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Complement activation in multiple sclerosis plaques: an immunohistochemical analysis.

Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, Robertson NP, Neal JW, Morgan BP - Acta Neuropathol Commun (2014)

Bottom Line: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain.This study aims to bring clarity to these questions.We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk.

ABSTRACT

Introduction: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.

Results: We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.

Conclusions: The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.

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Related in: MedlinePlus

Plaque morphology in MS cases. Paraffin wax sections stained with LFB (A1, B1 and C1) and anti-HLA DR (A2, B2 and C2) showing an active (A1-A2; case MS160_S3), chronic active (B1-B2; case MS225_S13) and chronic inactive plaque (C1-C2; case MS61_B). The active plaque shows profound inflammation with anti-HLA-DR immunopositive microglia (A2 and inset) and foamy macrophages containing myelin degradation products demonstrated using LFB (inset in A1). The chronic active plaque shows little inflammation in the centre of the plaque (insets in B1 and B2) but abundant anti-HLA-DR immunopositive microglial at the plaque border (B2). The chronic inactive plaque shows an immunologically silent lesion centre (inset in C1 and C2) and a well demarcated lesion border showing only mild inflammation (C2 and inset) Scale bars are shown in B2 and are applicable for all plates and inserts.
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Fig1: Plaque morphology in MS cases. Paraffin wax sections stained with LFB (A1, B1 and C1) and anti-HLA DR (A2, B2 and C2) showing an active (A1-A2; case MS160_S3), chronic active (B1-B2; case MS225_S13) and chronic inactive plaque (C1-C2; case MS61_B). The active plaque shows profound inflammation with anti-HLA-DR immunopositive microglia (A2 and inset) and foamy macrophages containing myelin degradation products demonstrated using LFB (inset in A1). The chronic active plaque shows little inflammation in the centre of the plaque (insets in B1 and B2) but abundant anti-HLA-DR immunopositive microglial at the plaque border (B2). The chronic inactive plaque shows an immunologically silent lesion centre (inset in C1 and C2) and a well demarcated lesion border showing only mild inflammation (C2 and inset) Scale bars are shown in B2 and are applicable for all plates and inserts.

Mentions: Anti-HLA-DR antibody was used to identify microglia and anti-MOG antibody to detect myelin. MS lesions were classified as either classical active (profound inflammation with microglia and macrophages containing myelin degradation products) or slowly expanding (central profound axonal loss with loss of macrophages, with a rim of activated microglia and moderate inflammation) [14]. Slowly expanding lesions were further subdivided into either chronic active (residual plaque centre inflammation and profound microglial inflammation at the plaque border) or chronic inactive (immunologically silent lesion centre with a well demarcated lesion border showing only mild inflammation) (examples shown in Figure 1) [14]. Spinal cord sections were also analysed for plaque subtype according to this classification. To ensure accuracy of lesion classification, all sections were assessed by three independent trained observers (JWN; OWH; GI); inter-observer concordance was 100%.Figure 1


Complement activation in multiple sclerosis plaques: an immunohistochemical analysis.

Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, Robertson NP, Neal JW, Morgan BP - Acta Neuropathol Commun (2014)

Plaque morphology in MS cases. Paraffin wax sections stained with LFB (A1, B1 and C1) and anti-HLA DR (A2, B2 and C2) showing an active (A1-A2; case MS160_S3), chronic active (B1-B2; case MS225_S13) and chronic inactive plaque (C1-C2; case MS61_B). The active plaque shows profound inflammation with anti-HLA-DR immunopositive microglia (A2 and inset) and foamy macrophages containing myelin degradation products demonstrated using LFB (inset in A1). The chronic active plaque shows little inflammation in the centre of the plaque (insets in B1 and B2) but abundant anti-HLA-DR immunopositive microglial at the plaque border (B2). The chronic inactive plaque shows an immunologically silent lesion centre (inset in C1 and C2) and a well demarcated lesion border showing only mild inflammation (C2 and inset) Scale bars are shown in B2 and are applicable for all plates and inserts.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4048455&req=5

Fig1: Plaque morphology in MS cases. Paraffin wax sections stained with LFB (A1, B1 and C1) and anti-HLA DR (A2, B2 and C2) showing an active (A1-A2; case MS160_S3), chronic active (B1-B2; case MS225_S13) and chronic inactive plaque (C1-C2; case MS61_B). The active plaque shows profound inflammation with anti-HLA-DR immunopositive microglia (A2 and inset) and foamy macrophages containing myelin degradation products demonstrated using LFB (inset in A1). The chronic active plaque shows little inflammation in the centre of the plaque (insets in B1 and B2) but abundant anti-HLA-DR immunopositive microglial at the plaque border (B2). The chronic inactive plaque shows an immunologically silent lesion centre (inset in C1 and C2) and a well demarcated lesion border showing only mild inflammation (C2 and inset) Scale bars are shown in B2 and are applicable for all plates and inserts.
Mentions: Anti-HLA-DR antibody was used to identify microglia and anti-MOG antibody to detect myelin. MS lesions were classified as either classical active (profound inflammation with microglia and macrophages containing myelin degradation products) or slowly expanding (central profound axonal loss with loss of macrophages, with a rim of activated microglia and moderate inflammation) [14]. Slowly expanding lesions were further subdivided into either chronic active (residual plaque centre inflammation and profound microglial inflammation at the plaque border) or chronic inactive (immunologically silent lesion centre with a well demarcated lesion border showing only mild inflammation) (examples shown in Figure 1) [14]. Spinal cord sections were also analysed for plaque subtype according to this classification. To ensure accuracy of lesion classification, all sections were assessed by three independent trained observers (JWN; OWH; GI); inter-observer concordance was 100%.Figure 1

Bottom Line: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain.This study aims to bring clarity to these questions.We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk.

ABSTRACT

Introduction: Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.

Results: We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.

Conclusions: The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.

Show MeSH
Related in: MedlinePlus