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1.  [No title available] 
PMCID: PMC3943692  PMID: 24292724
2.  Requirements for growth and IL-10 expression of highly purified human T regulatory cells 
Journal of clinical immunology  2012;32(5):1118-1128.
Human regulatory T cells (TR) cells have potential for the treatment of a variety of immune mediated diseases but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human TR cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimulation with a superagonistic anti-CD28 antibody (clone 9D4) and IL-2 partially reversed the proliferative defect, and this correlated with reversal of the defective calcium mobilization in these cells. Dendritic cells were effective at promoting TR cell proliferation, and under these conditions the proliferative capacity of TR cells was comparable to conventional CD4 lymphocytes. Blocking TGF-β activity abrogated IL-10 expression from these cells, while addition of TGF-β resulted in IL-10 production. These data demonstrate that highly purified populations of TR cells are anergic even in the presence of high doses of IL-2. Furthermore, antigen presenting cells provide proper co-stimulation to overcome the anergic phenotype of TR cells, and under these conditions they are highly sensitive to IL-2. In addition, these data demonstrate for the first time that TGF-β is critical to enable human TR cells to express IL-10.
doi:10.1007/s10875-012-9701-4
PMCID: PMC4271826  PMID: 22562448
3.  Whole Genome Sequencing Reveals a Chromosome 9p Deletion Causing DOCK8 Deficiency in an Adult Diagnosed with Hyper IgE Syndrome Who Developed Progressive Multifocal Leukoencephalopathy 
Purpose
A 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing.
Methods
Whole genome sequencing was completed to 30X coverage, and whole genome SNP typing was used to complement these data. The methods revealed single nucleotide variants, structural variants, and copy number variants across the genome. Genome-wide data were analyzed for homozygous or compound heterozygous null mutations for all protein coding genes. Mutations were confirmed by PCR and/or Sanger sequencing.
Results
Whole genome analysis revealed deletions near the telomere of both copies of chromosome 9p. Several genes, including DOCK8, were impacted by the deletions but it was unclear whether each chromosome had identical or distinct deletions. PCR across the impacted region combined with Sanger sequencing of selected fragments confirmed a homozygous deletion from position 10,211 to 586,751.
Conclusion
While several genes are impacted by the deletion, DOCK8 deficiency is the most probable cause of HIES in this patient. DOCK8 deficiency may have also predisposed the patient to develop PML.
Electronic supplementary material
The online version of this article (doi:10.1007/s10875-014-0114-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10875-014-0114-4
PMCID: PMC4306731  PMID: 25388448
Hyper IgE Syndrome; DOCK8 deficiency; primary immune deficiency; Progressive Multifocal Leukoencephalopathy (PML); JC virus
4.  Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease 
Journal of clinical immunology  2013;33(8):10.1007/s10875-013-9953-7.
We describe a boy who developed autoinflammatory (chronic sterile multifocal osteomyelitis) and autoimmune (autoimmune cytopenias; vitiligo) phenotypes who subsequently developed disseminated granulomatous disease. Whole exome sequencing revealed homozygous RAG1 mutations thus expanding the spectrum of combined immunodeficiency with autoimmunity and granuloma that can occur with RAG deficiency.
doi:10.1007/s10875-013-9953-7
PMCID: PMC3873094  PMID: 24122031
Granulomatous disease; Chronic recurrent multifocal osteomyelitis (CRMO); Immune deficiency; Recombinase activating gene (RAG); Autoimmune hemolytic anemia
5.  Interleukin-2-Inducible T-Cell Kinase (ITK) Deficiency - Clinical and Molecular Aspects 
Journal of Clinical Immunology  2014;34(8):892-899.
