Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0603252

Interferon-γ: an overview of signals, mechanisms and functions

Nicole Beydon, Stephanie D. Davis, Enrico Lombardi, Julian L. Allen, Hubertus G. M. Arets, Paul Aurora, Hans Bisgaard, G. Michael Davis, Francine M. Ducharme, Howard Eigen, Monika Gappa, Claude Gaultier, Per M. Gustafsson, Graham L. Hall, Zoltán Hantos, Michael J. R. Healy, Marcus H. Jones, Bent Klug, Karin C. Lødrup Carlsen, Sheila A. McKenzie, François Marchal, Oscar H. Mayer, Peter J. F. M. Merkus, Mohy G. Morris, Ellie Oostveen, J. Jane Pillow, Paul C. Seddon, Michael Silverman, Peter D. Sly, Janet Stocks, Robert S. Tepper, Daphna Vilozni, and Nicola M. Wilson, on behalf of the American Thoracic Society/ European Respiratory Society Working Group on Infant and Young Children Pulmonary Function Testing

An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children.

The T helper lymphocyte is responsible for orchestrating the appropriate immune response to a wide variety of pathogens. The recognition of the polarized T helper cell subsets Th1 and Th2 has led to an understanding of the role of these cells in coordinating a variety of immune responses, both in responses to pathogens and in autoimmune and allergic disease. Here, we discuss the mechanisms that control lineage commitment to the Th1 phenotype. What has recently emerged is a rich understanding of the cytokines, receptors, signal transduction pathways, and transcription factors involved in Th1 differentiation. Although the picture is still incomplete, the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.

Molecular Mechanisms RegulatinG Th1 Immune Responses

▪ Abstract Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guerin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of i...

Genetic dissection of immunity to mycobacteria: the human model

The roles of IFNγ in protection against tumor development and cancer immunoediting

The immunogenetic basis of severe infections caused by bacille Calmette-Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

As little is known about the natural history of bronchial responsiveness and the development of wheezing symptoms in early childhood, a cohort of children at risk of allergy, whose lung function and bronchial responsiveness had been measured in the neonatal period, was followed prospectively for 10 (SD, 0.8) years in order to determine the role of neonatal measurements on wheezing history and later lung function. A potential role for beta-2 adrenoceptor (β2AR) polymorphisms in these relationships was also sought as a secondary objective. Of the original 73 children, wheezing history was available in 65 (89%), and 49 (67%) attended the laboratory for physiological measurements and genotyping of β2AR. Wheezing was categorized as occurring 1) only before the fourth birthday, 2) after the fourth birthday, or 3) never. No relation was seen between neonatal and later lung function. However, neonatal bronchial responsiveness predicted subsequent FEV1 (P = 0.03). Increased neonatal bronchial responsiveness was associated with transient wheeze <4 years but not with later wheeze. Neonatal V′maxFRC was reduced in those possessing Gln27 or Arg16 alleles, but there was no effect of β2AR polymorphisms on FEV1 at 10 years. Wheeze after 4 years of age was typical of classical asthma, as it was strongly related to atopy and bronchial responsiveness at age 10. In conclusion, we confirmed the association of neonatal bronchial responsiveness with both early wheezing and later lung function. We also showed an influence of polymorphisms at both aa16 and aa27 on neonatal lung function. Wheezing beyond 4 years, typical of classical asthma, was unrelated to early measurements of lung function or bronchial responsiveness. Pediatr Pulmonol. 2004; 38:75–81. © 2004 Wiley-Liss, Inc.

Symptoms, lung function, and β2-adrenoceptor polymorphisms in a birth cohort followed for 10 years

Bronchiolitis is a lower respiratory tract infection commonly seen in children less than 1 year of age.1 ,2 Predominantly occurring in winter months, bronchiolitis is in the majority managed in the primary care setting, but it contributes to a significant proportion of the admissions to paediatric wards with a small number requiring intensive care. The National Institute for Health and Care Excellence (NICE) guideline ‘Bronchiolitis in Children’ was published in June 2015.1 It aims to direct management of bronchiolitis in both primary and secondary care. The guideline was developed by the National Collaborating Centre for Women's and Children's Health.

This is the first NICE guideline that covers bronchiolitis. The Scottish Intercollegiate College Network published a guideline in 2006 detailing diagnosis, management and prevention of bronchiolitis.3 The American Association of Paediatrics published a guideline with a similar scope in October 2014.2 Traditionally, there is discrepancy in terminology between the UK and the USA, with clinical conditions described in the UK as virus-induced wheeze or infantile asthma termed bronchiolitis in USA. This makes it difficult to compare studies and guidelines (see table 1 and box 1). Box 1 
### Resources

▸ http://www.nice.org.uk/guidance/ng9 ( link to NICE guideline and full guideline )

▸ http://www.nice.org.uk/guidance/ng9/ifp/chapter/About-this-information ( link to public information on bronchiolitis in children in English )

▸ http://www.nice.org.uk/guidance/ng9/resources ( link …

https://ep.bmj.com/content/edpract/early/2015/12/01/archdischild-2015-309156.full.pdf

NICE clinical guideline: bronchiolitis in children

A 2.5 year old girl with metachromatic leukodystrophy presented with acute respiratory distress and was initially wrongly diagnosed with pneumothorax. Barium meal showed bowel loops in the left hemithorax, which prompted surgical intervention; spontaneous rupture of the diaphragm was diagnosed at surgery.

https://adc.bmj.com/content/archdischild/81/4/341.full.pdf

Spontaneous rupture of the diaphragm

Background: Accurate identification of lower respiratory tract pathogens is important in the management of cystic fibrosis patients. Aim: To evaluate the cough plate as an alternative method of obtaining respiratory samples for microbiological culture. Methods and Results: Using sputum culture as the “gold standard”, the cough plate method identified significantly more positive cases than either dry or moistened cough swabs. Of 20 patients who had a positive sputum culture, 16 had a positive culture on cough plate compared to seven positive cultures each on moistened swab and on dry swab respectively. Conclusions: In this study cough plates were more sensitive than cough swabs in isolating respiratory pathogens in sputum producers. As patients prefer it, the cough plate merits further evaluation, particularly in non-sputum producers.

https://adc.bmj.com/content/archdischild/89/6/577.full.pdf

Jane R. Clarke

Papers

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Symptoms, lung function, and β2-adrenoceptor polymorphisms in a birth cohort followed for 10 years

NICE clinical guideline: bronchiolitis in children

Spontaneous rupture of the diaphragm

Cough plate versus cough swab in patients with cystic fibrosis; a pilot study