[Show abstract][Hide abstract] ABSTRACT: The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine.
Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function.
Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders.
Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.
[Show abstract][Hide abstract] ABSTRACT: Genetics unquestionably contributes to systemic lupus erythematosus (SLE) predisposition, progression and outcome. Nevertheless, single-gene defects causing lupus-like phenotypes have been infrequently documented. The majority of the identified genetic SLE risk factors are, therefore, common variants, responsible for a small effect on the global risk. Recently, genome wide association studies led to the identification of a growing number of gene variants associated with SLE susceptibility, particular disease phenotypes, and antibody profiles. Further studies addressed the biological effects of these variants. In addition, the role of epigenetics has recently been revealed. These combined efforts contributed to a better understanding of SLE pathogenesis and to the characterization of clinically relevant pathways. In this review, we describe SLE-associated single-gene defects, common variants, and epigenetic changes. We also discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice.
Current Rheumatology Reports 09/2013; 15(9):369. · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES:Cornelia de Lange syndrome (CdLS) is a genetic syndrome with multisystem abnormalities. Infections are a significant cause of morbidity and mortality. The goals of our study were to identify the frequency and types of infections in CdLS and to determine if underlying immunodeficiency contributes to the clinical spectrum of this syndrome.METHODS:We assessed infectious histories in 45 patients with CdLS and evaluated conventional immunologic screening tests in 27 patients. Among these 27 subjects, additional phenotypic enumeration of T-cell subsets, expression of activation markers in T cells, and production of cytokines in response to T-cell stimulants were studied in 12 CdLS subjects compared with 12 normal case control subjects.RESULTS:Recurrent infections were reported at high frequency in CdLS patients and included chronic ear infections (53%), chronic viral respiratory infections (46%), pneumonia (42%), sinus infections (33%), oral candidiasis (13%), sepsis (6%), and bacterial skin infections (4%). Full immune evaluation in 27 subjects led to identification of 9 cases of antibody deficiency syndrome in patients with severe forms of CdLS. Subjects with CdLS had decreased percentages of T regulatory cells and T follicular helper cells compared with normal control subjects (P < .05).CONCLUSIONS:This study identified for the first time a high frequency of antibody deficiency in CdLS subjects, indicating a critical need for screening and management of immunodeficiency in CdLS patients with a history of well-documented severe or recurrent infections. Furthermore, our results indicate that impaired T-cell populations may be associated with antibody deficiency in CdLS.
[Show abstract][Hide abstract] ABSTRACT: Chronic recurrent multifocal osteomyelitis is a rare auto-inflammatory condition that primarily affects children and adolescents. It presents with recurrent episodes of pain related to the presence of foci of sterile bone inflammation. The long bones of the lower extremities are more frequently affected and the spine can also be involved. Imaging studies, including whole-body magnetic resonance, are important for diagnosis and detection of asymptomatic lesions. Bone biopsies may be necessary to exclude other diseases, including malignancy and infections. Non-steroidal anti-inflammatory drugs cause relief of symptoms in the majority of cases. Bisphosphonates and TNF-α blockers are alternatives for patients who do not respond or who have spinal involvement.
Journal of Clinical Immunology 05/2013; 33(6). · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 13 year old female presented 2 years ago with episodic CUA, marginally responsive to corticosteroids. Extensive workup was negative for hereditary angioedema, different autoimmune, rheumatological, malignant and infectious conditions. Her CUA initially responded to high dose antihistamines and LTRA but worsened, required hospitalization and was unresponsive to doxepin, accolate, dapsone, cyclosporine, methotrexate and omalizumab. Workup for sinusitis revealed CVID and after 3 IVIG infusions her angioedema resolved. A 16 year old boy with recurrent sinusitis was diagnosed with CVID at age 11 and started IVIG. 4 years later he developed CUA. Extensive workup, as for the girl, was negative. During 2 months of refractory angioedema and ICU care he did not respond to high dose antihistamines, LTRA, corticosteroids, immunomodulatory IVIG doses, icatibant, FFP, omalizumab or berinert. His flares of angioedema continue and he has a tracheostomy for airway protection.The increased incidence of autoimmune disease in CVID is well established. CUA, a common diagnosis, can occur in CVID without relation to the immunodeficiency. 25-50% of CUA patients have auto-antibodies to the high affinity IgE-receptor, however this was not found in our patients. Possibly CVID patients, being prone to autoimmune conditions, have IgG auto-antibodies triggering mast cell and/or basophil activation.