In patients with underlying immunodeficiency, Epstein-Barr virus (EBV) may lead to severe immune dysregulation manifesting as fatal mononucleosis, lymphoma, lymphoproliferative disease (LPD), lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis (HLH) and dysgammaglobulinemia. Several newly discovered primary immunodeficiencies (STK4, CD27, MAGT1, CORO1A) have been described in recent years; our group and collaborators were able to reveal the pathogenicity of mutations in the Interleukin-2-inducible T-cell Kinase (ITK) in a cohort of nine patients with most patients presenting with massive EBV B-cell lymphoproliferation. This review summarizes the clinical and immunological findings in these patients. Moreover, we describe the functional consequences of the mutations and draw comparisons with the extensively investigated function of ITK in vitro and in the murine model.
doi:10.1007/s10875-014-0110-8
PMCID: PMC4220104  PMID: 25339095
Epstein-Barr virus (EBV); IL-2 inducible kinase (ITK) deficiency
6.  Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis 
Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities.
doi:10.1007/s10875-014-0103-7
PMCID: PMC4306732  PMID: 25312698
Tuberculosis; TLRs; inflammasome
7.  Newborn Screening for SCID in New York State: Experience from the First Two Years 
Journal of clinical immunology  2014;34(3):289-303.
Purpose
To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS).
Methods
The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency.
Results
During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as ‘other’. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant’s DNA.
Conclusions
Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.
doi:10.1007/s10875-014-0006-7
PMCID: PMC4090801  PMID: 24578017
Severe Combined Immunodeficiency; newborn screening; DiGeorge syndrome; idiopathic T-cell lymphopenia
8.  Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1 
Journal of clinical immunology  2013;33(7):1223-1239.
Purpose & methods
The immunopathogenic mechanisms responsible for debilitating neurodegenerative and oncologic diseases associated with human T-cell leukemia virus type 1 (HTLV-1) are not fully understood. In this respect, a patient cohort from HTLV-1 endemic region that included seronegative controls (controls), asymptomatic carriers (ACs), and patients with adult T-cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was analyzed for CD8+ T cells polyfunctionality in response to the viral antigen Tax.
Results
Compared to ACs, ATL and HAM/TSP patients had lower frequency and polyfunctionality of CTLs in response to Tax suggesting dysfunction of CD8+ T cells in these individuals. As an underlying mechanism, programmed death-1 (PD-1) receptor was found to be highly unregulated in Tax-responsive as well as total CD8+ T cells from ATL and HAM/TSP but not from ACs and directly correlated with the lack of polyfunctionality in these individuals. Further, PD-1 expression showed a direct whereas MIP-1α expression had an indirect correlation with the proviral load providing new insights about the immunopathogenesis of HTLV-associated diseases. Additionally, we identified key cytokine signatures defining the immune activation status of clinical samples by the luminex assay.
Conclusions
Collectively, our findings suggest that reconstitution of fully functional CTLs, stimulation of MIP-1α expression, and/or blockade of the PD-1 pathway are potential approaches for immunotherapy and therapeutic vaccine against HTLV-mediated diseases.
doi:10.1007/s10875-013-9918-x
PMCID: PMC3784618  PMID: 23888327
Chronic viral infections; Cytotoxic T cell; CD4+ T cell; CD8+ T cell; Human T-cell leukemia virus type 1; HTLV-associated myelopathy/tropical spastic paraparesis; Tax
9.  The Natural History of Children with Severe Combined Immunodeficiency: Baseline Features of the First Fifty Patients of the Primary Immune Deficiency Treatment Consortium Prospective Study 6901 
Journal of clinical immunology  2013;33(7):1156-1164.
The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID.
From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research.
Most patients (92%) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92%) were treated with HCT within 1–2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement.
The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes.
doi:10.1007/s10875-013-9917-y
PMCID: PMC3784642  PMID: 23818196
Severe Combined Immunodeficiency; Hematopoietic Cell Transplantation; Newborn Screening
10.  Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease 
Journal of clinical immunology  2013;33(7):10.1007/s10875-013-9926-x.
Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss with periods of hearing decline triggered by unknown stimuli. Here we examined whether an environmental exposure to mold in these AIED patients is sufficient to generate a pro-inflammatory response that may, in part, explain periods of acute exacerbation of disease. We hypothesized that molds may stimulate an aberrant immune response in these patients as both several Aspergillus species and penecillium share homology with the LCCL domain of the inner ear protein, cochlin. We showed the presence of higher levels of anti-mold IgG in plasma of AIED patients at dilution of 1:256 (p=0.032) and anti-cochlin IgG 1:256 (p=0.0094 and at 1:512 p=0.024) as compared with controls. Exposure of peripheral blood mononuclear cells (PBMC) of AIED patients to mold resulted in an up-regulation of IL-1β mRNA expression, enhanced IL-1β and IL-6 secretion, and generation of IL-17 expressing cells in mold-sensitive AIED patients, suggesting mold acts as a PAMP in a subset of these patients. Naïve B cells secreted IgM when stimulated with conditioned supernatant from AIED patients’ monocytes treated with mold extract. In conclusion, the present studies indicate that fungal exposure can trigger autoimmunity in a subset of susceptible AIED patients.
