depends on multiple factors: the availability of products, the type of immunodeficiency and any comorbidities of the individual patient. Essential components include long-term follow-up, regular monitoring and a close relationship between the patient and the multidisciplinary clinical immunology team. In this article, we describe the current immunoglobulin products and the types of adverse reactions. We provide evidence for clinical decision-making regarding dosing, route of administration and location of therapy, highlighting current ‘best practice’ recommendations.

PMID: 25290417 [PubMed – as supplied by publisher]

Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chronic Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of Anti-IL-17F Autoantibody.

October 8, 2014 By Manish Butte

Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chronic Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of Anti-IL-17F Autoantibody.

J Immunol. 2014 Oct 6;

Authors: Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, Watanabe N, Takada H, Takezaki S, Chida N, Kobayashi I, Ariga T

Abstract
Heterozygous gain-of-function (GOF) mutations of STAT1 are responsible for chronic mucocutaneous candidiasis disease (CMCD), one of the primary immunodeficiency diseases characterized by susceptibility to mucocutaneous Candida infection. To date, 30 aa changes have been reported: 21 in the coiled-coil domain and 9 in the DNA-binding domain. In this study, we report two novel STAT1 GOF mutations of p.K278E in coiled-coil domain and p.G384D in DNA-binding domain in Japanese CMCD patients. Ectopic expression of these STAT1 mutants in HeLa cells was associated with increased phosphorylation of the mutant and the endogenous wild-type STAT1 due to impaired dephosphorylation, indicating heterodimers of the wild-type and mutant STAT1 cause impaired dephosphorylation, as did homodimers of the mutants. Because IL-17A production was not significantly reduced at least in one of the patients following PMA plus ionomycin stimulation, we further studied Th17-associated cytokines IL-17A, IL-17F, and IL-22 in response to more physiologically relevant stimulations. IL-17A and IL-22 production from PBMCs and CD4(+) cells was significantly reduced in four patients with STAT1 GOF mutations, including the previously reported R274Q in response to anti-CD3 plus anti-CD28 Abs or Candida stimulations. In contrast, IL-17F production was comparable to healthy controls in response to anti-CD3 plus anti-CD28 Abs stimulation. These results indicate impaired production of IL-17A and IL-22 rather than IL-17F was associated with the development of CMCD in these patients. Additionally, only the anti-IL-17F autoantibody was detected in sera from 11 of 17 patients with STAT1 GOF mutations, which may be useful as a marker for this disease.

PMID: 25288569 [PubMed – as supplied by publisher]

Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies.

October 7, 2014 By Manish Butte

Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies.

J Clin Oncol. 2014 Jun 10;32(17):1830-9

Authors: Ponader S, Burger JA

Abstract
Discovery of Bruton’s tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.

PMID: 24778403 [PubMed – indexed for MEDLINE]