From Infectious Diseases to Primary Immunodeficiencies

Bustamante, Jacinta; Zhang, Shen-Ying; Bernuth, Horst von; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1016/j.iac.2008.01.009

Cited by 24 publications

(24 citation statements)

References 155 publications

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“…Individuals with a defect in production or response to IFN-g have been shown to have increased susceptibility to Mendelian susceptibility to mycobacterial disease, viral disease, or Salmonella infection. These genetic deficiencies have been identified in the following genes: IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, NEMO, and TYK2 (15,56,57). Deficient IL-12 signaling results in impaired Th1 differentiation and IFN-g production.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, neutralization of IL-12 in a mouse model of typhoid fever abrogates host immunity to primary Salmonella infection (13). In addition, clinical reports have shown that patients immunocompromised as a consequence of HIV infection, chronic granulomatous disease, or functional genetic defects in the IL-12/ IL-23 (IL-12b, IL-12Rb1) and IFN-g (IFN-gR1, IFN-gR2, STAT1) pathways are predisposed to Mendelian susceptibility to mycobacterial disease and/or disseminated Salmonella infection (14)(15)(16)(17)(18)(19). The following highlights the importance of systemic immunity to control invasive S. enterica infections.…”

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confidence: 99%

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Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Eva

Yuki

Dauphinee

et al. 2014

The Journal of Immunology

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Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ–mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4Ity14/Ity14 mice. Stat4Ity14/Ity14 mice had increased expression of genes involved in cell–cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4Ity14/Ity14 presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4Ity14/Ity14 mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Eva

Yuki

Dauphinee

et al. 2014

The Journal of Immunology

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“…Die Messung der Sauerstoffburstreaktion in neutrophilen Granulozyten zeigte eine fehlende Bildung reaktiver Sauerstoffmetaboliten, so dass die Diagnose einer septischen Granulomatose ("chronic granulomatous disease", CGD) gestellt werden konnte. [5,9,12,23].…”

Section: Fall 2 (Fortsetzung)unclassified

Diagnostik primärer Immundefekte

Bernuth

Schwarz

Renner

et al. 2011

Monatsschr Kinderheilkd

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Leitthema Der Beitrag von Baumann u. Niehues[2] vermittelt, wann ein angeborener Immundefekt wahrscheinlich ist. Im vorliegenden Beitrag wird ein abgestuftes Vorgehen zur Diagnostik bei Verdacht auf Immundefekt vorgestellt: Die Basisdiagnostik mit Differenzialblutbild und Immunglobulinspiegeln soll die meisten lebensbedrohlichen und häufige immunologische Erkrankungen erkennen. Erweiterte Diagnostik richtet sich am Infektionsspektrum, an Zeichen einer gestörten Immunregulation, an syndromalen Manifestationen und den Ergebnissen der Basisdiagnostik aus. Sie schließt Lücken derselben und grenzt die molekulare Ursache des Immundefekts auf einen Teilbereich des Immunsystems ein. Die exakte Beschreibung des klinischen und immunologischen Phänotyps ist Voraussetzung für eine gezielte und ökonomische molekulargenetische Dia gnostik.

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“…Until the introduction of the pneumococcal vaccine, Streptococcus pneumoniae was considered the most common bacterial pathogen that caused a variety of infections in childhood, including pneumonia, otitis media, meningitis, osteomyelitis, and sepsis (75). Susceptibility to invasive pneumococcal disease may be contributed by several conditions, such as secondary immunodeficiency (HIV infection, chemotherapy), physical disruption of the upper respiratory tract epithelium (as observed after viral respiratory tract infections), anatomical or functional asplenia, as well as several classical PID, including antibody deficiencies (as in XLA), WAS, and some complement deficiencies (5,7,75,76). However, all of these situations contribute to susceptibility to other pathogens as well.…”

Section: Predisposition To Herpes Simplex Encephalitis (Hse)mentioning

confidence: 99%

Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes

2009

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Primary immunodeficiencies (PIDs) have traditionally been defined according to their immunologic phenotype. Far from being concluded, the search for human genes that, when mutated, cause PID is actively being pursued. During the last year, four novel genetic defects that cause severe combined immunodeficiency and severe congenital neutropenia have been identified. At the same time, the immunologic definition of primary immunodeficiencies has been expanded by the recognition that genetic defects affecting innate immunity may result in selective predisposition to certain infections, such as mycobacterial disease, herpes simplex encephalitis, and invasive pneumococcal infections. Studies of genetically determined susceptibility to infections have recently shown that immunologic defects may also account for novel infectious phenotypes, such as malaria or leprosy. Finally, a growing body of evidence indicates that primary immunodeficiencies may present with a noninfectious clinical phenotype that may be restricted to single organs, as in the case of atypical hemolytic uremic syndrome or pulmonary alveolar proteinosis. Overall, these achievements highlight the importance of human models, which often differ from the corresponding animal models. (Pediatr Res 65: 3R-12R, 2009) F or many years, "classical primary immunodeficiencies," in which broad susceptibility to infections is due to mutations of a single gene, have represented a unique model to identify gene products that play a key role in initiating, maintaining, or regulating immune function. The study of diseases such as severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), chronic granulomatous disease (CGD), and many more has led to better understanding of the mechanisms that are involved in development and function of T and B lymphocytes and of phagocytic cells. Since 1952, when unique susceptibility to recurrent infections was linked to lack of serum gammaglobulins (1), and for more than 30 y, primary immunodeficiencies (PID) were mainly defined in terms of clinical and immunologic phenotype. The careful analysis of the pattern of inheritance of PIDs, and the availability of more potent immunologic tools, such as MAb and sophisticated assays to explore the phenotype and function of immune cells, have helped identify an unexpected heterogeneity within clinically homogeneous forms of PID. For example, both X-linked and autosomal recessive forms of SCID have been identified; furthermore, it became clear that-while retaining similar clinical features and the consistent lack of circulating T cells-infants with SCID may or may not present deficiencies also of B and/or NK lymphocytes (2). Similarly, X-linked and autosomal recessive forms of congenital agammaglobulinemia and of CGD were disclosed.The heterogeneity of PIDs was further illustrated when advances in molecular genetics and the development of the Human Genome Project made cloning of PID-causing genes feasible. Yet, many forms of PID are still "orphan" as to the genetic defect...

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From Infectious Diseases to Primary Immunodeficiencies

Cited by 24 publications

References 155 publications

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Diagnostik primärer Immundefekte

Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes

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