Alexandra F Freeman

Publications (64)516.48 Total impact

• Article: Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism.

  Amy P Hsu, Kathryn J Sowerwine, Monica G Lawrence, Joie Davis, Carolyn J Henderson, Kol A Zarember, Mary Garofalo, John I Gallin, Douglas B Kuhns, Theo Heller, Joshua D Milner, Jennifer M Puck, Alexandra F Freeman, Steven M Holland
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  ABSTRACT: BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. OBJECTIVE: Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. METHODS: Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. RESULTS: The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. CONCLUSION: STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo.
  The Journal of allergy and clinical immunology 04/2013; · 9.17 Impact Factor
• Article: Lung Parenchyma Surgery in Autosomal Dominant Hyper-IgE Syndrome.

  Alexandra F Freeman, Ellen D Renner, Carolyn Henderson, Anne Langenbeck, Kenneth N Olivier, Amy P Hsu, Beate Hagl, Annette Boos, Joie Davis, Beatriz E Marciano, Lisa Boris, Pamela Welch, Julie Sawalle-Belohradsky, Bernd H Belohradsky, King F Kwong, Steven M Holland
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  ABSTRACT: PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. METHODS: We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. RESULTS: More than 50 % of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. CONCLUSION: Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection.
  Journal of Clinical Immunology 04/2013; · 3.08 Impact Factor
• Article: The use of (14)C-FIAU to predict bacterial thymidine kinase presence: Implications for radiolabeled FIAU bacterial imaging.

  Kristin L Peterson, William C Reid, Alexandra F Freeman, Steven M Holland, Roderic I Pettigrew, Ahmed M Gharib, Dima A Hammoud
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  ABSTRACT: Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with (124)I-FIAU-PET. METHODS: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with (14)C-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter. RESULTS: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of (14)C-FIAU uptake, except for P. aeruginosa. CONCLUSION: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all retain FIAU. Our technique is simple, and can be easily used to assess whether a certain bacterial strain of interest can or cannot be visualized using radiolabeled FIAU.
  Nuclear Medicine and Biology 03/2013; · 3.02 Impact Factor
• Article: Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.

  Gulbu Uzel, Elizabeth P Sampaio, Monica G Lawrence, Amy P Hsu, Mary Hackett, Morna J Dorsey, Richard J Noel, James W Verbsky, Alexandra F Freeman, Erin Janssen, [......], Sarah K Browne, Anahita Agharahimi, Ahmed M Gharib, Sara C Mannurita, Jae Joon Yim, Eleonora Gambineri, Troy Torgerson, Dat Q Tran, Joshua D Milner, Steven M Holland
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  ABSTRACT: 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.
  The Journal of allergy and clinical immunology 03/2013; · 9.17 Impact Factor
• Article: Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation.

  Minal J Bhanushali, Sarah M Kranick, Alexandra F Freeman, Jennifer M Cuellar-Rodriguez, Minoo Battiwalla, Juan C Gea-Banacloche, Dennis D Hickstein, Steven Pavletic, Gary Fahle, Avindra Nath
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  ABSTRACT: OBJECTIVE: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review. METHODS: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT. RESULTS: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT. CONCLUSION: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research.
  Neurology 03/2013; · 8.31 Impact Factor
• Article: Anti-GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis.

  Lindsey B Rosen, Alexandra F Freeman, Lauren M Yang, Kamonwan Jutivorakool, Kenneth N Olivier, Nasikarn Angkasekwinai, Yupin Suputtamongkol, John E Bennett, Vasilios Pyrgos, Peter R Williamson, Li Ding, Steven M Holland, Sarah K Browne
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  ABSTRACT: Cryptococcal meningitis has been described in immunocompromised patients, as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control. We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in four current patients with cryptococcal meningitis and identified and tested 103 archived plasma/cerebrospinal fluid samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody-containing plasmas to inhibit GM-CSF signaling. We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis (PAP). Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified seven HIV-negative patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the seven later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal PBMCs. This effect was limited to their IgG fraction. Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated PAP.
  The Journal of Immunology 03/2013; · 5.79 Impact Factor
• Article: An update on the hyper-IgE syndromes.

