Ciliary activity, serum proteins and cystic fibrosis

Sanderson, Michael John (1980) Ciliary activity, serum proteins and cystic fibrosis. University of Southampton, Doctoral Thesis.

Abstract

Cystic fibrosis (CF) is a lethal genetic condition of caucasian children, inherited in an autosomal recessive manner, characterised by chronic pulmonary disease, pancreatic insufficiency and elevated sweat electrolyte concentrations, occurring with a frequency of 1 in 2000. There is a need for a test to diagnose both CF patients (pre and post-natally)and CF heterozygotes. Previous studies demonstrated that CF subjects could be discriminated from healthy individuals by the differential effect of their serum on the ciliary activity of certain molluscan or rabbit tracheal cilia. In their present form, these bioassays are unsuitable for routine use. This thesis reviews mucociliary clearance within the respiratory tract and the detection of CF by ciliary assays, describes the normal activity of rabbit tracheal cilia and evaluates the use of these cilia, protozoan cilia, and a new assay using the cilia from the gill of the sea mussel Mytilus edulis for the detection of the CF gene. Rabbit tracheal cilia normally rest with their tips pointing in the direction of mucus transport. Each beat cycle begins with a recovery stroke, in which the cilium moves backwards with a clockwise sweep and then progresses, to complete the cycle, into the near planar effective stroke during which the ciliary tip penetrates and propels the mucus. The cilia display a laeoplectic coordination; short repetitive metachronal waves travelling only small distances across the epithelium. The small size, high density and complicated weak metachrony hinder the practical use of these cilia in an assay for CF. Similarly, the protozoan cilia or tilus frontal or marginal cilia either lack a prominent metachrony, or are difficult to quantify, or both, and do not display a differential response to CF serum; consequently these were considered unsuitable for CF detection. A new quantifiable assay using the M tilus lateral cilia is described. A variety of mammalian sera, including human, induced an abnormal beat pattern (ciliary dyskinesia) in these cilia; the metachronal wavelength was increased whilst the beat frequency remained stable. This change in activity was caused by an increase in coupling between the cilia, brought about by the agglutination of adjacent cilia by serum IgM. The presence of ciliary-specific IgM in serum is due to natural immunity acquired by heterophilic antigenic stimulation. The levels of this specific IgM are likely to vary between individuals and this may account for the variable results of many previous assays. These findings suggest that the Mytilus assay and possibly other ciliary assays are unreliable for the detection of CF since ciliary dyskinesia is a common property of all sera. The serum IgM may mask the effects of another dyskinetic factor specific to CF.

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