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 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. We reporte for the first time that geosmithia argillacea is an emerging fungus infection in CGD. We report the first 7 cases 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. In collaboration with Mt Sinai School of Medicine, a survey of CGD plasma found high levels of Crohns disease-associated anti-microbial antibodies which were independent of colitis in CGD, raising interesting questions regarding immune dysregulation in CGD. We also are finding that patients with CGD with autoinflammatory lung disease may respond to treatment with methotrexate, though studies are ongoing. Thus, we have increasingly recognized and documented that autoimmune problems can affect patients with a variety of primary immune deficiencies (PID). Many types of PID are more aptly characterized as diseases of immune dysregulation rather than just as immune deficiency with recurrent infections. We published a paper describing two patients in which chronic granulomatous disease appears to have triggered the development of sarcoidosis, an autoimmune disease not generally seen in CGD. This was the first report of sarcoidosis in CGD, although Crohns disease, discoid lupus erythematosis and rheumatoid arthritis have been noted in CGD patients. We proposed in this paper an important new paradigm in understanding CGD, suggesting that there is immune dysregulation associated with CGD that 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. Recently our interest in the autoimmune diseases affecting patients with primary immune deficiencies drew our attention to Severe Combined Immune Deficiency caused by mutations in Rag1 (essential for forming diversity in T lymphocyte receptor) because Rag1 deficiency SCID causes Omenn's syndrome, a severe autoimmunity associated with the immune deficiency. This work resulted in two papers published in 2010 (one primarily from our laboratory;the other from the laboratory of Dr. L Notarangelo at Harvard on which we are collaborators)(De Ravin et al, Blood 2010;Walter et al, J Exp Med 2010). The papers, respectively, define both new clinical features of the disorder and important information about the mechanism by which autoimmunity occurs because of limitations in T cell receptor diversity particularly in the regulatory T cell compartment. Specifically, we identified an extremely unusual presentation of Rag1 defect as a destructive midline granulomatous disease process that resembles Wegener's granulomatosis. This supports our notion of the dysregulation of immunity and hyperinflammation in primary immune deficiencies. 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.
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