Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the lung. These diseases are characterized by pulmonary inflammation and poor respiratory function. The underlying mechanisms controlling these diseases are still being elucidated. Interestingly, COPD patients and in some cases asthma patients develop inducible Bronchus Associated Lymphoid Tissue (iBALT). Bronchus Associated Lymphoid Tissue (BALT) was considered by early investigators to be a mucosal secondary lymphoid tissue embedded in the walls of the large airways, similar to Peyer's patches in the small intestine. However, we now know that BALT is not constitutively present in all mammalian species, notably mice and humans, and is induced in response to microbial exposure or other types of pulmonary inflammation. Therefore, the inducible lymphoid tissues in the lung may be more properly referred to as tertiary or ectopic lymphoid tissues and we have coined the term inducible BALT (iBALT) to describe them. Once formed, iBALT is maintained in the lung for several months or even longer and acts as a secondary lymphoid tissue that supports primary and secondary B and T cell responses to pulmonary antigens and pathogens. Importantly, pulmonary immune responses that occur in the presence of iBALT often have dramatically different characteristics than those that occur in the absence of iBALT. Thus, prior exposures of the respiratory tract can lead to lung remodeling and the development of iBALT, which regulates subsequent pulmonary immune responses via poorly defined mechanisms. We now have preliminary data showing that iBALT requires IL-17 and IL-22-expressing T cells for its formation, suggesting that iBALT forms in response to and participates in Th17 immune responses. Given the important role for Th17 cells in pulmonary diseases like asthma and COPD and the dramatic effects that iBALT has on pulmonary immune function to infectious agents, we believe that it is important to define the cellular and molecular mechanisms that control iBALT formation and to determine the mechanisms by which iBALT regulates pulmonary immune responses in the context of inflammatory disease.

Public Health Relevance

The experiments in this proposal will determine the mechanisms underlying the development of specific lymphoid structures that develop in the lung following pulmonary infection or inflammation. They will also determine the function of these structures in the context of pulmonary diseases like asthma and COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069409-14
Application #
8847763
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2001-09-30
Project End
2017-05-31
Budget Start
2015-06-01
Budget End
2017-05-31
Support Year
14
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Meza-Perez, Selene; Randall, Troy D (2017) Immunological Functions of the Omentum. Trends Immunol 38:526-536
Munguía-Fuentes, Rosario; Yam-Puc, Juan Carlos; Silva-Sánchez, Aarón et al. (2017) Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult. Front Immunol 8:13
Nellore, Anoma; Randall, Troy D (2016) Narcolepsy and influenza vaccination-the inappropriate awakening of immunity. Ann Transl Med 4:S29
Hwang, Ji Young; Randall, Troy D; Silva-Sanchez, Aaron (2016) Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung. Front Immunol 7:258
Randall, T D; Mebius, R E (2014) The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol 7:455-66
Randall, Troy D; Kern, Jeffrey A (2014) Tertiary lymphoid structures target the antitumor immune response to lung cancer. Am J Respir Crit Care Med 189:767-9
Ballesteros-Tato, André; León, Beatriz; Lee, Byung O et al. (2014) Epitope-specific regulation of memory programming by differential duration of antigen presentation to influenza-specific CD8(+) T cells. Immunity 41:127-40
Ballesteros-Tato, André; Randall, Troy D (2014) Priming of T follicular helper cells by dendritic cells. Immunol Cell Biol 92:22-7
León, Beatriz; Bradley, John E; Lund, Frances E et al. (2014) FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 5:3495
Johnston, Carl J; Manning, Casey M; Rangel-Moreno, Javier et al. (2013) Neonatal irradiation sensitizes mice to delayed pulmonary challenge. Radiat Res 179:475-84

Showing the most recent 10 out of 51 publications