  Patrick Fk Yong, Alexandra F Freeman, Karin R Engelhardt, Steven Holland, Jennifer M Puck, Bodo Grimbacher
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  ABSTRACT: The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.
  Arthritis research & therapy 11/2012; 14(6):228. · 4.27 Impact Factor
• Article: Safety of Major Abdominal Surgical Procedures in Patients with Hyperimmunoglobulinemia E (Job's Syndrome): a Changing Paradigm?

  Russell C Langan, Richard M Sherry, Itzhak Avital, Theo Heller, Carolyn Henderson, Steven M Holland, Alexandra F Freeman, Udo Rudloff
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  ABSTRACT: INTRODUCTION: Autosomal dominant hyperimmunoglobulinemia E syndrome (HIES), also called Job's syndrome, is a primary immunodeficiency characterized by the triad of elevated immunoglobulin E levels, eczema, and infections. Its clinical course manifests as recurrent skin and pulmonary infections, and variable skeletal, connective tissue, and vascular abnormalities. There is evidence of abnormal tissue remodeling with pneumatocoeles frequently complicating pyogenic pneumonias and leading to secondary infections that cause the majority of morbidity and mortality. Complications are known to occur after lung surgery with a high frequency of bronchopleural fistulae, but little has been reported concerning abdominal surgeries. DISCUSSION: Here, we report on the outcome and safety of two separate complex cases (hepatectomy and subtotal gastrectomy) and document our entire experience with abdominal surgical procedures performed on patients with HIES. Despite initial complications, all patients eventually made a full recovery. CONCLUSION: As HIES patients now frequently live beyond the third and fourth decade, surgical issues similar to those in the general population may increase. Complex surgical procedures can be performed safely and benefit select patients with HIES, but benefit strongly from multidisciplinary teams and awareness of complications related to abnormal healing. We discuss current treatment and potential complications post-operatively in patients with HIES.
  Journal of Gastrointestinal Surgery 11/2012; · 2.83 Impact Factor
• Article: Serum free light chains as predictors of lymphomagenesis in patients with autosomal dominant hyper-IgE syndrome (Job's syndrome).

  Elisabet E Manasanch, Alexandra F Freeman, Stefania Pittaluga, Rene Costello, Steven M Holland, Ola Landgren
  Leukemia & lymphoma 10/2012; · 2.40 Impact Factor
• Article: Genetic causes of bronchiectasis.

  Christine M Gould, Alexandra F Freeman, Kenneth N Olivier
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  ABSTRACT: Our understanding of the pathologic cycle leading to the development of bronchiectasis is enhanced by greater understanding of the genetic influences contributing to its development. Genome-wide linkage analysis, family-based genetic linkage studies, and the testing of candidate genes have all greatly advanced our understanding of the complexity of the genetic basis of bronchiectasis. This article discusses how allelic variations, gene modifiers, HLA associations, and the interplay of developmental, host, and environmental factors all contribute in lesser and greater degrees, depending on the specific disease, toward the development of bronchiectasis in a spectrum of disease processes.
  Clinics in chest medicine 06/2012; 33(2):249-63. · 2.51 Impact Factor
• Article: Anti-CD20 (rituximab) therapy for anti-IFN-γ autoantibody-associated nontuberculous mycobacterial infection.