doi:10.1007/s10875-013-9926-x
PMCID: PMC3809107  PMID: 23912888
mold; cochlin; Interleukin-1 beta (IL-1β); LCCL domain; Autoimmune Inner Ear Disease (AIED)
11.  Modulation of mTOR Effector Phosphoproteins in Blood Basophils from Allergic Patients 
Journal of clinical immunology  2012;32(3):565-573.
The mammalian target of rapamycin (mTOR) pathway contributes to various immunoinflammatory processes. Yet, its potential involvement in basophil responses in allergy remains unclear. In this pilot study, we quantified two key mTOR effector phosphoproteins, the eukaryotic initiation factor 4E (peIF4E) and S6 ribosomal protein (pS6rp), in blood basophils from nut allergy patients (NA, N= 16) and healthy controls (HC, N= 13).Without stimulation in vitro, basophil peIF4E levels were higher in NA than HC subjects (P=0.014). Stimulation with nut (offending) but not chicken / rice (non-offending) extract increased basophil peIF4E and pS6rp levels (+32%, P=0.018, and +98%, P=0.0026, respectively) in NA but not HC subjects, concomitant with increased surface levels of CD203c and CD63, both known to reflect basophil activation. Pre-treatment with the mTOR inhibitor rapamycin decreased pS6rp and CD203c responses in nut extract-stimulated basophils in NA subjects. Thus, basophil responses to offending allergens are associated with modulation of mTOR effector phosphoproteins.
doi:10.1007/s10875-012-9651-x
PMCID: PMC4161465  PMID: 22350221
Eosinophils; flow cytometry; food allergy; inflammation; neutrophils
12.  Combined Immunodeficiency Evolving into Predominant CD4+ Lymphopenia Caused by Somatic Chimerism in JAK3 
Journal of Clinical Immunology  2014;34(8):941-953.
Purpose
Idiopathic CD4 lymphopenia constitutes a heterogeneous group of immunodeficiencies with characteristically low CD4+ T-cell counts with largely unknown genetic etiology. We here sought to determine the underlying molecular cause in an index family with two patients suffering from combined immunodeficiency that evolved into predominant CD4+ lymphopenia. The more severely affected index patient also presented with selective antibody deficiency against bacterial polysaccharide antigens.
Methods
For the genetic analysis, we used combined homozygosity mapping and exome sequencing. Functional assays included immunoblot analysis, flow cytometry and TCR Vβ spectratyping.
Results
A novel homozygous missense mutation was revealed in the kinase domain of JAK3 (c.T3196C, p.Cys1066Arg). Further analysis showed revertant chimerism in CD8+ T-cells in both patients. The additional presence of revertant CD4+ T-cells was associated with a milder clinical and immunological phenotype in the second patient, although the role somatic chimerism plays in amelioration of disease phenotype is uncertain, as presence of revertant cells had no effect on residual CD4 cell JAK3 signaling function. Residual activity of JAK3-dependent STAT3 and STAT5 signaling was also found in immortalized B-cell lines indicating a hypomorphic nature of the described mutation which likely contributes to the milder clinical phenotype.
Conclusions
We here present the first case of revertant mosaicism in JAK3 deficiency, manifesting as combined immunodeficiency evolving into predominant CD4+ lymphopenia. Revertant chimerism or hypomorphic mutations in genes typically associated with more severe T-cell deficiency should be considered when assessing patients with milder forms of combined immunodeficiencies.
Electronic supplementary material
The online version of this article (doi:10.1007/s10875-014-0088-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10875-014-0088-2
PMCID: PMC4220108  PMID: 25205547
Primary immunodeficiency; idiopathic CD4+ lymphopenia; JAK3 deficiency; somatic reversion; somatic mosaicism; TCR Vβ spectratyping
13.  Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility 
Journal of clinical immunology  2014;34(3):272-276.
Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients’ elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.
doi:10.1007/s10875-014-0012-9
PMCID: PMC4159085  PMID: 24610295
Immunodeficiency; hyper IgM; PI3K; lymphoma; cancer susceptibility; epstein-barr virus
14.  Autoimmunity and Inflammation in X-linked Agammaglobulinemia 
Journal of clinical immunology  2014;34(6):627-632.
Purpose
In the past, XLA was described as associated with several inflammatory conditions, but with adequate immune globulin treatment, these are presumed to have diminished. The actual prevalence is not known.
Methods
A web-based patient survey was conducted December 2011- February 2012. Respondents were recruited from the Immune Deficiency Foundation (IDF) patient database, online patient discussion forums and physician recruitment of patients. The questionnaire was developed jointly by IDF and by members of the USIDNET-XLA Disease Specific Working Group. Information regarding inflammatory conditions in patients with XLA was also obtained from the United States Immune Deficiency Network (USIDNET) Registry.
Results
Based on 128 unique patient survey responses, the majority of respondents (69 %) reported having at least one inflammatory symptom, with 53 % reporting multiple symptoms. However, only 28 % had actually been formally diagnosed with an inflammatory condition. Although 20 % reported painful joints and 11 % reported swelling of the joints, only 7 % were given a diagnosis of arthritis. Similarly, 21 % reported symptoms of chronic diarrhea and 17 % reported abdominal pain, however only 4 % had been diagnosed with Crohn’s disease. Data from the USIDNET Registry on 149 patients with XLA, revealed that 12 % had pain, swelling or arthralgias, while 18 % had been diagnosed with arthritis. Similarly, 7 % of these patients had abdominal pain and 9 % chronic diarrhea.
Conclusions
Although patients with XLA are generally considered to have a low risk of autoimmune or inflammatory disease compared to other PIDD cohorts, data from this patient survey and a national registry indicate that a significant proportion of patients with XLA have symptoms that are consistent with a diagnosis of arthritis, inflammatory bowel disease or other inflammatory condition. Documented diagnoses of inflammatory diseases were less common but still increased over the general population. Additional data is required to begin implementation of careful monitoring of patients with XLA for these conditions. Early diagnosis and proper treatment may optimize clinical outcomes for these patients.
doi:10.1007/s10875-014-0056-x
PMCID: PMC4157090  PMID: 24909997
X-linked agammaglobulinemia; primary immunodeficiency; antibody deficiency; autoimmune; inflammation
15.  INTERFERON ALPHA TREATMENT OF PATIENTS WITH IMPAIRED INTERFERON GAMMA SIGNALING 
Journal of clinical immunology  2013;33(5):991-1001.
Patients with deficiency in the interferon gamma receptor (IFN-γR) are unable to respond properly to IFN-γ and develop severe infections with nontuberculous mycobacteria (NTM). IFN-γ and IFN-α are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-α for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-γ signaling defect.
We treated four patients with IFN-γR deficiency with adjunctive IFN-α therapy in addition to best available antimicrobial therapy, with or without IFN-γ, depending on the defect. During IFN-α treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-α driven gene expression in patients’ cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-α therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-γ signaling who have refractory infections, IFN-α may have adjunctive anti-mycobacterial effects.
doi:10.1007/s10875-013-9882-5
PMCID: PMC4136390  PMID: 23512243
IFN-γ receptor deficiency; mycobacterial disease; IFN-α; STAT1; IFN-γ; nontuberculous mycobacteria
16.  Chitotriosidase is a Biomarker for the Resistance to World Trade Center Lung Injury in New York City Firefighters 
Journal of clinical immunology  2013;33(6):1134-1142.
Purpose
World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction.
Methods
With a nested case-control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after one second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N=125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N=126). In a secondary analysis, resistant cases (N=66) had FEV1 (≥107%) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function.
Results
Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1≥107%. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort.
Conclusions
Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline.
doi:10.1007/s10875-013-9913-2
PMCID: PMC3722498  PMID: 23744081
Chitotriosidase; Immunoglobulin E; WTC Particulate Matter; Pulmonary Function Testing
17.  A NOVEL STAT1 MUTATION ASSOCIATED WITH DISSEMINATED MYCOBACTERIAL DISEASE 
Journal of clinical immunology  2012;32(4):681-689.
STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961 T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.
doi:10.1007/s10875-012-9659-2
PMCID: PMC4112946  PMID: 22437822
STAT1; SH2 domain; mycobacterial disease; IFN-γ
18.  Method of Identifying Natural Antibodies for Remyelination 
Journal of clinical immunology  2010;30(0 1):S50-S55.
Naturally autoantibodies are part of the normal human immunoglobulin repertoire. These antibodies react to self antigens, are usually polyreactive with relatively low affinity and typically of the IgM isotype. Mouse natural IgMs that stimulated remyelination in CNS demyelinating disease all shared the characteristics of binding to the surface of live oligodendrocytes and myelinated tracts in living slices of CNS tissue. A screen for human IgMs with similar character resulted in two human natural antibodies that, when injected peripherally into animal models of demyelination induced remyelination. A recombinant human IgM was constructed (rHIgM22) that also promoted remyelination in vivo. Very small doses of this IgM are required for the promotion of remyelination—the EC50 is 460 ng per 20 gram mouse. It is clear that after peripheral delivery rHIgM22 enters the CNS and accumulates in CNS lesions. rHIgM22 was tracked in living mice using ferritin-labeled anti-human mu chain antibodies visualized by MRI and traditional immunocytochemistry. Although the exact antigen recognized by rHIgM22 is not clear, all mouse IgMs that promote remyelination bind to myelin membrane lipids, suggesting the antigen for rHIgM22 is similar. We propose that the IgMs bind to CNS cells and reorganize the membrane initiating a signal that results in oligodendrocyte proliferation and/or protection the end result being more myelin. Recombinant natural human antibodies are potentially important therapeutic molecules that may modulate a wide spectrum of human disease.
doi:10.1007/s10875-010-9406-5
PMCID: PMC4108241  PMID: 20387101
19.  Adequate Patient’s Outcome Achieved with Short Immunoglobulin Replacement Intervals in Severe Antibody Deficiencies 
Journal of Clinical Immunology  2014;34(7):813-819.
Purpose
The optimal immune globulin replacement dosages required over time to minimize infection risks in patients with Primary Antibody Deficiencies are not definitely established. As with many interventions, there may be specific subgroups of patients who are more likely to benefit from treatment with higher or lower dosages. The aim of the study was to verify the efficacy of a rationale for individualized immune globulin utilization and to elucidate the effects of care on patient outcome.
Methods
Single centre interventional study on 108 patients with Primary Antibody Deficiencies. The objective was to determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).
Results
Ninthly eight per cent of patients achieved the objective of the study. Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite pre-medications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. The adverse events were reduced by administrating low Ig dosages in a single setting. Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks.
Conclusions
The exact timing and optimal immunoglobulin prophylaxis regimen might be tailored according to clinical and immunological markers.
doi:10.1007/s10875-014-0081-9
PMCID: PMC4165867  PMID: 25047154
Primary antibody deficiencies; patients’ outcomes; replacement therapy; immunoglobulins; intervals; dosages; cost
20.  Acidomonas Methanolica-Associated Necrotizing Lymphadenitis in a Patient with Chronic Granulomatous Disease 
Journal of clinical immunology  2012;32(6):1193-1196.
Purpose
Adenitis for which no causative organism can be isolated is a common occurrence in patients with chronic granulomatous disease (CGD). Here we identify Acidomonas methanolica as a pathogen associated with adenitis in a patient with CGD.
Methods
The causative pathogen was obtained after prolonged incubation of an excised lymph node in thioglycolate broth. Identification was carried out by sequencing the 16s rRNA. Immunoblots were prepared utilizing protein extracts from the case patient’s A. methanolica isolate, an ATCC type strain of A. methanolica and G. bethesdensis.
Results
Fastidious gram-negative rods grew after prolonged incubation of an excised lymph node in thioglycolate broth. Sequencing of the 16s rRNA identified the organism as A. methanolica. Immunoblot confirmed the pathogen’s role in the patient’s adenitis by showing the patient’s specific immune response to the organism.