2013 Clinical Immunology Society Annual Meeting; 04/2013
[Show abstract][Hide abstract] ABSTRACT: Human DOCK8 deficiency is associated with diffuse warts, combined immunodeficiency and malignancy. NK cells serve as an innate defense against virally infected cells and function in tumor surveillance. NK cell cytotoxicity requires reorganization of actin at the lytic NK cell immunologic synapse (IS) formed with target cells. Since DOCK8-deficient patients have severe cutaneous viral infections and malignancy, we hypothesized that NK cell function was abnormal. Ten patients with biallelic DOCK8 mutations as well as NK cell lines with stably reduced DOCK8 expression were evaluated experimentally using in vitro NK cell cytotoxicity, F-actin quantification, and high-resolution analyses of the NK cell IS. Cytolytic function was decreased in DOCK8-deficient patients and cell lines and was not corrected by IL-2 stimulation. Importantly, DOCK8 deficiency did not affect total NK cell filamentous actin content, but abrogated filamentous actin accumulation at the lytic IS. DOCK8 deficiency impairs NK cell function by blocking formation of a mature lytic IS owing to ineffective synaptic actin accumulation. This previously unappreciated defective host defense mechanism may explain the unusual susceptibility to viral infections and related cancers in DOCK8-deficient patients.
2013 Clinical Immunology Society Annual Meeting; 04/2013
[Show abstract][Hide abstract] ABSTRACT: Dyskeratosis congenita (DC) is a multisystem disease caused by genetic mutations that result in defective telomere maintenance. Herein, we describe a 17-year-old patient with severe DC, manifested by bone marrow failure, severe immunodeficiency, and enterocolitis requiring prolonged infliximab therapy, who developed fatal hepatic failure caused by an aggressive, infiltrating hepatic angiosarcoma. Although DC patients have known increased risk of developing liver failure and multiple types of malignancy, this report is the first to describe angiosarcoma in a DC patient. Malignancy should thus be considered in the differential diagnosis of progressive liver dysfunction in DC patients.
Journal of Pediatric Hematology/Oncology 04/2013; · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. OBJECTIVES: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. METHODS: A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. RESULTS: DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. CONCLUSIONS: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.
The Journal of allergy and clinical immunology 02/2013; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Influenza is a common respiratory pathogen. Its severity can be unpredictable, but people with chronic illness are at increased risk of severe infection, complications, and death from influenza. This review examines evidence to support various strategies to protect pediatric oncology patients from influenza-related morbidity. Influenza vaccination should be considered standard. Additional evidence-supported measures include antiviral treatment, antiviral prophylaxis, cohorting of patients, and hospital infection control measures. Data from other high-risk populations support the vaccination of family members, double-dose or high-dose vaccination, and the use of barrier methods. These measures have the potential to optimize patient outcomes because there will be fewer treatment interruptions for acute illness. These strategies can also protect patients from prolonged hospitalizations and morbidity related to influenza.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype. METHODS: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals. RESULTS AND CONCLUSIONS: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.
Journal of Medical Genetics 12/2012; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Please cite this paper as: Kersun et al. (2012) A prospective study of chemotherapy immunologic effects and predictors of humoral influenza vaccine responses in a pediatric oncology cohort. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12058. Background: Pediatric oncology patients represent a cohort of individuals uniquely at risk of complications from influenza, yet less likely to respond to the vaccine. It is not yet clear how to best protect this vulnerable population. Methods: We performed a prospective analysis of 177 pediatric oncology patients to define the predictors of influenza vaccine responses. Each variable was examined over three time points and a repeated measure analysis was performed. Results: Patients with ALL vaccinated during induction phase had superior influenza vaccine responses than those subjects vaccinated during post-induction or maintenance phases (P = 0·0237). Higher aggregate HAI titer responses were associated with a higher baseline B-cell count (P = 0·0240), and higher CD4 and CD8 influenza-specific T-cell responses, suggesting prior antigen exposure is a significant contributor. The solid tumor cohort had equivalent responses during all time frames of chemotherapy. Discussion: The optimal protection from influenza of pediatric patients on chemotherapy should include vaccination, but it is clear that not all patients produce high titers of antibodies after vaccination. This study identified biomarkers that could be used to individualize vaccine approaches. Immunologic predictors might have a role in targeting resources, as B-cell counts predicted of vaccine responses among the patients with ALL.
