Smoke exposure as a determinant of autoantibody titre in  1-antitrypsin deficiency and COPD

Abstract

Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear.Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with a 1 -antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure.Anti-elastin antibodies were higher in controls relative to AATD (p50.008) and usual COPD (p,0.00001), and in AATD relative to usual COPD (p,0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p50.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p50.002) but the relationship to smoke exposure was less clear.Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 packyrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.KEYWORDS: a 1 -Antitrypsin deficiency, autoimmune disease, chronic obstructive pulmonary disease, smoking and health T he protease-antiprotease hypothesis of the pathogenesis of chronic obstructive pulmonary disease (COPD) concerns imbalances between proteases that digest elastin and other components of the extracellular matrix in the lung parenchyma, and antiproteases that protect [1][2]. The origin of this theory comes from the observation that patients with a 1 -antitrypsin deficiency (AATD) develop early onset emphysema [3]. a 1 -Antitrypsin (AAT) is an antiprotease, which acts predominantly to block the action of neutrophil elastase, a protease released by neutrophils. Neutrophil elastase is a serine protease, the first of three classes of protease important in COPD. The remaining two classes are the cysteine proteases, such as cathepsin-B, and the matrix metalloproteases (MMPs) [4]. In general, the serine and cysteine proteases are capable of degrading elastin and some forms of collagen [4], whilst MMPs have more of an effect on collagen, gelatin and laminin [2], all of which are components of the extracellular matrix of the lung.Breakdown of the extracellular matrix, particularly elastin, in the lung is a key feature of both COPD and AATD, as shown by the presence of high levels of elastin breakdown products. A desmosine cross-link is unique to elastin and may be used as a marker of its degradation [5]. Desmosine and elastin peptides are elevated in the plasma, urine and sputum of COPD patients [6], whilst urinary levels positively correlate with the annual rate of decline in forced expiratory volume in 1 s (FEV1) in smokers [7]. In general, elastin breakdown is greater i...

The Lung Tissue Microbiome in Chronic Obstructive Pulmonary Disease

“…These results support the hypothesis that the innate and adaptive immune response contributes to the pathology in peripheral lung lesions in COPD, but the antigens that drive this response remain to be determined (8)(9)(10)(11)(12)(13). Some have suggested that autoantigens drive the pathogenesis of COPD (14), whereas others propose that the emergence of new strains of foreign microbes (9)(10)(11)(15)(16)(17)(18) initiates a cycle of infection, inflammation, and dysfunctional repair, which drives the progression of COPD (10,15). The increase in frequency and severity of exacerbations that occurs with the progression of COPD might be a manifestation of this vicious cycle of infection and inflammation (19).…”

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

“…It should be noted, however, that we [21] and others [22][23][24] could not demonstrate this anti-elastin autoantibody response in COPD. Recent data demonstrating that long-term cigarette smoke exposure can induce antibodies in mice that can induce COPD-like pathology upon transfer into naïve recipients supports a possible pathogenetic role for autoantibodies in COPD [25].…”

Anti-citrullinated peptide antibodies in the serum of heavy smokers without rheumatoid arthritis. A differential effect of chronic obstructive pulmonary disease?

“…Autoimmune phenomena, including the production of several autoantibodies in sera, have been described in patients with COPD [11,12]. The frequency of autoantibodies, including ACPA, has recently been investigated in a study comparing the frequency of anti-elastin and ACPA (anti-CCP2 and anti-citrullinated vimentin) in patients with COPD, alpha1 antitrypsin deficiency (AATD) and healthy non-smokers [13]. A higher prevalence of anti-CCP2 was observed in patients with COPD (5.2%) in comparison with AATD patients (3.3%) and non-smokers (0%), although the number of non-smokers was very small (n022).…”