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High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

PLoS One. 2014;9(6):e100328

Authors: Rakhmanov M, Sic H, Kienzler AK, Fischer B, Rizzi M, Seidl M, Melkaoui K, Unger S, Moehle L, Schmit NE, Deshmukh SD, Ayata CK, Schuh W, Zhang Z, Cosset FL, Verhoeyen E, Peter HH, Voll RE, Salzer U, Eibel H, Warnatz K

Abstract
Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.

PMID: 24945754 [PubMed – indexed for MEDLINE]

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[Malignancies in adult patients with common variable immunodeficiency].

Rev Alerg Mex. 2015 Jan-Mar;62(1):22-27

Authors: López-Rocha E, Rodríguez-Mireles K, Segura-Méndez NH, Yamazaki-Nakashimada MA

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) implies an increased risk of cancer, with an estimated incidence of 11-13%, particularly during the 5th and 6th decade of life. B cell-Hodgkin lymphomas are the more frequent cancer, followed by non-Hodgkin lymphoma and epithelial tumors (gastric, breast, bladder and cervix).
OBJECTIVE: To describe the types of cancers in a cohort of adult patients with CVID.
MATERIAL AND METHOD: An observational, cross-sectional and descriptive study was made in which we reviewed the charts of patients with CVID attending the Primary Immunodeficiencies Clinic at Specialties Hospital Dr. Bernardo Sepulveda, Centro Medico Nacional Siglo XXI, Mexico City.
RESULTS: There were included 23 patients with CVID diagnosis, 13 women (56%) and 10 men (44%), with an average age of 36.7 years. Four patients developed malignancies (2 men and 2 women), with a prevalence of 17.3%. The types of cancers in this group of patients were: B cell-Hodgkin lymphoma (1/23), neuroendocrine carcinoma of the pancreas (1/23), myeloid chronic leukemia (1/23) and thyroid papillary carcinoma (1/23). In two of the subjects the diagnosis of cancer was established previous to CVID diagnosis. The average age of diagnosis of cancer was 27 years (19-34 years).
CONCLUSIONS: In our patients we found different types of malignancies compared to previously described. We consider necessary a screening protocol for an early diagnosis of cancer in these patients. The frequency of cancer in our population was the same as reported in the literature.

PMID: 25758110 [PubMed – as supplied by publisher]

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[Prevalence of gastrointestinal disorders in adults with common variable immunodeficiency at Specialty Hospital Dr. Bernardo Sepulveda].

Rev Alerg Mex. 2015 Jan-Mar;62(1):1-7

Authors: Rodríguez-Negrete EV, Mayoral-Zavala A, Rodríguez-Mireles KA, Díaz de León-Salazar OE, Hernández-Mondragón O, Gómez-Jiménez LM, Moreno-Alcántar R, González-Virla B

Abstract
BACKGROUND: The common variable immunodeficiency (CVID) shows a variable incidence, from 1:15,000 to 1:117,000, without gender predominance. The incidence of gastrointestinal manifestations in these patients ranges from 20-60%, and these may be the first and only clinical manifestation of CVID, while other patients develop gastrointestinal complications during the course of it. In Mexico there is little information regarding the type and frequency of gastrointestinal disorders presented by adult patients with CVID.
OBJECTIVE: To determine the prevalence of gastrointestinal manifestations in adult patients with CVID.
MATERIAL AND METHOD: A descriptive, cross-sectional and observational study was made including patients with CVID attending Primary Immunodeficiency Clinic of Allergy and Clinical Immunology Department, Specialties Hospital, National Medical Center SXXI, Mexico City. All patients underwent gastrointestinal symptoms questionnaire, laboratory, cabinet, endoscopy and breath test for bacterial overgrowth.
RESULTS: We evaluated 17 patients, 8 men and 9 women with an average age of 36 years with a definitive diagnosis of CVID according to international criteria; 59% had abdominal pain, 53% abdominal distension; only 3 patients (17.6%) reported constipation; 47% had chronic diarrhea, of which only 2 (11.8%) had rectal pushing. The diagnoses of gastrointestinal manifestations of this population were: 18% chronic diarrhea, celiac disease and bacterial overgrowth, 24% gastrointestinal functional disorder, 12% constipation and 6% dyspepsia. One patient (6%) had no gastrointestinal symptoms.
CONCLUSIONS: Prevalence of gastrointestinal diseases in adult patients with common variable immunodeficiency was 94%. There was no gender predominance. It is therefore important that patients with CVID will conduct a study protocol that includes a complete medical history considering gastrointestinal symptoms and signs, in order to determine timely diagnosis and therapeutic approach.

PMID: 25758107 [PubMed – as supplied by publisher]

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Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)-Newer Insights into Pathogenesis and Emerging Newer Treatment Options.

J Clin Exp Hepatol. 2014 Sep;4(3):247-56

Authors: Goel A, Elias JE, Eapen CE, Ramakrishna B, Elias E

Abstract
Chronic microangiopathy of portal venules results in idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH). Recent data suggest a role for vasoactive factors of portal venous origin in the pathogenesis of this ‘pure’ vasculopathy of the liver. Enteropathies (often silent), are an important ‘driver’ of this disease. NCIPH is under-recognized and often mis-labeled as cryptogenic cirrhosis. Liver biopsy is needed to prove the diagnosis of NCIPH. In these patients, with advancing disease and increased porto-systemic shunting, the portal venous vasoactive factors bypass the liver filter and contribute to the development of pulmonary vascular endothelial disorders-porto-pulmonary hypertension and hepato-pulmonary syndrome as well as mesangiocapillary glomerulonephritis. Prognosis in NCIPH patients is determined by presence, recognition and management of associated disorders. With better understanding of the pathogenesis of NCIPH, newer treatment options are being explored. Imbalance in ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13): vWF (von-Willebrand factor) ratio is documented in NCIPH patients and may have a pathogenic role. Therapeutic interventions to correct this imbalance may prove to be important in the management of NCIPH.

PMID: 25755567 [PubMed]

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Non-Hodgkin lymphoma in pediatric patients with common variable immunodeficiency.

Eur J Pediatr. 2015 Mar 10;

Authors: Piquer Gibert M, Alsina L, Giner Muñoz MT, Cruz Martínez O, Ruiz Echevarria K, Dominguez O, Plaza Martín AM, Arostegui JI, de Valles G, Juan Otero M, Martin-Mateos MA

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency associated with an increased risk of malignancy in adulthood, with lymphoma as one of the major causes of death. The aim of this study is to describe those malignancies detected in our cohort of pediatric CVID patients. We reviewed the clinical and laboratory data and the treatments and their outcomes in all pediatric CVID patients from our institution that developed a neoplasia. Four malignancies were diagnosed in three out of 27 pediatric CVID patients. Three malignancies were non-Hodgkin lymphoma (NHL) of B cell origin (mean age at diagnosis: 8 years old), and the remaining was a low-grade astrocytoma. Among NHL, two were mucosa-associated lymphoid tissue (MALT) lymphomas and one was associated with Epstein-Barr virus infection. NHL developed before CVID diagnosis in two patients. CVID patients showed different clinical phenotypes and belonged to different groups according Euroclass and Pediatric classification criteria. Conclusions: Malignancies, especially lymphoma, may develop in pediatric CVID patients with no previous signs of lymphoid hyperplasia and even before CVID diagnosis. Consequently, strategies for cancer prevention and/or early diagnosis are required in pediatric CVID patients. What is Known: • Non-Hodgkin lymphomas are the most frequent neoplasm reported in pediatric CVID patients. • “Polyclonal lymphoproliferation” clinical phenotype is associated with increased risk of lymphoid malignancy and group smB-Tr (hi) of the Euroclass classification with an increased risk of lymphadenopathy. What is New: • We report a higher incidence of non-Hodgkin lymphomas compared to previous publications in pediatric patients, and our patients are younger than reported. • None of our patients belongs to “polyclonal lymphoproliferation” clinical phenotype, and a common B cell subphenotyping (smB+21 (lo) ) was identified in two of lo the three patients.

PMID: 25749928 [PubMed – as supplied by publisher]

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The Duesseldorf Warning Signs for Primary Immunodeficiency: Is it Time to Change the Rules?

J Clin Immunol. 2015 Mar 8;

Authors: Lankisch P, Schiffner J, Ghosh S, Babor F, Borkhardt A, Laws HJ

Abstract
OBJECTIVE: Different sets of warning signs can be used if primary immunodeficiency (PID) is suspected: those of the Jeffrey Modell Foundation (JMF), the German Patients’ Organisation for Primary Immunodeficiencies (DSAI) and the Association of the Scientific Medical Societies in Germany (AWMF). A few studies have tested the JMF criteria, with unconvincing results, but the diagnostic models of the DSAI and AWMF have not been tested at all. We set out to establish the utility of these three scoring systems and compare them with our own set of five warning signs (Duesseldorf criteria).
DESIGN: Prospective study.
PATIENTS: Two hundred ten patients admitted to our hospital between 2010 and 2012 with suspected PID.
RESULTS: PID were found in 36 (17 %) of the patients admitted. Of the established sets of warning signs, the JMF and the DSAI had inadequate sensitivity, while the DSAI and the AWMF showed insufficient specificity. Our own criteria were analyzed with regard to maximal specificity and sensitivity (Youden Index) and sensitivity and yielded NPV of 0.89 and 0.91 respectively. Youden index revealed combination of five signs and symptoms: lymphopenia, otitis media >7, failure to thrive, failure to grow normally, pneumonia >1. For maximum negative predictive value the following set was found: lymphopenia, hypogammglobulinemia, failure to thrive, growth disorders, iv antibiotics and abscesses.
CONCLUSION: In contrast to the new, evaluated Duesseldorf criteria, all three established sets of warning signs proved inadequate for preselection of patients for admission to specialized PID centers. The Duesseldorf criteria should now being tested in further studies.

