B Cells in ALI/ARDS: A Neglected Culprit or Therapeutic Target?
Abstract
Topic Area Being Addressed: Research on the etiology and prevention of ARDS caused by the immune system s response to infectious disease. Central Problem to Be Addressed: Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are severe disorders affecting the lung. In these diseases, injury to the lung develops rapidly causing flooding of the lungs with fluid that leaks in from the circulation. This process impairs the capacity of the lung to transport oxygen to the body. Despite advances in the care of patients with ALI/ARDS, this disease still has very high death rates (30%-40%), even in young adults. Survivors of ALI/ARDS can be left with permanent disability. Thus, we need new medications that reduce death rates from ALI/ARDS, lessen its severity, and result in better outcomes for patients. ALI/ARDS can be caused by many factors in Veterans and civilians including severe bacterial lung infections and influenza virus infections of the lung. Military personnel are at increased risk for bacterial pneumonia and influenza infections due to their close living conditions, young age, and the fact that many recruits have not been exposed previously to bacteria and viruses and thus lack immunity to them. Military personnel are also often highly stressed due to their intense physical training conditions, which increases their susceptibility to lung infections. As lung infections are a common cause of ALI/ARDS in both military and Veteran populations, we will focus on lung infections as the cause of ALI/ARDS in this application. We hypothesize that severe lung infections caused by bacteria and the influenza virus start the injury process to the lung that eventually leads to ALI/ARDS. However, this injury is made worse by excessive activation of B-cells, which are one component of our normal immune system. Activated B-cells produce proteins called antibodies, which can help fight infections caused by killing bacteria and viruses. However, when lungs are injured, antibodies can be made by B-cells against human lung structures (called auto-antibodies). These auto-antibodies could attack and destroy components of the lung, which could make lung injury worse. Our goal is to determine whether these "bad" auto-antibody-making B-cells promote ALI/ARDS and whether removing these bad B-cells using a medication (which is already being used to treat patients with arthritis and blood cancers in humans) reduces the severity of ALI in mice. We will also examine B-cells and their damaging products in samples from human ALI/ARDS cases and controls to see whether our findings in mice are relevant to the human disease. Study Design: Our study is divided into two parts (aims). Aim 1 will test the hypothesis that activated B-cells make ALI worse in mice. We will infect normal mice or mice genetically engineered to lack B-cells with a type of bacteria and influenza virus that often cause pneumonia in military recruits and Veterans. These infections can lead to ALI/ARDS. We will assess whether mice lacking B-cells are protected from ALI. We will also identify the different types of B-cells in the lungs of infected normal mice (some of these B-cells have harmful and others have protective functions). Also, we will investigate whether autoantibodies (which attack one s own cells and proteins) and other molecules that activate B-cells are increased in blood and lung samples from normal mice with ALI. We will assess whether a B-cell destroying medication reduces ALI and death rates in infected mice. Aim 2 will test the hypothesis that ALI/ARDS human patients have increased numbers and more activated B-cells in their lungs and higher blood levels of harmful B-cell products. Our colleagues will provide blood and lung samples from ALI/ARDS cases caused by lung infections, patients with lung infections that did not develop ALI/ARDS, and patients without lung infections. We will ass
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610430
Entities
People
- Caroline A Owen
Organizations
- United States Army