Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis.
BACKGROUND
Genetic and environmental factors are thought to contribute to the etiology of the autoimmune disease myasthenia gravis (MG). Viral involvement has long been suspected, but direct evidence of involvement has not been found. We recently reported that Toll-like receptor 4 (TLR4)-a key activator of innate immunity-was overexpressed in the thymus of some patients with MG, suggesting that thymic infection by pathogens might be involved in MG pathogenesis. We searched for evidence of intrathymic infection in patients with MG.


METHODS
Twenty-seven MG thymuses (6 involuted, 7 hyperplastic, 5 thymitis, and 9 thymoma) previously tested for TLR4 expression, 18 nonpathologic control thymuses, and 10 pathologic control thymuses from patients without MG (8 thymoma and 2 hyperplastic) were analyzed for cytomegalovirus, varicella-zoster virus, herpes simplex virus types 1 and 2, eubacteria, respiratory syncytial virus, and enteroviruses using PCR techniques. Immunohistochemistry and double immunofluorescence were used to detect enterovirus capsid protein VP1 in thymic specimens and analyze TLR4 expression in VP1-positive cells.


RESULTS
Poliovirus was detected in 4 MG thymuses (14.8%; 2 thymitis and 2 thymoma). No virus was detected in any control thymus. A linear correlation between plus and minus strand poliovirus RNA levels was observed in all 4 thymuses, suggesting persistent thymic infection. VP1 protein was detected in the cytoplasm of CD68-positive macrophages scattered through thymic medulla in all PV-positive thymuses. VP1 and TLR4 colocalized in infected cells.


CONCLUSIONS
Poliovirus-infected macrophages are present in thymus of some patients with myasthenia gravis, suggesting a viral contribution to the intrathymic alterations leading to the disease.
Cavalcante
P
P
Department of Neurology, Neurological Institute Foundation Carlo Besta, Milan, Italy.
Barberis
M
M
Cannone
M
M
Baggi
F
F
Antozzi
C
C
Maggi
L
L
Cornelio
F
F
Barbi
M
M
Didò
P
P
Berrih-Aknin
S
S
Mantegazza
R
R
Bernasconi
P
P
D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis / Q000378:metabolism; D036022:Capsid Proteins / Q000032:analysis / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology / Q000821:virology*; D009157:Myasthenia Gravis / Q000276:immunology* / Q000503:physiopathology / Q000821:virology*; D011051:Poliomyelitis / Q000150:complications*; D017955:Poliovirus / Q000235:genetics / Q000276:immunology*; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000235:genetics; D013950:Thymus Gland / Q000166:cytology / Q000821:virology*; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D036022:Capsid Proteins; D012367:RNA, Viral; D051197:Toll-Like Receptor 4; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C495345:TLR4 protein, human; C442540:VP1 protein, Poliovirus