Research

Primary Immunodeficiencies with Elevated IgE.

Int Rev Immunol. 2015 May 13;

Authors: Mogensen TH

Abstract
In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules. However, in some patients with the relevant phenotype, mutations in these molecules are not identified, suggesting additional genetic etiologies of HIES not yet discovered. As the immunological and molecular basis of HIES is being unraveled, important insights are emerging that may have implications for our understanding of basic principles of immunology and protective immunity as well as for the pathogenesis and clinical management of patients with these complex and challenging PIDs. In this review, are presented the current knowledge on the clinical presentation, infectious phenotype, and the genetic and immunological pathogenesis of hyper-IgE syndromes as well as some other PIDs with elevated levels of IgE.

PMID: 25970001 [PubMed – as supplied by publisher]

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Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration.

AAPS J. 2015 May 13;

Authors: Rosengren S, Dychter SS, Printz MA, Huang L, Schiff RI, Schwarz HP, McVey JK, Drake FH, Maneval DC, Kennard DA, Frost GI, Sugarman BJ, Muchmore DB

Abstract
Recombinant human PH20 hyaluronidase (rHuPH20) is used to facilitate dispersion of subcutaneously delivered fluids and drugs. This report summarizes rHuPH20 immunogenicity findings from clinical trials where rHuPH20 was co-administered with SC human immunoglobulin, trastuzumab, rituximab, or insulin. Plasma samples were obtained from evaluable subjects participating in ten different clinical trials as well as from healthy plasma donors. A bridging immunoassay and a modified hyaluronidase activity assay were used to determine rHuPH20-reactive antibody titers and neutralizing antibodies, respectively. rHuPH20-binding antibody populations from selected subjects with positive titers were affinity-purified and subjected to further characterization such as cross-reactivity with endogenous PH20. Among individual trials, the prevalence of pre-existing rHuPH20-reactive antibodies varied between 3 and 12%, excepting the primary immunodeficiency (PID) studies. Incidence of treatment-induced rHuPH20 antibodies was 2 to 18%, with the highest titers (81,920) observed in PID. No neutralizing antibodies were observed. Within most trials, the kinetics of antibody responses were comparable between pre-existing and treatment-induced antibody responses, although responses classified as persistent were more common in subjects with pre-existing titers. There was no association between antibody positivity and either local or systemic adverse events. Pre-existing and treatment-induced antibody populations were of similar immunoglobulin isotypes and cross-reacted to endogenous PH20 to similar extents. No cross-reactivity to PH20 paralogs was detected. rHuPH20 induces only modest immunogenicity which has no association with adverse events. In addition, antibodies purified from baseline-positive individuals are qualitatively similar to those purified from individuals developing rHuPH20-reactive antibodies following exposure to the enzyme.

PMID: 25967925 [PubMed – as supplied by publisher]

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A Clinical and Laboratory Approach to the Evaluation of Innate Immunity in Pediatric CVID Patients.

Front Immunol. 2015;6:145

Authors: Kutukculer N, Azarsiz E, Karaca NE, Ulusoy E, Koturoglu G, Aksu G

Abstract
Defective adaptive immune responses are well studied in common variable immunodeficiency (CVID) patients; however, more focus is needed on innate immune system defects to explain CVID’s clinical and laboratory heterogeneity. This is the first study comparing migratory function of granulocytes, oxidative burst activity of phagocytic cells, surface integrin expressions on neutrophils and lymphocytes, natural killer (NK) cell numbers and cytotoxic activity, natural killer T cells, lymphocyte subsets such as CD8(+)CD28(+), CD4(+)CTLA-4(+) cells in CVID patients (n: 20) and healthy controls (n: 26). The relationship between laboratory findings and some clinical was also investigated. CD3(+)CD8(+) T cytotoxic cells were found to be elevated in CVID patients, but CD3(+)CD8(+)CD28(+) or CD3(+)CD8(+)CD28(-) cells did not show any significant difference. CD4(+)CTLA-4(+) cell percentages were significantly lower in CVID patients compared to healthy controls. Severe CVID patients had decreased percentages of NK cells with increased NK cell cytotoxicity suggesting possibly increased activation. Furthermore, CD3(-)CD16(+)CD56(+)CD28(+) cells of CVID patients were elevated while percentage of CD28(-) NK cells was decreased. Neutrophil migration percentages were lower but and oxidative burst activity was not affected. CD11a expressions on these cells were depressed in contrast to increased expression of CD18. Innate immunity defects may affect the extent of recurrence and severity of infections in CVID. Our observations highlight some of these associations and indicate the need for further similar studies for improving better innate system evaluation batteries for these patients. Further phenotypic correlations of these analyses will help clinicians reach a more definitive target for the molecular genetic diagnostic of pediatric CVID patients.

