SP-A binds alpha1-antitrypsin in vitro and reduces the association rate constant for neutrophil elastase.

BACKGROUND: Alpha1-antitrypsin and surfactant protein-A (SP-A) are major lung defense proteins. With the hypothesis that SP-A could bind alpha1-antitrypsin, we designed a series of in vitro experiments aimed at investigating the nature and consequences of such an interaction. METHODS AND RESULTS: At an alpha1-antitrypsin:SP-A molar ratio of 1:1, the interaction resulted in a calcium-dependent decrease of 84.6% in the association rate constant of alpha1-antitrypsin for neutrophil elastase. The findings were similar when SP-A was coupled with the Z variant of alpha1-antitrypsin. The carbohydrate recognition domain of SP-A appeared to be a major determinant of the interaction, by recognizing alpha1-antitrypsin carbohydrate chains. However, binding of SP-A carbohydrate chains to the alpha1-antitrypsin amino acid backbone and interaction between carbohydrates of both proteins are also possible. Gel filtration chromatography and turnover per inactivation experiments indicated that one part of SP-A binds several molar parts of alpha1-antitrypsin. CONCLUSION: We conclude that the binding of SP-A to alpha1-antitrypsin results in a decrease of the inhibition of neutrophil elastase. This interaction could have potential implications in the physiologic regulation of alpha1-antitrypsin activity, in the pathogenesis of pulmonary emphysema, and in the defense against infectious agents.

Complement receptor 1 gene polymorphisms in sarcoidosis.

Sarcoidosis is likely to result from exposure of genetically susceptible hosts to environmental agents. Erythrocyte (E) complement receptor 1 (CR1) is a membrane protein mediating the transport of immune complexes (ICs) to phagocytes, and at least three polymorphisms on the CR1 gene are related to erythrocyte surface density of CR1 molecules, in turn related to the rate of IC clearance from circulation. We hypothesized that sarcoidosis could be associated with increased frequency of the CR1 gene alleles coding for reduced CR1/E ratio. We studied 91 sarcoid patients and two control groups: 94 healthy volunteers and 71 patients with chronic obstructive pulmonary disease (COPD). Three polymorphic sites of CR1 gene, His1208Arg, intron 27 HindIII/RFLP, and Pro1827Arg, were analyzed. The three polymorphisms were in linkage disequilibrium. The GG genotype for the Pro1827Arg (C(5507)G) polymorphism was significantly associated with sarcoidosis in comparison to both control groups (odds ratio [OR] = 3.13; 95% confidence interval [CI] 1.49-6.69 versus healthy control subjects, and OR= 2.82, 95% CI 1.27-6.39 versus COPD control subjects). The same genotype was particularly associated to disease in females (OR = 7.05; 95% CI 3.10-16.61 versus healthy control subjects). These findings agree with speculations on the role of CR1 gene as a possible susceptibility factor.