The function of CX3CR1 receptors on circulating patrolling monocytes and other leukocytes determine the severity of emphysema in patients with ZZ genotype alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin (AAT) is the major serum anti-protease protein in humans.
Its genetic deficiency (AATD) lead in 1985 to the protease-antiprotease
imbalance hypothesis to explain emphysema development. This hypothesis
predicted that restoring the balance by intravenous AAT, isolated from healthy
donors, would stop the progression of emphysema. To date, this has not been
proven by an effect on lung function values (FEV1 or DLCO) in clinical trials.
Therefore, we aim to investigate a new hypothesis. Based on our preliminary
results we hypothesized that altered PBMC subpopulations and a consequent
defect in the CX3CL1/CX3CR1 axis has a critical role in the pathogenesis of
emphysema associated with inherited AAT deficiency. Furthermore, altered
subsets of PBMC, like patrolling monocytes, may contribute to pulmonary
microvascular endothelial cell (pMVEC) damage, which is enhanced in emphysema.

Primary Objective: To identify the variability in the circulation of the number
of patrolling monocytes and their expression of CX3CR1 obtained from adult
ZZ-AATD patients compared to spouse controls.
Secondary Objective(s): (1) To identify if low expression of CX3CR1 on PBMC in
blood is associated with the severity of emphysema in subjects with ZZ-AATD.
(2) To identify if expression of chemokine receptors other than CX3CR1 on PBMC
in blood is associated with the severity of emphysema associated with the
severity of emphysema in subjects with ZZ-AATD. (3) to identify if damage of
pulmonary microvascular endothelial cells (pMVECs) reflected by the level of
plasma E-selectin EMP ( Endothelial Micro Particles, which are von-Willebrand
negative) is correlated with any of the results identified in secondary
objective nr 2.

This is a case-control explorative study with an adaptive design for patients
known with the diagnosis of ZZ-AATD. Controls are spouses of ZZ-AATD patients.
To avoid analysis problems with mRNA sequence data, there should be about the
same distribution of gender of numbers of spouse controls and ZZ-AATD cases.To
compensate for effects of epigenetic factors on our hypothesis, we designed the
study with spouses as controls. In our experience, spouses frequently join
patients to our clinic, which is the only NFU-certified national reference
center for the AATD condition.

An expected adverse event caused by pulmonary function testing may be
tachycardia due to the required inhaled salbutamol. The tachycardia is
transient and can be treated with medication if the subject asks for it.

A possible but rare adverse event caused by venous blood sampling may be
phlebitis of the sampled vene.