PMID: 25749910 [PubMed – as supplied by publisher]

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[Primary and pulmonary tuberculosis.]

Rev Pneumol Clin. 2015 Mar 4;

Authors: Toujani S, Ben Salah N, Cherif J, Mjid M, Ouahchy Y, Zakhama H, Daghfous J, Beji M, Mehiri-Ben Rhouma N, Louzir B

Abstract
Tuberculosis is a major public health problem worldwide. Indeed, a third of the world population is infected with Mycobacterium tuberculosis and more than 8 million new cases of tuberculosis each year. Pulmonary tuberculosis is the most common location. Its diagnosis is difficult and often established with a delay causing a spread of infection. The diagnosis of tuberculosis infection is mainly based on immunological tests represented by the tuberculin skin test and detection of gamma interferon, while the diagnosis of pulmonary tuberculosis is suspected on epidemiological context, lasting general and respiratory symptoms, contrasting usually with normal lung examination, and a chest radiography showing suggestive lesions. The radioclinical feature may be atypical in patients with extreme ages and in case of immunodeficiency. Confirmation of tuberculosis is bacteriological. Conventional bacteriological methods remain the reference. Innovative tests using the technique of molecular biology have improved the diagnosis of tuberculosis in terms of sensitivity and especially speed. However, those techniques are of limited use.

PMID: 25749628 [PubMed – as supplied by publisher]

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X-linked Inhibitor of Apoptosis Protein Deficiency: More than an X-linked Lymphoproliferative Syndrome.

J Clin Immunol. 2015 Mar 4;

Authors: Aguilar C, Latour S

Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency (also known as X-linked lymphoproliferative syndrome type 2, XLP-2) is a rare primary immunodeficiency. Since the disease was first described in 2006, more than 70 patients suffering from XIAP-deficiency have been reported, thus extending the clinical presentations of the disease. The main clinical features of XLP-2 are (i) elevated susceptibility to hemophagocytic lymphohistiocytosis (HLH, frequently in response to infection with Epstein-Barr virus (EBV)), (ii) recurrent splenomegaly and (iii) inflammatory bowel disease (IBD) with the characteristics of Crohn’s disease. XIAP deficiency is now considered to be one of the genetic causes of IBD in infancy. Although XIAP is an anti-apoptotic molecule, it is also involved in many other pathways, including the regulation of innate immunity and inflammation. XIAP is required for signaling through the Nod-like receptors NOD1 and 2, which are intracellular sensors of bacterial infection. XIAP-deficient T cells (including innate natural killer T cells and mucosal-associated invariant T cells) are overly sensitive to apoptosis. NOD2 function is impaired in XIAP-deficient monocytes. However, the physiopathological mechanisms underlying the clinical phenotypes in XIAP deficiency, notably the HLH and the EBV susceptibility, are not well understood. Here, we review the clinical aspects, molecular etiology and physiopathology of XIAP deficiency.

PMID: 25737324 [PubMed – as supplied by publisher]

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Evolving Practice: X-Linked Agammaglobulinemia and Lung Transplantation.

Am J Transplant. 2015 Mar 3;

Authors: Barnes S, Kotecha S, Douglass JA, Paul E, Hore-Lacey F, Stirling R, Snell GI, Westall GP

Abstract
X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD).

PMID: 25736826 [PubMed – as supplied by publisher]

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The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency.

J Allergy Clin Immunol. 2015 Feb 25;

Authors: Engelhardt KR, Gertz ME, Keles S, Schäffer AA, Sigmund EC, Glocker C, Saghafi S, Pourpak Z, Ceja R, Sassi A, Graham LE, Massaad MJ, Mellouli F, Ben-Mustapha I, Khemiri M, Kilic SS, Etzioni A, Freeman AF, Thiel J, Schulze I, Al-Herz W, Metin A, Sanal Ö, Tezcan I, Yeganeh M, Niehues T, Dueckers G, Weinspach S, Patiroglu T, Unal E, Dasouki M, Yilmaz M, Genel F, Aytekin C, Kutukculer N, Somer A, Kilic M, Reisli I, Camcioglu Y, Gennery AR, Cant AJ, Jones A, Gaspar BH, Arkwright PD, Pietrogrande MC, Baz Z, Al-Tamemi S, Lougaris V, Lefranc G, Megarbane A, Boutros J, Galal N, Bejaoui M, Barbouche MR, Geha RS, Chatila TA, Grimbacher B

Abstract
BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management.
OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings.
METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations.
RESULTS: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations.
CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.

PMID: 25724123 [PubMed – as supplied by publisher]

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