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Browne S.K.,National Institute of Allergy and Infectious Diseases
Annual Review of Immunology | Year: 2014

Anticytokine autoantibodies are an emerging mechanism of disease in previously healthy adults. Patients with these syndromes demonstrate a unique infectious phenotype associated with neutralizing autoantibodies that target a specific cytokine. Examples include anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria; anti-granulocyte macrophage colony-stimulating factor autoantibodies and cryptococcal meningitis; anti-interleukin (IL)-6 autoantibodies and staphylococcal skin infection; and anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies and mucocutaneous candidiasis in the setting of either APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome) or thymoma. Other anticytokine autoantibodies may contribute to an infectious phenotype such as anti-granulocyte colony stimulating factor and anti-IFN-α autoantibodies, although the strength of the association is less clear. Their identification not only affects disease management but also may uncover key mechanisms of host defense against specific organisms. Furthermore, it raises the possibility that currently idiopathic diseases will someday be explained by a yet unidentified anticytokine autoantibody. This review focuses on the current understanding, both clinical and mechanistic, of anticytokine autoantibody-Associated immunodeficiency.

Graham B.S.,National Institute of Allergy and Infectious Diseases
Immunological Reviews | Year: 2011

Summary: Respiratory syncytial virus (RSV) is an important cause of respiratory disease causing high rates of hospitalizations in infants, significant morbidity in children and adults, and excess mortality in the elderly. Major barriers to vaccine development include early age of RSV infection, capacity of RSV to evade innate immunity, failure of RSV-induced adaptive immunity to prevent reinfection, history of RSV vaccine-enhanced disease, and lack of an animal model fully permissive to human RSV infection. These biological challenges, safety concerns, and practical issues have significantly prolonged the RSV vaccine development process. One great advantage compared to other difficult viral vaccine targets is that passively administered neutralizing monoclonal antibody is known to protect infants from severe RSV disease. Therefore, the immunological goals for vaccine development are to induce effective neutralizing antibody to prevent infection and to avoid inducing T-cell response patterns associated with enhanced disease. Live-attenuated RSV and replication-competent chimeric viruses are in advanced clinical trials. Gene-based strategies, which can control the specificity and phenotypic properties of RSV-specific T-cell responses utilizing replication-defective vectors and which may improve on immunity from natural infection, are progressing through preclinical testing. Atomic level structural information on RSV envelope glycoproteins in complex with neutralizing antibodies is guiding design of new vaccine antigens that may be able to elicit RSV-specific antibody responses without induction of RSV-specific T-cell responses. These new technologies may allow development of vaccines that can protect against RSV-mediated disease in infants and establish a new immunological paradigm in the host to achieve more durable protection against reinfection. Published 2010. This article is a US Government work and is in the public domain in the USA.

Moss B.,National Institute of Allergy and Infectious Diseases
Immunological Reviews | Year: 2011

Summary: The eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively benign relative of variola virus, the causative agent of smallpox. Nevertheless, recent fears that variola virus may be used as a biological weapon together with the present susceptibility of unimmunized populations have spurred the development of new-generation vaccines that are safer than the original and can be produced by modern methods. Predicting the efficacy of such vaccines in the absence of human smallpox, however, depends on understanding the correlates of protection. This review outlines the biology of poxviruses with particular relevance to vaccine development, describes protein targets of humoral and cellular immunity, compares animal models of orthopoxvirus disease with human smallpox, and considers the status of second- and third-generation smallpox vaccines. Published 2010. This article is a US Government work and is in the public domain in the USA.

Merling R.K.,National Institute of Allergy and Infectious Diseases
Blood | Year: 2013

A variety of somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs), but CD34(+) hematopoietic stem cells (HSCs) present in nonmobilized peripheral blood (PB) would be a convenient target. We report a method for deriving iPSC from PB HSCs using immunobead purification and 2- to 4-day culture to enrich CD34(+) HSCs to 80% ± 9%, followed by reprogramming with loxP-flanked polycistronic (human Oct4, Klf4, Sox2, and c-Myc) STEMCCA-loxP lentivector, or with Sendai vectors. Colonies arising with STEMCCA-loxP were invariably TRA-1-60(+), yielding 5.3 ± 2.8 iPSC colonies per 20 mL PB (n = 17), where most colonies had single-copy STEMCCA-loxP easily excised by transient Cre expression. Colonies arising with Sendai were variably reprogrammed (10%-80% TRA-1-60(+)), with variable yield (6 to >500 TRA-1-60(+) iPSC colonies per 10 mL blood; n = 6). Resultant iPSC clones expressed pluripotent cell markers and generated teratomas. Genomic methylation patterns of STEMCCA-loxP-reprogrammed clones closely matched embryonic stem cells. Furthermore, we showed that iPSCs are derived from the nonmobilized CD34(+) HSCs enriched from PB rather than from any lymphocyte or monocyte contaminants because they lack somatic rearrangements typical of T or B lymphocytes and because purified CD14(+) monocytes do not yield iPSC colonies under these reprogramming conditions.

Strober W.,National Institute of Allergy and Infectious Diseases
Trends in Immunology | Year: 2013

In the past 10 years it has become increasingly apparent that the gut microbiome has profound effects on the immune system to which it is juxtaposed, the mucosal immune system. Here, I explore recent studies in which the effects of the microbiota expand or facilitate anti-inflammatory or regulatory immunological machinery or which favor development of proinflammatory immunological machinery in this system. I then focus on how these opposing processes play out in inflammatory bowel disease (IBD); a disease in which normal immune homeostasis is disturbed and inflammation takes hold. © 2013.

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