PMID: 25964782 [PubMed]

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Early-onset hypogammaglobulinemia: A survey of 44 patients.

J Allergy Clin Immunol. 2015 May 8;

Authors: Brignier AC, Mahlaoui N, Reimann C, Picard C, Kracker S, de Vergnes N, Rieux-Laucat F, Frange P, Suarez F, Neven B, Masseau A, Aladjidi N, Donadieu J, Corby A, Bienvenu B, Cony-Makhoul P, Fischer A, Cavazzana M, Durandy A

PMID: 25959671 [PubMed – as supplied by publisher]

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Related Articles

The intersection of immune deficiency and autoimmunity.

Curr Opin Rheumatol. 2014 Sep;26(5):570-8

Authors: Maggadottir SM, Sullivan KE

Abstract
PURPOSE OF REVIEW: Immune deficiency and autoimmunity have been recognized as cotravelers for decades. This clinically oriented review brings together our evolving mechanistic understanding to highlight associations of particular relevance to rheumatologists.
RECENT FINDINGS: Conceptually, all autoimmunity derives from a loss of tolerance. This distinguishes it from autoinflammation in which the innate immune system is dysregulated without necessarily affecting tolerance. Studies have demonstrated the profound effects of signaling defects, apoptotic pathways and the ramifications of homeostatic proliferation on tolerance. This foundation has translated into an improved understanding of the specific associations of autoimmune diseases with immune deficiencies. This important foundation paves the way for personalized treatment strategies.
SUMMARY: This review identifies critical mechanisms important to conceptualize the association of primary immune deficiencies and autoimmunity. It highlights a growing appreciation of the hidden single gene defects affecting T-cells within the group of patients with early-onset pleomorphic autoimmunity.

PMID: 25014038 [PubMed – indexed for MEDLINE]

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Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses.

J Innate Immun. 2014;6(3):253-62

Authors: Smeekens SP, Huttenhower C, Riza A, van de Veerdonk FL, Zeeuwen PL, Schalkwijk J, van der Meer JW, Xavier RJ, Netea MG, Gevers D

Abstract
BACKGROUND: Chronic mucocutaneous candidiasis (CMC) and hyper-IgE syndrome (HIES) are primary immunodeficiencies mainly caused by mutations in STAT1 and STAT3, respectively. CMC and HIES patients have an increased risk for skin and mucosal infections with fungal pathogens and Staphylococcus aureus. However, it is unknown whether the genetic defects in these patients also affect the skin and mucosal microbiome, which in turn may influence host defense mechanisms.
METHODS: The skin and oral microbiome of CMC and HIES patients was compared to that of healthy controls at five body sites using 16S rRNA sequencing. The influence of skin colonizers on the immune response was investigated using in vitro experiments.
RESULTS: The microbiome of CMC and HIES patients contained more Gram-negative bacteria, especially Acinetobacter spp., and less of the normal Corynebacterium spp. compared to healthy controls. Exposure of human primary leukocytes to Acinetobacter suppressed the cytokine response to Candida albicans and S. aureus, while the normal corynebacteria did not suppress cytokine responses.
DISCUSSION: These results demonstrate that central mediators of immune responses like STAT1 and STAT3 not only directly influence immune responses, but also result in changes in the skin microbiome that in turn can amplify the defective immune response against fungal and microbial pathogens.

PMID: 23796786 [PubMed – indexed for MEDLINE]

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Immunoglobulin deficiency in patients with Streptococcus pneumoniae or Haemophilus influenzae invasive infections.