  Sarah K Browne, Rifat Zaman, Elizabeth P Sampaio, Kamonwan Jutivorakool, Lindsey B Rosen, Li Ding, Minjal J Pancholi, Lauren M Yang, Debra Long Priel, Gulbu Uzel, Alexandra F Freeman, Carlton E Hayes, Roger Baxter, Stuart H Cohen, Steven M Holland
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  ABSTRACT: Patients with anti-IFN-γ autoantibodies have impaired IFN-γ signaling, leading to severe disseminated infections with intracellular pathogens, especially nontuberculous mycobacteria. Disease may be severe and progressive, despite aggressive treatment. To address the underlying pathogenic IFN-γ autoantibodies we used the therapeutic monoclonal rituximab (anti-CD20) to target patient B cells. All subjects received between 8 and 12 doses of rituximab within the first year to maintain disease remission. Subsequent doses were given for relapsed infection. We report 4 patients with refractory disease treated with rituximab who had clinical and laboratory evidence of therapeutic response as determined by clearance of infection, resolution of inflammation, reduction of anti-IFN-γ autoantibody levels, and improved IFN-γ signaling.
  Blood 03/2012; 119(17):3933-9. · 9.90 Impact Factor
• Article: Detection of molluscum contagiosum virus (MCV) DNA in the plasma of an immunocompromised patient and possible reduction of MCV DNA with CMX-001.

  Jeffrey I Cohen, Wilmer Davila, Mir A Ali, Siu-Ping Turk, Edward W Cowen, Alexandra F Freeman, Kening Wang
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  ABSTRACT: Molluscum contagiosum virus (MCV) is a poxvirus that causes localized papules in healthy persons. We evaluated a woman with severe immunodeficiency and disseminated MCV. During treatment with CMX-001, an antiviral with activity against other poxviruses, MCV DNA was detected in 20% of plasma samples. When the patient was not receiving CMX-001, MCV DNA was detected in 50% of samples. We also noted improvement in warts on her fingers during CMX-001 therapy. Although MCV is caused by direct inoculation of virus into skin in healthy persons, in a severely immunocompromised person MCV DNA was present in blood and may spread by viremia.
  The Journal of Infectious Diseases 03/2012; 205(5):794-7. · 6.41 Impact Factor
• Article: Hyper-IgE syndrome update.

  Kathryn J Sowerwine, Steven M Holland, Alexandra F Freeman
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  ABSTRACT: Autosomal dominant hyper-IgE syndrome (AD-HIES) or Job's syndrome is a primary immunodeficiency with a wide array of clinical features caused by dominant negative mutations in STAT3. In recent years, not only the clinical phenotype of the disease has been expanded with recognition of features such as arterial aneurysms, but also our understanding of the pathogenesis of the disease has greatly improved.
  Annals of the New York Academy of Sciences 02/2012; 1250:25-32. · 3.15 Impact Factor
• Article: Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

  Michael J Ombrello, Elaine F Remmers, Guangping Sun, Alexandra F Freeman, Shrimati Datta, Parizad Torabi-Parizi, Naeha Subramanian, Tom D Bunney, Rhona W Baxendale, Marta S Martins, [......], Elizabeth T Cirulli, David B Goldstein, Eric O Long, Susan Moir, Eric Meffre, Steven M Holland, Daniel L Kastner, Matilda Katan, Hal M Hoffman, Joshua D Milner
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  ABSTRACT: Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ(2) (PLCγ(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).
  New England Journal of Medicine 01/2012; 366(4):330-8. · 53.30 Impact Factor
• Article: Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

  Andrew P Demidowich, Alexandra F Freeman, Douglas B Kuhns, Ivona Aksentijevich, John I Gallin, Maria L Turner, Daniel L Kastner, Steven M Holland
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  ABSTRACT: To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.
  Arthritis & Rheumatism 12/2011; 64(6):2022-7. · 7.87 Impact Factor
• Article: Corticosteroid therapy for liver abscess in chronic granulomatous disease.

  Jennifer W Leiding, Alexandra F Freeman, Beatriz E Marciano, Victoria L Anderson, Gulbu Uzel, Harry L Malech, SukSee DeRavin, David Wilks, Aradhana M Venkatesan, Christa S Zerbe, Theo Heller, Steven M Holland
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  ABSTRACT: Liver abscesses in chronic granulomatous disease (CGD) are typically difficult to treat and often require surgery. We describe 9 X-linked CGD patients with staphylococcal liver abscesses refractory to conventional therapy successfully treated with corticosteroids and antibiotics. Corticosteroids may have a role in treatment of Staphylococcus aureus liver abscesses in CGD.
  Clinical Infectious Diseases 12/2011; 54(5):694-700. · 9.15 Impact Factor
• Article: A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory.

