CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin

PLOS ONE, Nov 2019

The skin tuberculin test (TST), an example of a delayed-type hypersensitivity (DTH) reaction, is based on measuring the extent of skin induration to mycobacterial tuberculin (PPD). Little is known about the genetic basis of TST reactivity, widely used for diagnosing TB infection. The study investigated the relationship of the single base change polymorphic variants in CD14 gene (CD14(-159C/T)) with the development of DTH to PPD in BCG-vaccinated Polish Caucasian individuals. We found persistent lack of TST reactivity in about 40% of healthy subjects despite receiving more than one dose of BCG. The TST size was negatively correlated with the number of BCG inoculations. The distribution of C/T genotype was significantly more frequent among TST-negative compared with TST-positive individuals. The concentration of serum sCD14 was positively associated with mCD14 expression, but not with the TST status or CD14(-159C/T) polymorphism. A significant increase in mCD14 expression and serum sCD14 levels was found in TB group. We hypothesize that CD14(-159C/T) polymorphic variants might be one of genetic components in the response to attenuated M. bovis BCG bacilli.

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CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin

December CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin Magdalena Druszczynska 1 2 Marcin Wlodarczyk 1 2 Grzegorz Kielnierowski 2 Michal Seweryn 0 2 Sebastian Wawrocki 1 2 Wieslawa Rudnicka 1 2 0 Center for Medical Genomics OMICRON, Jagiellonian University, Medical College , Cracow , Poland 1 Division of Cell Immunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland, 2 Regional Specialized Hospital of Tuberculosis, Lung Diseases and Rehabilitation , Tuszyn , Poland 2 Editor: Pere-Joan Cardona, Fundacio Institut d'Investigacio en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona , SPAIN The skin tuberculin test (TST), an example of a delayed-type hypersensitivity (DTH) reaction, is based on measuring the extent of skin induration to mycobacterial tuberculin (PPD). Little is known about the genetic basis of TST reactivity, widely used for diagnosing TB infection. The study investigated the relationship of the single base change polymorphic variants in CD14 gene (CD14(-159C/T)) with the development of DTH to PPD in BCG-vaccinated Polish Caucasian individuals. We found persistent lack of TST reactivity in about 40% of healthy subjects despite receiving more than one dose of BCG. The TST size was negatively correlated with the number of BCG inoculations. The distribution of C/T genotype was significantly more frequent among TST-negative compared with TST-positive individuals. The concentration of serum sCD14 was positively associated with mCD14 expression, but not with the TST status or CD14(-159C/T) polymorphism. A significant increase in mCD14 expression and serum sCD14 levels was found in TB group. We hypothesize that CD14 (-159C/T) polymorphic variants might be one of genetic components in the response to attenuated M. bovis BCG bacilli. - Data Availability Statement: All relevant data are within the paper. Funding: This work was supported by the grant from the Polish Ministry of Science and Higher Education (N N402 098539). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) is mentioned together with AIDS and malaria among the most dangerous infectious diseases threatening human health and life. Despite the generally accepted standard of treatment TB is still a huge global epidemiological problem. Annually, there are 7±10 million new TB cases in the world, which is the cause of death of about 3 million people each year [ 1 ]. An attenuated strain of M. bovis BCG (Bacillus Calmette-Guerin) is still the only generally accepted vaccine against TB. Approximately 100 million newborns are vaccinated with BCG every year in more than 180 countries. Despite the fact that it has been more than 80 years since the first administration of BCG, the effectiveness of the vaccine is still the subject of disputes and discussions. BCG vaccination protects children from TB, especially from its most dangerous forms±miliary TB and TB meningitis but the effectiveness of the vaccine in adults does not exceed the average of 50%, ranging from 0% in India and Sub-Saharan Africa to 80% in the United Kingdom [ 2, 3, 4 ]. The WHO recommends that BCG should be given once, on the first day of life, to all children born in countries highly endemic for TB. Since 2006 BCG revaccinations of children, adolescents and adults have been discontinued as they were found ineffective and expensive [ 5 ]. A cutaneous tuberculin skin test (TST) is a classic example of a delayed-type hypersensitivity (DTH) reaction of skin to mycobacterial antigens present in PPD (purified protein derivative). The concept of the test was invented by Robert Koch in 1890 and introduced by Clemens von Pirquet in 1909 as a method for diagnosing M.tb infection [ 6 ]. Tuberculin hypersensitivity, which is a result of intensive infiltration of skin by monocytes and T and B lymphocytes is initiated by Th1 cells localized in the skin that recognize secreted proteins included in the intradermally administered PPD. Although it does not fully reflect the state of immunity to TB, it proves the development of acquired immunity to mycobacterial products, which occurs in the majority, but not all BCG vaccinated individuals. TST is currently the only assay that allows in vivo testing responses to mycobacterial antigens and is still considered a useful tool in TB diagnosis, however high rates of false positive reactions resulting from antigenic similarity between BCG, M.tb and environmental nontuberculous mycobacteria lower its diagnostic usefulness [ 6, 7, 8 ]. It is known that the host genetic background plays a role in the susceptibility to TB, restricting the infection or leading to active TB disease (...truncated)


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Magdalena Druszczynska, Marcin Wlodarczyk, Grzegorz Kielnierowski, Michal Seweryn, Sebastian Wawrocki, Wieslawa Rudnicka. CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin, PLOS ONE, 2017, Volume 12, Issue 12, DOI: 10.1371/journal.pone.0190106