Int J Infect Dis. 2014 Feb;19:79-84

Authors: Martinot M, Oswald L, Parisi E, Etienne E, Argy N, Grawey I, De Briel D, Zadeh MM, Federici L, Blaison G, Koebel C, Jaulhac B, Hansmann Y, Christmann D

Abstract
OBJECTIVES: Immunoglobulin (Ig) deficiency is a well-known risk factor for Streptococcus pneumoniae or Haemophilus influenzae infections and noteworthy invasive diseases. However, the proportion of these deficiencies in cases of invasive disease is unknown. The objective of this study was to evaluate the rate of Ig deficiency in cases of invasive disease.
METHODS: A prospective study was conducted from January 2008 to October 2010 in two French hospitals. Measurement of Ig levels was carried out in patients hospitalized for invasive diseases.
RESULTS: A total of 119 patients were enrolled in the study, with nine cases of H. influenzae and 110 cases of S. pneumoniae invasive disease. There were 18 cases of meningitis, 79 of invasive pneumonia, and 22 other invasive diseases. Forty-five patients (37.8%) had an Ig abnormality, 37 of whom had an Ig deficiency (20 IgG <6g/l, four isolated IgA <0.7g/l, and 13 isolated IgM <0.5g/l), while eight had an elevated monoclonal paraprotein. Nineteen of these 45 patients had a clearly defined Ig abnormality, with five primary deficiencies (three common variable immunodeficiencies and two complete IgA deficiencies) and 14 secondary deficiencies, mainly lymphoproliferative disorders. All these deficiencies were either not known or not substituted.
CONCLUSIONS: Humoral deficiency is frequent in patients with S. pneumoniae or H. influenzae invasive disease and Ig dosage should be proposed systematically after such infections.

PMID: 24326288 [PubMed – indexed for MEDLINE]

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[Orofacial clinical manifestations in adult patients with variable common immunodeficiency].

Rev Alerg Mex. 2015 Apr-Jun;62(2):107-111

Authors: Chávez-García AA, Moreno-Alba MÁ, Elizalde-Monroy M, Segura-Méndez NH, Romero-Flores J, Cambray-Gutiérrez JC, López-Pérez P, Del Rivero-Hernández LG

Abstract
BACKGROUND: Common variable immunodeficiency is the primary immunodeficiency (CVID) frequently found in adults. Its prevalence is estimated from 1:25,000 to 75,000 alive newborns; there are variations by ethnic groups, it is estimated about 50-70% in Caucasian patients. Oral cavity lesions are rarely found in adult patients with CVID, there are reports about lesions on pediatric patients mostly caused by infections.
OBJECTIVE: To describe the orofacial lesions (oral, maxillofacial and neck area) affecting adults with CVID.
MATERIAL AND METHOD: A transversal, prospective study was done in patients with CVID attended at Specialties Hospital, CMN SXXI, Mexico City. Patients where examined by the oral and maxillofacial surgeon and clinical findings were reported, then the descriptive analysis of the lesions was done.
RESULTS: We evaluated 26 patients, 16 female and 10 males, average age of 38.6 years. In 18/26 patients we found oral lesions on 7 different types. The most frequent was minor salivary glands hiperplasia (19/26),petechiae (12/26) and herpetic ulcers (7/26). In head and neck, we found 4 different lesions, the most common was lymphadenopathy <2cm (4/26).
CONCLUSIONS: The immunologic alterations associated to CVID favors the development of lesions mainly of infectious and probably autoinmune origin that affects the oral cavity and head and neck area.

PMID: 25958373 [PubMed – as supplied by publisher]

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[Discriminant analysis to predict the clinical diagnosis of primary immunodeficiencies: a preliminary report].