  Andrea M Siegel, Jennifer Heimall, Alexandra F Freeman, Amy P Hsu, Erica Brittain, Jason M Brenchley, Daniel C Douek, Gary H Fahle, Jeffrey I Cohen, Steven M Holland, Joshua D Milner
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  ABSTRACT: STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4(+) and CD8(+) T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors BCL6 and SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses.
  Immunity 11/2011; 35(5):806-18. · 21.64 Impact Factor
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  Article: Cutaneous manifestations of DOCK8 deficiency syndrome.

  Emily Y Chu, Alexandra F Freeman, Huie Jing, Edward W Cowen, Joie Davis, Helen C Su, Steven M Holland, Maria L Chanco Turner
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  ABSTRACT: Mutations in the dedicator of cytokinesis 8 gene (DOCK8) cause a combined primary immunodeficiency syndrome that is characterized by elevated serum IgE levels, depressed IgM levels, eosinophilia, sinopulmonary infections, cutaneous viral infections, and lymphopenia. Many patients with DOCK8 deficiency were previously thought to have a variant of Job's syndrome. Distinguishing between DOCK8 deficiency and Job's syndrome, also referred to as autosomal dominant hyper-IgE syndrome, on the basis of clinical findings alone is challenging. The discovery of the DOCK8 mutation has made it possible to differentiate the cutaneous manifestations of these hyper-IgE syndromes. Twenty-one patients from 14 families with confirmed homozygous or compound heterozygous mutations in DOCK8 were evaluated. Clinical findings included dermatitis, asthma, food and environmental allergies, recurrent sinopulmonary infections, staphylococcal skin abscesses, and severe cutaneous viral infections. Malignant neoplasms, including aggressive cutaneous T-cell lymphoma, anal and vulvar squamous cell carcinomas, and diffuse large B-cell lymphoma, developed in 5 patients during adolescence and young adulthood. DOCK8 deficiency and Job's syndrome share several clinical features, including elevated serum IgE levels, dermatitis, recurrent sinopulmonary infections, and cutaneous staphylococcal abscesses. However, the presence of recalcitrant, widespread cutaneous viral infections, asthma, and food and environmental allergies, as well as the absence of newborn rash and coarse facies, favors the clinical diagnosis of DOCK8 deficiency. Rates of malignancy and overall mortality in patients with DOCK8 deficiency were higher than in those with Job's syndrome, highlighting the value of distinguishing between these conditions and the importance of close monitoring for neoplasia.
  Archives of dermatology 09/2011; 148(1):79-84. · 4.76 Impact Factor
• Article: Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome.

  Vibhav Sekhsaria, Lori E Dodd, Amy P Hsu, Jennifer R Heimall, Alexandra F Freeman, Li Ding, Steven M Holland, Gulbu Uzel
  The Journal of allergy and clinical immunology 08/2011; 128(5):1124-7. · 9.17 Impact Factor
• Article: Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency.

  Jennifer Cuellar-Rodriguez, Juan Gea-Banacloche, Alexandra F Freeman, Amy P Hsu, Christa S Zerbe, Katherine R Calvo, Jennifer Wilder, Roger Kurlander, Kenneth N Olivier, Steven M Holland, Dennis D Hickstein
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  ABSTRACT: We performed nonmyeloablative HSCT in 6 patients with a newly described genetic immunodeficiency syndrome caused by mutations in GATA2-a disease characterized by nontuberculous mycobacterial infection, monocytopenia, B- and NK-cell deficiency, and the propensity to transform to myelodysplastic syndrome/acute myelogenous leukemia. Two patients received peripheral blood stem cells (PBSCs) from matched-related donors, 2 received PBSCs from matched-unrelated donors, and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched-related and -unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI); UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB, GVHD in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplantation. Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype. Registered at www.clinicaltrials.gov as NCT00923364.
  Blood 08/2011; 118(13):3715-20. · 9.90 Impact Factor