Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. Nowadays, COPD is the fourth leading cause of death in the world and its morbidity and mortality are constantly increasing. COPD is characterized by emphysema and chronic bronchitis, usually present simultaneously, with a wide range of severity. COPD was considered as a lung-restricted disease for many years, but from 2000 increasing new evidence, including a number of comorbid conditions accompanying this pathology and the presence of systemic inflammation, indicate that COPD should be considered a systemic disease. Systemic inflammation is the most common systemic manifestation of COPD, and it is associated with a progressive worsening of symptoms and comorbidities. In addition to soluble inflammatory markers, such as TNFα, several research groups focused their attention on peripheral blood leukocytes to assess the changes occurring in these cells in COPD and their relation to the inflammatory pattern in the lungs. However, the data about peripheral leukocyte composition and functional changes in COPD are quite controversial. COPD was traditionally considered as a disease affecting principally males, but rising evidence show that it probably equally concerns male and female populations. However, there are differences in symptoms severity, disease progression and treatment benefits between male and female COPD. Yet, despite the clear evidence of sexual dimorphism in COPD manifestation and progression, there are, to our knowledge, no publications about the difference in the immune state between male and female COPD. Given the lack of data assessing gender-related differences in COPD systemic immune system manifestations and the discordance in the data about circulating leukocyte alterations in COPD, we aimed at thoroughly characterize circulating leukocyte alterations in COPD as compared to age-matched controls. Additionally, results have been stratified according to gender in order to identify male- and/or female-specific COPD immunophenotype. Blood samples from 50 COPD patients and 63 age and sex-matched controls have been collected and analyzed. Flow cytometry analysis revealed the existence of well-defined gender-related pattern of circulating leukocytes in COPD. Specifically, while neutrophilia and increased neutrophil to lymphocyte ratio are hallmarks of COPD in male, on the contrary, female COPD are characterized by a generalized leukopenia. Remarkably, we demonstrated that T cell exhaustion is more prominent in female COPD, nevertheless it increases with disease severity in both male and female groups. Moreover, several observations suggest that that T cells decrease in both male and female COPD may be related to PD1-dependent apoptosis. Additionally, we showed that absolute numbers and/or frequencies of several leukocyte populations correlate with different clinical parameters of COPD disease severity. Given the relevance of the increase in neutrophil absolute count and frequency in male COPD, we subsequently characterized circulating neutrophil phenotype, function and transcriptome of male COPD and related controls. Despite the fact that phenotype and function of neutrophils purified from COPD subjects were comparable to those from controls, differential gene expression analysis highlighted a number of differentially expressed genes. On the basis of the correlation of the differentially expressed genes with the disease severity, we identified a neutrophil-specific COPD signature. Finally, this proposed COPD signature was successfully validated on a larger cohort of male COPD subjects.

HIGH-THROUGHPUT CHARACTERIZATION OF CIRCULATING LEUKOCYTE ALTERATIONS IN MALE AND FEMALE COPD PATIENTS

Troianova
2021

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes obstructed airflow from the lungs. Nowadays, COPD is the fourth leading cause of death in the world and its morbidity and mortality are constantly increasing. COPD is characterized by emphysema and chronic bronchitis, usually present simultaneously, with a wide range of severity. COPD was considered as a lung-restricted disease for many years, but from 2000 increasing new evidence, including a number of comorbid conditions accompanying this pathology and the presence of systemic inflammation, indicate that COPD should be considered a systemic disease. Systemic inflammation is the most common systemic manifestation of COPD, and it is associated with a progressive worsening of symptoms and comorbidities. In addition to soluble inflammatory markers, such as TNFα, several research groups focused their attention on peripheral blood leukocytes to assess the changes occurring in these cells in COPD and their relation to the inflammatory pattern in the lungs. However, the data about peripheral leukocyte composition and functional changes in COPD are quite controversial. COPD was traditionally considered as a disease affecting principally males, but rising evidence show that it probably equally concerns male and female populations. However, there are differences in symptoms severity, disease progression and treatment benefits between male and female COPD. Yet, despite the clear evidence of sexual dimorphism in COPD manifestation and progression, there are, to our knowledge, no publications about the difference in the immune state between male and female COPD. Given the lack of data assessing gender-related differences in COPD systemic immune system manifestations and the discordance in the data about circulating leukocyte alterations in COPD, we aimed at thoroughly characterize circulating leukocyte alterations in COPD as compared to age-matched controls. Additionally, results have been stratified according to gender in order to identify male- and/or female-specific COPD immunophenotype. Blood samples from 50 COPD patients and 63 age and sex-matched controls have been collected and analyzed. Flow cytometry analysis revealed the existence of well-defined gender-related pattern of circulating leukocytes in COPD. Specifically, while neutrophilia and increased neutrophil to lymphocyte ratio are hallmarks of COPD in male, on the contrary, female COPD are characterized by a generalized leukopenia. Remarkably, we demonstrated that T cell exhaustion is more prominent in female COPD, nevertheless it increases with disease severity in both male and female groups. Moreover, several observations suggest that that T cells decrease in both male and female COPD may be related to PD1-dependent apoptosis. Additionally, we showed that absolute numbers and/or frequencies of several leukocyte populations correlate with different clinical parameters of COPD disease severity. Given the relevance of the increase in neutrophil absolute count and frequency in male COPD, we subsequently characterized circulating neutrophil phenotype, function and transcriptome of male COPD and related controls. Despite the fact that phenotype and function of neutrophils purified from COPD subjects were comparable to those from controls, differential gene expression analysis highlighted a number of differentially expressed genes. On the basis of the correlation of the differentially expressed genes with the disease severity, we identified a neutrophil-specific COPD signature. Finally, this proposed COPD signature was successfully validated on a larger cohort of male COPD subjects.
COPD, Chronic Obdstructive Pulmonary Disease, Sex-related Immunity, Circulating Leukocytes
File in questo prodotto:
File Dimensione Formato  
Tesi_Dottorato_Troianova.pdf

accesso aperto

Descrizione: Doctoral thesis on sex-related alterations in circulating leukocytes in Chronic Obstructive Pulmonary Disease
Tipologia: Tesi di dottorato
Licenza: Creative commons
Dimensione 9.24 MB
Formato Adobe PDF
9.24 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/1048691
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact