Normal Ciliary Ultrastructure and Function

The upper and lower respiratory tracts are continuously exposed to inhaled pathogens, and local defenses have evolved to protect the airway. The respiratory epithelium in the nasopharynx, middle ear, paranasal sinuses, and larger airways are lined by a ciliated, pseudostratified columnar epithelium that is essential for mucociliary clearance (Fig. 396-1). Motile cilia are hairlike organelles that move fluids, mucus, and inhaled particulates vectorially from conducting airways, paranasal sinuses, and eustachian tubes.

Figure 396-1 Scanning electron photomicrograph of an airway epithelium grown in primary culture showing ciliated and non-ciliated cells.

A mature ciliated epithelial cell has approximately 200 uniform motile cilia that are functionally and anatomically oriented in the same direction, moving with intracellular and intercellular synchrony. Anchored by a basal body to the apical cytoplasm and extending from the cell surface into the extracellular space, each cilium is a complex, specialized structure, composed of roughly 250 proteins. It contains a cylinder of microtubule doublets, arranged around a central pair of microtubules (Fig. 396-2), the characteristic “9+2” arrangement as viewed by cross-sectional views on electron microscopy. Multiple, different adenosine triphosphatases (ATPases), called dyneins, serve as “motors” of the cilium. Attached to the microtubules as distinct inner and outer dynein arms, dyneins cleave ATP to promote microtubule sliding, which is converted into bending. Nexin links and radial spokes act to restrict the degree of sliding between microtubules, allowing the cilium to bend.

Figure 396-2 Electron photomicrograph of a normal cilium demonstrating the complex structure and arrangement of the ciliary axoneme. Each inner and outer dynein arm is composed of numerous proteins and multiple dyneins.

The ciliary axoneme is highly conserved across species, and the structural elements of simple protozoan flagella and the mammalian cilium are similar. The inner dynein arm influences the bend shape of the cilium, whereas the outer dynein arm controls beat force and frequency. Ciliary beat frequency is constant throughout the airway, 8 to 20 beats/seconds, but can be negatively affected by several factors, such as anesthetics and dehydration. Alternatively, beat frequency may be accelerated by exposure to irritants or bioactive molecules, including β-adrenergic agents, acetylcholine, and serotonin. Cilia beat frequency can also be increased through the activity of nitric oxide synthases that are localized in the apical cytoplasm. The coordinated wavelike pattern of ciliary motion has important functions in fluid and cell movement, and any disturbance in the precise, orchestrated movement of the cilia can lead to disease.

In contrast to motile cilia, sensory or primary cilia lack a central microtubule doublet and outer dynein arms, thus creating a “9+0” arrangement and leaving these structures immotile. Primary cilia have specialized sensory functions and are present in the retina, renal nephron, bile duct, hypothalamus, and inner ear. Defects in primary cilia have been linked to wide-ranging conditions, including retinitis pigmentosa, polycystic kidney disease, polycystic liver disease, nephronophthisis, Bardet-Biedl syndrome, Meckel-Gruber syndrome, Joubert syndrome, Alström syndrome, and Jeune syndrome.

A third distinct classification of cilia also exists, but only during embryonic development. These nodal cilia have a “9+0” microtubule arrangement similar to that of primary cilia, but they exhibit rotational movement, resulting in leftward flow of extracellular fluid that establishes body sidedness. Nodal cilia defects result in left-right body orientation abnormalities, such as situs ambiguus (Chapter 425.11).

Genetics of Primary Ciliary Dyskinesia

Primary ciliary dyskinesia is considered to have autosomal recessive patterns of inheritance, though rare cases of autosomal dominant and X-linked inheritance have been reported. The calculated frequency of PCD ranges from 1/12,000 to 1/20,000 live births, but these measures likely underestimate disease incidence in the general population.

PCD is a genetically heterogeneous disorder involving multiple genes; mutations in any of over 250 proteins that are involved in ciliary assembly or structure could theoretically cause disease. Linkage analyses have shown substantial locus heterogeneity, making correlations between ciliary defects and the underlying mutations difficult.

Investigations into the genetic basis of PCD have focused on dynein proteins; candidates genes involved in PCD include DNAI1 (IC78) and DNAH5 (γ-heavy chain). DNAI1, a large gene located on chromosome 9 (9p13-21) and highly expressed in trachea and testes, encodes for an intermediate chain found in the outer dynein arms. Mutations in DNAI1 have been found in PCD patients with outer dynein arm defects, and have been estimated to occur in 10% of PCD patients. Several different mutations in another gene, DNAH5, an axonemal dynein heavy-chain gene localized to chromosome 5p (5p14-5p15) expressed in lung, kidney, brain, and testis, have also been found in families with PCD. More than half of PCD patients with known outer dynein arm defects have DNAH5 mutations. Additional genes (DNAH11, TXNDC, and DNAI2) are also implicated in PCD. DNAH11 is particularly interesting because mutations in this gene have been shown to cause typical clinical phenotypes without apparent axonemal ultrastructural defects.

Clinical Manifestations of Primary Ciliary Dyskinesia (Table 396-1)