Autoimmunity in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease or COPD is characterized by a temporally
variable chronic bronchitis (infection of the lower respiratory tract) and
emphysema. COPD gives rise to coughing, mucus production, and a distressing
reduction of the oxygen carrying capacity of the lungs under physical exercise.
Ultimately, the lack of oxygen intake will lead to death. In 2020, COPD will be
death cause number three worldwide.

The cause of COPD is unknown, but smoking is the most important risk factor.
The chronic inflammation in the lung associated with COPD can not be stopped
and disease progression can not be slowed by currently available medication. As
a consequence, further research is needed to improve treatments.

Recently, findings of high concentrations of B cells in lungs and various
corollaries between COPD and other autoimmune diseases were noted. A postulated
antigen-specificity is used here to identify cytotoxicity in sera of COPD
patients and healhty participants. In addition, we will identify cellular
targets of the autoantibodies in cell cultures and in primary tissue. If
autoimmunity indeed operates, it is to be expected that sera of COPD patients
and healthy controls differ in cytotoxicity and in specificity of the
antibodies in terms of the cell types that are targeted.

Our hypothesis is that antibodies of COPD patients contribute to inflammatory
processes leading to cell death, and that the level of cytotoxicity differs
between COPD patients and healthy volunteers.

The prime aim is to detect differences in antibody-mediated cytotoxicity in
serum of COPD patients and healthy participants using an in-vitro based system
encompassing target cells (cell lines, primary material), effector cells
(PBMCs), and serum and to identify the lung cells that are most susceptible to
antibody-mediated cytotoxicity.

Although most COPD patients exhibit features of autoimmunity, it is likely that
the level of cytotoxicity varies form patient to patient. Consequently, also
the level of self-reactivity and lung damage as well as the susceptibility of
different types of lung cells to cytotoxic serum is likely to vary among groups
of patients. Monitoring this variability in the COPD population is an important
goal of this study.

We will also examine the cytotoxic effect of (heat inactivation of) complement,
different effector populations, and antibody-free sera in this in-vitro
system.

Antibody-mediated cytotoxicity in COPD patients and healthy volunteers will be
studied by in-vitro assays, in which target cells, PBMCs, and serum are
incubated, followed by a determination of cell death (here radioactive
labeling). As target cells, we will use primary bronchial epithelial cells,
primary airway smooth muscle cells, primary lung fibroblasts, an alveolar
epithelial cell line (A549 cells), and a lung fibroblast cell line (MRC5). Lung
primary cells are obtained from surgical resection material. Effector cells
(PBMCs) from healthy donors are sampled and used freshly.

We will use serum from COPD patients (n=60) and smoking and non-smoking (n=60)
healthy age-matched controls. Each serum sample will be used untreated
(complement active) as well as complement-inactivated and as antibody-free
serum. Also different effector populations will be tested (neutrophils,
macrophages).

The level of cytotoxicity and the impact of complement (in)activation will all
be studied by comparing cases and controls. For all participants, information
on general health status and respiratory characteristics (spirometry, allergy)
will be collected.

A small amount of blood will be donated by COPD patients and healthy controls.
This may cause localized bruising. For patients who have not yet been seen at
the UMCG, a physical examination, a spirometry before and after
bronchodilatation, and a skin test will be performed. For both patients and
healthy participants, there are limited risks (haematoma resultin from the
donation of blood and an irritated skin after the skin test). As this is an
exploratory study, there are no direct benefits resulting from participation.