Conclusions
A. methanolica is the second member of the family, Acetobacteaceae to be associated with adenitis in patients with CGD.
doi:10.1007/s10875-012-9728-6
PMCID: PMC4103907  PMID: 22752310
Chronic granulomatous disease; Acidomonas methanolica
21.  Streptococcal Infections in Patients with Chronic Granulomatous Disease: Case Report and Review of the Literature 
Streptococcus intermedius caused a liver abscess in a patient with chronic granulomatous disease (CGD). In contrast to typical staphylococcal abscesses in CGD, this abscess was liquid, easily drained, and resolved without surgery or steroids. This case and literature review provide insight into this organism’s pathogenesis, including in CGD.
doi:10.1007/s10875-012-9823-8
PMCID: PMC4103909  PMID: 23108438
Chronic granulomatous disease; liver abscess; streptococcus intermedius
22.  Coronary Abnormalities in Hyper-IgE Recurrent Infection Syndrome: Depiction at Coronary MDCT Angiography 
Journal of clinical immunology  2011;31(3):338-345.
OBJECTIVE
Hyper-IgE recurrent infection syndrome (HIES or Job’s syndrome) is a rare disorder affecting the immune system and connective tissues. The purpose of this study is to describe the coronary abnormalities in genetically confirmed HIES patients as depicted by coronary MDCT angiography (MDCTA).
CONCLUSION
Coronary MDCTA has provided an opportunity for noninvasive evaluation of the coronary arteries in patients with HIES. These coronary abnormalities vary from tortuosity to ectatic dilation and focal aneurysms of the coronary arteries. Such an evaluation has potential value in identifying new aspects of this disease and thereby providing better understanding of the pathophysiology of the disorder.
doi:10.1007/s10875-011-9515-9
PMCID: PMC4091041  PMID: 21494893
coronary abnormalities; coronary aneurysms; ectatic coronaries; hyper-IgE recurrent infection syndrome (HIES or Job’s syndrome); coronary MDCT angiography
23.  Quality of Life in Children with Primary Antibody Deficiency 
Journal of Clinical Immunology  2014;34(7):844-852.
Primary antibody deficiency disorders (PADs) can have an excellent outlook if diagnosed early and treated appropriately, but require lifelong treatment with immunoglobulin replacement. Some carry risks of inflammatory complications even with optimal treatment. Quality of life (QoL) and the psychological impact of PADs has been relatively little studied, particularly in children. The purpose of this study was to evaluate QoL and psychological impact in a large group of children affected by a range of PADs, as well as a group with transient hypogammaglobulinemia of infancy (THI). Both parental and, where appropriate, child ratings, were collected using standardised questionnaires (PedsQL and SDQ). Higher rates of psychological difficulties, particularly emotional and peer-relationship difficulties were found in children with PAD when compared with healthy controls. Quality of life was poorer than in healthy controls, and also worse than in children affected by diabetes mellitus. Variations in QoL and the degree of psychological difficulties were found between specific diagnostic groups, with children affected by THI being amongst those with the lowest scores for QoL. Further studies are needed to corroborate and extend these findings, but this study confirms previous findings that primary antibody deficiency has a significant impact on quality of life and psychological well-being, and additionally suggests that the impact varies according to severity of the underlying condition. For those with significant difficulties psychological intervention at an early stage may be beneficial.
Electronic supplementary material
The online version of this article (doi:10.1007/s10875-014-0072-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s10875-014-0072-x
PMCID: PMC4165866  PMID: 25005831
Primary antibody deficiency; quality of life; psychological difficulty; immunoglobulin; children
24.  A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside 
Journal of clinical immunology  2013;33(6):1078-1087.
The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way.We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.
doi:10.1007/s10875-013-9901-6
PMCID: PMC4083684  PMID: 23657403
Primary immunodeficiency; classification; IUIS; diagnosis tool
25.  Diabetes, Renal and Cardiovascular Disease in p47phox−/− Chronic Granulomatous Disease 
Journal of clinical immunology  2013;33(4):725-730.
Chronic granulomatous disease is a rare immunodeficiency due to defects in the phagocyte NADPH oxidase. The X-linked form (gp91phox deficiency) accounts for about 70 % of cases; autosomal recessive p47phox deficiency accounts for about 25 % of cases. We identified a 10 % incidence of diabetes in p47phox deficient CGD, but none in X-linked CGD. Renal and cardiovascular diseases were also higher in p47phox deficiency. p47phox deficient CGD has noninfectious morbidities distinct from those in X-linked CGD.
doi:10.1007/s10875-013-9871-8
PMCID: PMC4082696  PMID: 23386289
Chronic granulomatous disease; p47phox; diabetes; kidney; renal

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