Contributions
Abstract: 141
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: Microglia and macrophages accumulate at sites of inflammatory and vascular lesions and are thought to play a central role in the disease process. However, information on lesion stage dependent polarization is sparse in humans due to absence of markers and well defined lesions.
Objective: The central aim of this study is to provide an in-depth characterization of the microglia and macrophage response in brain lesions of inflammatory and vascular diseases of the human CNS.
Methods: We used recently described markers to characterize the origin and functional states of microglia/macrophages on carefully staged lesions in a large archival collection of brain autopsies of MS and stroke cases.
Results: In lesions of MS microglia lost the expression of homeostatic markers, but highly expressed activation markers. Although overall the expression of pro-inflammatory markers dominated in active lesions, many microglia and macrophages showed an intermediate activation status with expression of both, pro-inflammatory and anti-inflammatory markers. The major proportion of phagocytes in early stages of MS lesions is derived from the microglia pool, while with lesion maturation an increasing fraction of phagocytes were recruited from the blood.
In the center of initial stroke lesions microglia were complete lost while in the penumbra microglia massively accumulated, proliferated and partly expressed a homeostatic and pro-inflammatory phenotype. Entering the resorption stage most cells were recruited myeloid cells. Overall these cells showed an intermediate phenotype. In contrast to MS some cells still expressed homeostatic markers. In the late phase of scar formation there was a global reduction of microglia in comparison to controls with re-appearance of the homeostatic profile, similar to inactive MS lesions. The microglia activation in disease occurred on the background of a diffuse pattern of microglia activation, also seen in age-matched controls.
Conclusion: In the human brain MS and stroke lesions develop on a background of age related partial microglia activation. In both situations a pro-inflammatory phenotype dominated in early lesions followed by a mixed phenotype at later stages and macrophages in the lesions were derived from the resident microglia pool and from recruited myeloid cells. Differences were mainly seen in the expression of “homeostatic” markers, which were completely lost in MS lesions, but partially preserved in stroke lesions.
Disclosure: Hans Lassmann: honoraria from Biogen, Novartis, and Sanofi
Howard Weiner: scientific advisor for Tiziana and Medday, and receive research support from Biogen, Verily, Serono, and Sanofi.
Oleg Butovsky: Biogen Idec, Genzyme, miRagen Therapeutics, Teva Pharmaceutical Industries Ltd.
Tobias Zrzavy: nothing to disclose
Simon Hametner: nothing to disclose
Isabella Wimmer: nothing to disclose
Source of funding:Austrian Science Fund (F.W.F.), NIH-NINDS, National Multiple Sclerosis Society, Nancy Davis Foundation Award
Abstract: 141
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Background: Microglia and macrophages accumulate at sites of inflammatory and vascular lesions and are thought to play a central role in the disease process. However, information on lesion stage dependent polarization is sparse in humans due to absence of markers and well defined lesions.
Objective: The central aim of this study is to provide an in-depth characterization of the microglia and macrophage response in brain lesions of inflammatory and vascular diseases of the human CNS.
Methods: We used recently described markers to characterize the origin and functional states of microglia/macrophages on carefully staged lesions in a large archival collection of brain autopsies of MS and stroke cases.
Results: In lesions of MS microglia lost the expression of homeostatic markers, but highly expressed activation markers. Although overall the expression of pro-inflammatory markers dominated in active lesions, many microglia and macrophages showed an intermediate activation status with expression of both, pro-inflammatory and anti-inflammatory markers. The major proportion of phagocytes in early stages of MS lesions is derived from the microglia pool, while with lesion maturation an increasing fraction of phagocytes were recruited from the blood.
In the center of initial stroke lesions microglia were complete lost while in the penumbra microglia massively accumulated, proliferated and partly expressed a homeostatic and pro-inflammatory phenotype. Entering the resorption stage most cells were recruited myeloid cells. Overall these cells showed an intermediate phenotype. In contrast to MS some cells still expressed homeostatic markers. In the late phase of scar formation there was a global reduction of microglia in comparison to controls with re-appearance of the homeostatic profile, similar to inactive MS lesions. The microglia activation in disease occurred on the background of a diffuse pattern of microglia activation, also seen in age-matched controls.
Conclusion: In the human brain MS and stroke lesions develop on a background of age related partial microglia activation. In both situations a pro-inflammatory phenotype dominated in early lesions followed by a mixed phenotype at later stages and macrophages in the lesions were derived from the resident microglia pool and from recruited myeloid cells. Differences were mainly seen in the expression of “homeostatic” markers, which were completely lost in MS lesions, but partially preserved in stroke lesions.
Disclosure: Hans Lassmann: honoraria from Biogen, Novartis, and Sanofi
Howard Weiner: scientific advisor for Tiziana and Medday, and receive research support from Biogen, Verily, Serono, and Sanofi.
Oleg Butovsky: Biogen Idec, Genzyme, miRagen Therapeutics, Teva Pharmaceutical Industries Ltd.
Tobias Zrzavy: nothing to disclose
Simon Hametner: nothing to disclose
Isabella Wimmer: nothing to disclose
Source of funding:Austrian Science Fund (F.W.F.), NIH-NINDS, National Multiple Sclerosis Society, Nancy Davis Foundation Award