Influenza and Other Respiratory Viruses 11/2012; · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Children with high-risk neuroblastoma have a poor prognosis with chemotherapy alone and hematopoietic stem cell transplantation offers improved survival. As a dose escalation strategy, tandem transplants have been utilized, but are associated with persistent immune compromise. This study evaluated the provision of an autologous co-stimulated, activated T cell product to support immunologic function. EXPERIMENTAL DESIGN: Nineteen subjects with high risk neuroblastoma were enrolled in a pilot phase and twenty three subjects were entered in to the randomized study. Immunologic reconstitution was defined by flow cytometry and functional assays. Next generation sequencing was performed to identify changes to the T cell repertoire. Twenty-two patients were vaccinated to define effects on antibody responses. RESULTS: Subjects who received their autologous co-stimulated T cell product on Day 2 had significantly superior T cell counts and T cell proliferation compared to those who received T cells on Day 90. Early administration of autologous T cells suppressed oligoclonality and enhanced repertoire diversity. The subjects who received the Day 2 T cell product also had better responses to the pneumococcal vaccine. CONCLUSIONS: The infusion of activated T cells can improve immunologic function especially when given early after transplant. This study demonstrated the benefit of providing cell therapies during periods of maximum lymphopenia.
Clinical Cancer Research 10/2012; · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The efficacy of influenza vaccination in patients treated with rituximab is a clinically important question. Rheumatology clinics are populated with patients receiving rituximab for a broad array of disorders. Although several studies have explored the efficacy of other vaccines in rituximab-treated populations, results have been conflicting. We wished to define influenza vaccine efficacy in a rituximab-treated cohort. We examined 17 evaluable subjects treated with rituximab for rheumatologic conditions. T cell subsets, B cells subsets, T cell function, and B cell function were evaluated at specific time points along with hemagglutinination inhibition titers after receiving the standard inactivated influenza vaccine. T cell subset counts were significantly different than controls but did not change with rituximab. B cells depleted in all patients but were in various stages of recovery at the time of vaccination. Influenza vaccine responsiveness was poor overall, with only 16 % of subjects having a four-fold increase in titer. Pre-existing titers were retained throughout the study, however. The ability to respond to the influenza vaccine appeared to be related to the degree of B cell recovery at the time of vaccination. This study emphasizes that antibody responses to vaccine are impaired in subjects treated with rituximab and supports the concept that B cell recovery influences influenza vaccine responsiveness.
Journal of Clinical Immunology 10/2012; · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are few data characterizing the immunologic consequences of chemotherapy for acute myeloid leukemia (AML) and almost nothing is known about the effects of chemotherapy in a pediatric AML cohort. We identified T-cell subsets, B-cell subsets, and used Enzyme-linked immunosorbent spot analyses to define the function of T cells and B cells in 7 pediatric patients with AML on chemotherapy. The data show that the effects of chemotherapy disproportionately target the B cell and depletion of B cells is associated with impaired responses to the inactivated influenza vaccine. Diminished T-cell numbers were also observed although the magnitude of the effect was less than what was seen for B cells. Furthermore, measures of T-cell function were largely intact. We conclude that humoral immunity is significantly affected by chemotherapy for AML.
Journal of Pediatric Hematology/Oncology 09/2012; · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DiGeorge syndrome is associated with a T-lymphocyte immunodeficiency. The prevalence of hypogammaglobulinemia has not been reported. We found that 3% of patients with DiGeorge syndrome were receiving immunoglobulin replacement therapy and 6% of patients over the age of 3 years had hypogammaglobulinemia. We conclude that DiGeorge syndrome is associated with significant humoral immune deficiency.
The Journal of pediatrics 07/2012; 161(5):950-953.e1. · 4.02 Impact Factor