This project involves the conduct of diagnostic, natural history assessment and therapeutic clinical trials for inherited immune deficiencies. This project specifically include studies of the diagnostic procedures (including genetic diagnosis), and screens for treatment modalities that are alternatives to current standard treatment, such as novel allogeneic transplantation regimen and gene therapy (treatment modalities that are the subject of companion projects with the same types of patients). Patients with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21 often are treated as infants. XSCID patients are studied at NIH who have failed to achieve or maintain immune reconstitution after having as infants received non-conditioning haploidentical parental bone marrow transplants. Such patient often have waning immunity near the end of their first decade of life, and also have associated severe problems with short stature, malnutrition from gastrointestinal malabsorption, various kinds of pulmonary dysfunction, and chronic sinusitis. We have noted a defect in response to growth hormone in such patients and in our small clinical trial to treat short stature in a few pre-adolescent XSCID children with Increlex, improved growth was observed in some patients and no adverse effects were observed. We follow many patients with both autosomal and X-linked forms of chronic granulomatous disease (AR or X-CGD). Patients with CGD have defective circulating blood neutrophils that fail to produce microbicidal hydrogen peroxide. They suffer from recurrent life threatening infections and premature mortality. Some of these emerging infections are first diagnosed in CGD patients, for example, geosmithia argillacea as an emerging fungus infection in CGD (De Ravin SS, et al. Clin Infect Dis 52:e136, 2011). In addition to recurrent infections including many kinds of difficult to treat fungus infections, CGD patients often have a variety of autoinflammatory syndromes. In addition, we have also noted a high incidence of actual well-defined autoimmune disorders in CGD such as Crohns disease of the gastrointestinal system, systemic lupus erythematosis, sarcoidosis, IgA nephropathy, anti-phospholipid syndrome, and other syndromes of autoimmunity. In a small prospective clinical trial, we treated some CGD subjects with severe Crohn's-like disease with TNFa inhibitors such as infliximab and adalimumab and studied their responses to treatment as well as the mucosal immunity in CGD patients regardless of symptomatic inflammatory bowel disease. This is an ongoing study to better understand the pathogenesis of inflammatory bowel disease in CGD. Another organ in CGD that exhibits hyperinflammation is the lungs, which may respond to treatment with methotrexate, though studies are ongoing. Autoimmune problems can affect patients with a variety of primary immune deficiencies (PID), so that many types of PID are more aptly characterized as diseases of immune dysregulation rather than just as immune deficiency with recurrent infections. We have described in CGD autoimmune manifestations such as sarcoidosis, Crohns disease, discoid lupus erythematosis and juvenile idiopathic arthritis, and proposed an important new paradigm in understanding CGD, suggesting that the immune dysregulation associated with CGD may trigger autoimmune diseases in a subset of patients, where the specific autoimmune disease triggered likely related to an individual patients genetic predisposition to a particular autoimmune disease. This has important therapeutic management implications in that specific therapies proven to be effective for the specific autoimmune disease triggered by CGD must be used in such patients rather than just the general clinical management modalities designed to prevent infections, or control the general inflammation common to most CGD patients. CGD is a disorder of the phagocyte NADPH oxidase complex, and therefore a defect of the innate immune system. However abnormalities in B cell populations have been reported. Our study of the B cells in CGD subjects has provided new insight into alterations in the memory B-cell compartment that occur in CGD. An analysis of their responses to flu vaccines suggest that their B cell compartment is not functionally impaired. Moreover, non-classic IgG+CD27 negative memory B cells which are elevated in CGD may contribute to humoral immunologic memory, an observation that may be true in other disease settings. We have recently successfully created and corrected CGD in primitive iPS cells generated from CGD patients. Moreover,our group has also recently demonstrated that sufficient number of CD34+ stem cells can be obtained from a small quantity of peripheral blood for reprogramming to generate adequate numbers of iPS cells, providing a great resource for investigators in general. We have also in collaboration with Dr. Philip Murphy and Dr. David McDermott in the Lab of Molecular Immunity, NIAID, been studying the problems that affect patients with WHIM syndrome noting severe neutopenia, increased incidence of human papilloma related cancers and other problems such as chronic pulmonary disease. Studies are in progress to determine better treatments for this disorder. Study of WHIM also interfaced with our related project that seeks to understand the role of CXCR4 (defective in WHIM) in trafficking of hematopoietic cells, including CD34 stem cells into and out of the bone marrow. Our interest in patients with congenital neutropenia led to identification of some patients with syndromic features (venous angiectasia, urogenital and cardiac structural defects) recently attributed to defects in glucose-6-phosphatase, catalytic subunit 3. We plan to evaluate a broader array of patients with primary immune deficiencies, in particular, those with neutrophil defects and SCID.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$494,034
Indirect Cost
City
State
Country
Zip Code
Kuhns, Douglas B; Fink, Danielle L; Choi, Uimook et al. (2016) Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 128:2135-2143
Lood, Christian; Blanco, Luz P; Purmalek, Monica M et al. (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22:146-53
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Liu, Qian; Pan, Catherina; Lopez, Lizbeeth et al. (2016) WHIM Syndrome Caused by Waldenström's Macroglobulinemia-Associated Mutation CXCR4 (L329fs). J Clin Immunol 36:397-405
Khangura, Sajneet K; Kamal, Natasha; Ho, Nancy et al. (2016) Gastrointestinal Features of Chronic Granulomatous Disease Found During Endoscopy. Clin Gastroenterol Hepatol 14:395-402.e5
De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi et al. (2016) Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol 34:424-9
Feingold, Paul L; Quadri, Humair S; Steinberg, Seth M et al. (2016) Thoracic Surgery in Chronic Granulomatous Disease: a 25-Year Single-Institution Experience. J Clin Immunol 36:677-83
Felsburg, Peter J; De Ravin, Suk See; Malech, Harry L et al. (2015) Gene therapy studies in a canine model of X-linked severe combined immunodeficiency. Hum Gene Ther Clin Dev 26:50-6
McDermott, David H; Gao, Ji-Liang; Liu, Qian et al. (2015) Chromothriptic cure of WHIM syndrome. Cell 160:686-99
Marciano, Beatriz E; Spalding, Christine; Fitzgerald, Alan et al. (2015) Common severe infections in chronic granulomatous disease. Clin Infect Dis 60:1176-83

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