ProfessorJohn Prineas

Multiple sclerosis (MS) is a common chronic disease of the nervous system affecting chiefly young adults. It is described by most contemporary authors as a cell-mediated autoimmune disease specifically targeting oligodendrocytes (the cells that make myelin) and or myelin itself. Tissue damage is said to be effected by aggressive, proinflammatory MHCll+ phagocytic “microglia” Microglia are small, MHC class ll antigen – negative cells with thin branching processes present in large numbers throughout the normal brain and spinal cord. It is generally stated that MHC class ll+ phagocytes present in inflammatory diseases of the nervous system are derived from microglia.

Recent and ongoing research by Professor Prineas, Sandra Lee and Dr John Parratt, working in the RPAH Neurology Laboratory, reported in 2019, 2021, and June 2023, in the Oxford University Press Journal of Neuropathology and Experimental Neurology, the official journal of the American Association of Neuropathologists, describes immunohistochemical and electron microscopical findings in MS that differ radically from the above widely accepted view of microglia and MS pathogenesis:

1. Astrocytes as well as myelin are destroyed in early lesions early in the disease, reappearing initially as AQP4 -negative, GFAP+ reactive astrocytes, a finding not consistent with the view that MS is an autoimmune disease specifically targeting oligodendrocytes and myelin.

2. Oligodendrocyte loss begins in still- myelinated tissue and before there is evidence of phagocyte engagement with myelin sheaths. Loss by apoptosis and the formation of classical nuclear bodies is one of several ways oligodendrocyte loss occurs in MS.

3. Myelin breakdown involves direct contact by FcRγlll+, IgG+, MHCll+, MRP14+ phagocytes and myelin sheaths immunoreactive for activated complement (C9neo).

4. Hematogenous and locally proliferating monocytes, not microglia, appear to be the main and possibly the sole source of brain phagocytes in developing MS lesions.

5. Importantly, there is little evidence to support del Rio Hortega’s theory that resident microglia have the capacity to transform into phagocytes. Instead, findings in MS suggest that Hortega’s microglia are essentially anti-inflammatory in nature.

It is interesting that none of these findings have been anticipated regarding the role of microglia and macrophages in MS and other diseases in the now numerous recent studies of single cell transcriptomic profiling of cells harvested from diseased tissues.

Tissue used in these studies was obtained from neuropathologists and MS tissue brain banks in the US, Europe and Australia, the most important repositories Maida Vale Hospital in London, Frenchay Hospital, Bristol, and Runwell Hospital, Wickford, UK. At the time of moving to Sydney, this bank of MS tissue, mostly autopsy and some biopsy tissue from more than 300 cases of the disease, is one of the largest collections of such material anywhere.