The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the ...Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine–derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.
Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was ...reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified. Objectives We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome. Methods We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome. Results Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8) , encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+ T cells. Conclusion Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T h 17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
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.
Background Follicular helper T (TFH ) cells underpin T cell–dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, ...immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH ) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3 , STAT1 , TYK2 , IL21 , IL21R , IL10R , IFNGR1/2 , IL12RB1 , CD40LG , NEMO , ICOS , or BTK. Results Loss-of-function (LOF) mutations in STAT3 , IL10R , CD40LG , NEMO , ICOS , or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo , as corroborated by hypergammaglobulinemia in patients with IFNGR1/2 , STAT1 , and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell–induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
To the Editor: Class IA phosphoinositide 3-kinases (PI3Ks) are lipid kinases that transduce signals received from receptor tyrosine kinases, resulting in activation of downstream effectors including ...AKT, mammalian target of rapamycin, and Bruton tyrosine kinase and regulation of multiple cellular processes.1 PI3K heterodimers are composed of a catalytic p110 subunit and a regulatory subunit p85.2 p110δ, 1 of 3 isoforms of the catalytic subunit, encoded by the PIK3CD gene, is preferentially expressed in leukocytes and plays a critical role in signaling via the B-cell receptor, IL-4R, and, Toll-like receptors and is therefore critical in B-cell development, activation, proliferation, differentiation, and B-cell-mediated immunity.3 Overexpression of p110δ confers oncogenic potential.4 Recently, patients were described with germline gain-of-function (GOF) mutations in PIK3CD leading to immunodeficiency, lymphoproliferation, and increased incidence of B-cell lymphomas, termed p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency5 or activated PI3Kdelta syndrome.6 Clinical and laboratory findings in these patients include recurrent sinopulmonary bacterial infections, bronchiectasis, cytomegalovirus and EBV viremia, lymphoproliferation in tissues, progressive lymphopenia in peripheral blood, autoimmune cytopenias, and variable but mostly abnormal immunoglobulin levels with reduced total and class-switched memory B cells.
Background Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild ...disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. Objective We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. Methods We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation–polyendocrinopathy–enteropathy–X-linked (IPEX)–like phenotype for STAT1 mutations. Results We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M 2 patients). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4+ IL-17–producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4+ T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2–induced STAT5 phosphorylation. Conclusions Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
Abstract Background Chronic granulomatous disease (CGD) is characterized by recurrent life-threatening bacterial and fungal infections and aberrant inflammation. Mutations in CYBB cause X-linked CGD ...and account for 65%-70% of cases in western countries. Objective To understand the clinical manifestations associated with the X-linked CGD carrier state. Methods We undertook a comprehensive retrospective study of 162 affected females. We examined dihydrorhodamine oxidation (DHR) data for percent (%) X chromosome inactivation. We correlated lyonization (%DHR+) with clinical features. Where possible, we followed %DHR+ levels over time. Results Clinical data were available for 93 females: The %DHR+ was 46% (mean) and 47% (median)(SD=24). Using %DHR+ as the criterion for X inactivation, 78% of patients had levels of inactivation 20-80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD-type infections had median %DHR+ of 8% (n=14, range 0.06-48 %); those with only autoimmune or inflammatory manifestations (AIM) had median %DHR+ of 39% (n=31, range 7.4-74%). Those with both infections and autoimmunity had low %DHR+ (n=6, range=3-14%). A %DHR+ <10 % was strongly associated with infections (OR:99). Strong association persisted when the %DHR+ was <20% (OR=12) Autoimmunity was not associated with %DHR+. In two sets of identical twins the %DHR+ populations tracked closely over time. While the %DHR+ populations were very similar between sisters, those between mothers and daughters were unrelated. Conclusions A low %DHR+ strongly predicts infection risk in X-linked CGD carriers, while the carrier state itself is associated with autoimmunity.
To the Editor: Although the efficacy of granulocyte transfusion(s) (GT) has not been definitively proven, they are used as an adjunctive therapy to antimicrobials in the treatment of patients with ...severe or treatment-refractory infections in the setting of neutropenia or granulocyte dysfunction, as in chronic granulomatous disease (CGD).1-4 Despite new and improved antimicrobial prophylactic and therapeutic measures, severe infections continue to be life-threatening and the main cause of death in patients with CGD.5 We retrospectively reviewed the medical records of patients with CGD with severe and refractory infections who received GT at the National Institutes of Health (NIH) Clinical Center, from 1984 to 2012. Statistical analysis of all continuous variables was carried out using the Mann-Whitney test, and all categorical variables that potentially impacted outcome were analyzed using chi-square or Fisher exact test depending on sample size. ...58 GT courses in 40 patients with CGD (22 X-linked CYBB/gp91phox, 17 autosomal-recessive 14, NCF1/p47; 2, CYBA/p22phox; and 1, NCF3/p67phox, and 1 extremely lyonized X-linked CGD female carrier) were analyzed. Alloimmunization remains a concern for those patients anticipating HSCT.7 The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. GT characteristics n = 58 Improved n = 51 Not improved n = 7 Efficacy/significance CL n = 42 pCL n = 9 nCL n = 7∗ CL + pCL vs nCL Age at GT (y)† 16...
PDF