Rev Alerg Mex. 2015 Apr-Jun;62(2):125-133

Authors: Murata C, Ramírez AB, Ramírez G, Cruz A, Morales JL, Lugo-Reyes SO

Abstract
BACKGROUND: The features in a clinical history from a patient with suspected primary immunodeficiency (PID) direct the differential diagnosis through pattern recognition. PIDs are a heterogeneous group of more than 250 congenital diseases with increased susceptibility to infection, inflammation, autoimmunity, allergy and malignancy. Linear discriminant analysis (LDA) is a multivariate supervised classification method to sort objects of study into groups by finding linear combinations of a number of variables.
OBJECTIVE: To identify the features that best explain membership of pediatric PID patients to a group of defect or disease.
MATERIAL AND METHOD: An analytic cross-sectional study was done with a pre-existing database with clinical and laboratory records from 168 patients with PID, followed at the National Institute of Pediatrics during 1991-2012, it was used to build linear discriminant models that would explain membership of each patient to the different group defects and to the most prevalent PIDs in our registry. After a preliminary run only 30 features were included (4 demographic, 10 clinical, 10 laboratory, 6 germs), with which the training models were developed through a stepwise regression algorithm. We compared the automatic feature selection with a selection made by a human expert, and then assessed the diagnostic usefulness of the resulting models (sensitivity, specificity, prediction accuracy and kappa coefficient), with 95% confidence intervals.
RESULTS: The models incorporated 6 to 14 features to explain membership of PID patients to the five most abundant defect groups (combined, antibody, well-defined, dysregulation and phagocytosis), and to the four most prevalent PID diseases (X-linked agammaglobulinemia, chronic granulomatous disease, common variable immunodeficiency and ataxiatelangiectasia). In practically all cases of feature selection the machine outperformed the human expert. Diagnosis prediction using the equations created had a global accuracy of 83 to 94%, with sensitivity of 60 to 100%, specificity of 83 to 95% and kappa coefficient of 0.37 to 0.76.
CONCLUSIONS: In general, the selection of features has clinical plausibility, and the practical advantage of utilizing only clinical attributes, infecting germs and routine lab results (blood cell counts and serum immunoglobulins). The performance of the model as a diagnostic tool was acceptable. The study’s main limitations are a limited sample size and a lack of cross validation. This is only the first step in the construction of a machine learning system, with a wider approach that includes a larger database and different methodologies, to assist the clinical diagnosis of primary immunodeficiencies.

PMID: 25958376 [PubMed – as supplied by publisher]

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[Structural and functional heart diseases in adult patients with common variable immunodeficiency].

Rev Alerg Mex. 2015 Apr-Jun;62(2):91-97

Authors: Cambray-Gutiérrez JC, Fernández-Muñoz MJ, Del Rivero-Hernández LG, López-Pérez P, Chávez-García AA, Segura-Méndez NH

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the primary immunodeficiency with the largest number of comorbidities in adulthood. It has been associated with bronchiectasis between 17%-76%, and these with the presence of cardiovascular complications such as pulmonary hypertension and heart failure. The new image methods of diagnosis, to assess the cardiovascular structural and functional conformation of adult patients with bronchiectasis, help to establish more efficient and timely diagnoses.
OBJECTIVE: To define the presence of structural and functional heart disease in CVID patients by transthoracic echocardiography.
MATERIAL AND METHOD: A cross-sectional study was done in a cohort of 26 adult patients diagnosed with CVID and replacement therapy with intravenous immunoglobulin (IVIG), belonging to the Immunodeficiency Clinic. All patients underwent transthoracic echocardiography and tissue ECO doopler; the results were evaluated by a echocardiographer physician.
RESULTS: We evaluated 26 patients, of whom 10 patients were male, with a mean age of 35.7 ± 13.7 years. The results of thoracic echocardiography of the left cardiac cavities found the following functional changes: 17 patients presented with mitral insufficiency and only 2 had aortic insufficiency, none symptoms. Regarding the structural alterations of the right cavities: 8 adults with CVID had right cavities growth and 5 of them, hypermobile atrial septum was reported; respect to functional alterations, 24 patients had tricuspid insufficiency; in 20 it was mild and only in 3 is was moderate. Up to 12 had pulmonary valve insufficiency, and 8 had pulmonary arterial hypertension (PAH); of which, in 2 it was mild and in one it was moderate; and 4 patients had PSAP in high limit values.
CONCLUSIONS: Patients with CVID, despite having a high incidence of bronchiectasis, had low incidence of PAH, but a significant number of patients had PSAP in high cutoff level, so, these patients should be monitored annually, because probably they will evolve to PAH in the future. Also, they have a high incidence of mild valvular regurgitation due to mild degenerative changes with valvular sclerosis, therefore, they also require regular monitoring.

PMID: 25958371 [PubMed – as supplied by publisher]

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