Demyelination in VB2− chickens proceeds from paranodal to central internodal region
In the current study, morphometric analyses revealed significant changes from predominant paranodal demyelination at PH11d, to predominant partial internodal demyelination at PH16d, and then predominant internodal demyelination at PH21d. Sectional studies of TFs further demonstrated incipient myelin degeneration at paranodal and later at internodal region. These findings confirmed that, as expected, demyelination in VB2− chickens proceeds from paranodal to internodal region until the full length of the internode is affected. Macrophage-mediated myelin stripping was not found in the current and previous studies by electron microscopy and immunohistochemistry. In contrast, varying stages of degenerated myelin fragments were found in the cytoplasm of hypertrophic Schwann cells [5, 8, 14, 15], consistent with the myelin phagocytosis and clearance function of Schwann cell [2, 13]. Sectional studies of TFs here proved that the Schwann cell expressing such myelinolytic activity was the same Schwann cell enwrapping the internode, indicating that the original myelinating Schwann cell plays a critical role in initiating and promoting demyelination within the same internode. Such Schwann cell is named demyelinating Schwann cell [19]. The longitudinal extension of myelin degeneration and clearance from paranodal to internodal region by demyelinating Schwann cells is named Demyelination Driven by Demyelinating Schwann Cell (DDDSC), which is thought the common pathway of demyelination in immune-independent and some inflammatory demyelinating neuropathies [19, 20].
Interruptible demyelination and remyelination in VB2−/+ chickens
Although there has been no previous study specifying the possibility to interrupt the evolution from paranodal to internodal demyelination, it is believed that whenever initiated, DDDSC will progress unidirectionally toward complete removal of intracellular myelin sheath debris before remyelination happens. This process is so-called irreversible demyelination [19]. But in the notion of irreversible demyelination [19], two facts are overlooked, rapid progression of the disease and continuous, even irreversible, effect of the pathogen. As the progression from paranodal to complete internodal demyelination takes a few (5–10) days in the current avian model, it provides a time window to interfere with this procedure. Importantly, the pathogenic factor, VB2−, is readily rectified by VB2+. VB2+ was applied from PH12d as myelin degeneration in most affected internodes was limited to the paranodal and adjoining regions with preservation of central internodal myelin segments at this time. Co-existence of remyelination and active demyelination within individual internodes in VB2−/+PH14d chickens indicates occurrence of remyelination before complete internodal demyelination. Presence of short original internodes in remyelinating fibres, especially at PH21d, suggests the demyelinating procedure in affected internodes be interrupted. This type of demyelination and remyelination in avian riboflavin deficiency is here named as interruptible demyelination driven by Schwann cell (IDDSC). Whether IDDSC applies to avian riboflavin deficiency only? The morphological features, myelin debris in Schwann cell cytoplasm, intercalated internode and so called “hypomyelination” noticed by conventional pathological examinations [10, 16, 23], suggest that IDDSC may apply to demyelinating neuropathies with diverse aetiologies. Further studies may prove this speculation.
In conclusion, demyelination in avian VB2− neuropathy proceeds from paranodal gradually to internode region; the Schwann cell, originally myelinating the internode, plays a pivotal role in this demyelinating procedure, myelin degeneration and clearance; VB2+ interrupts the demyelinating procedure in affected internodes and promotes remyelination before complete internodal demyelination.