An "Outside-In" and "Inside-Out" Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

Abstract

The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting "outside-in" vs. "inside-out" roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system.

Keywords: complement; inside-out; multiple sclerosis; outside-in; pathology.

Figure 1

Activation and regulation of the complement (C) system. Recognition of target epitopes by C1q (Classical pathway) or MBL (Lectin pathway) result in the cleavage of C4 and formation of the C3 convertase, cleaving C3. C3 is also activated via the alternative pathway by a constant “tick-over” that can be amplified during pathological conditions. Cleaved C3 can nucleate the formation of the C5 convertase, cleaving C5 and eventually forming the terminal complement complex or membrane attack complex (TCC, MAC, C5b9), which can lyse membranes and/or induce cell activation. Activation of C4, C3, and C5 lead also to the formation of anaphylatoxins which cause chemotaxis and inflammation. Activation of the complement system is tightly regulated by soluble (shown in italics) and membrane-bound proteins which can either inhibit the formation or accelerate the decay of the convertases or impede assembly of the C5b9 complex. Abbreviations: C1INH, C1 inhibitor; C4bp, C4 binding protein; FI, factor I; MCP, membrane co-factor protein; CR1, complement receptor 1; DAF, decay-accelerating factor; FH, factor H; MBL, mannose-binding lectin.

Figure 2

Complement-mediated synapse elimination during development and in neurodegenerative diseases. (A) In the developing brain, astrocytes produce TGF-β that promotes the production of C1q by neurons. Neuron-derived and microglia-derived C1q tags weak synapses activating the classical complement pathway which results in the cleavage of C3 with deposition of C3b at synapses. C3b-tagged synapses are then removed through phagocytosis by microglia expressing the complement receptor CR3. (B) In neurodegenerative diseases, such as Alzheimer’s disease (AD), oAβ promotes the production of C1q by microglia. C1q-tagged synapses are then eliminated by microglia via the classical complement pathway as observed for synapses during development. Also, microglia-derived C1q (together with IL-1α and TNF) induces a subtype of C3⁺ reactive astrocytes, termed A1 astrocytes, which are neurotoxic. Abbreviations: oAβ, oligomeric amyloid β; TGFβ, transforming growth factor β; IL, interleukin; TNF, tumor necrosis factor.

Figure 3

Classification of white matter lesions in multiple sclerosis (MS). Schematic diagram illustrating different types of MS white matter lesions, including (A) (p)reactive sites, (B) active demyelinating lesions, (C) mixed active-inactive demyelinating lesions, and (D) inactive lesions. See the text in “MS White Matter” section for a detailed description of each lesion type.

Figure 4

A role for complement in the “outside-in” paradigm of white matter demyelination in MS. (A) During steady state, complement components circulate in the blood. Only leukocyte extravasation across the blood-brain barrier (BBB) occurs but is limited to few activated CD4⁺ T lymphocytes that perform immunological surveillance. These activated lymphocytes interact with adhesion molecules (ICAM-1, VCAM-1) expressed on the lumen of vascular endothelial cells. Chemokine (CXCL12) expression by endothelial cells on the abluminal side contributes to sequestering the activated CD4⁺ T cells in the perivascular space through binding to the chemokine receptor (CXCR4) on the T cell. (B) During MS/EAE, the efficiency of leukocyte diapedesis is increased. CCL19, CCL21, and CXCL12 are up-regulated by cerebrovascular endothelial cells that promote the recruitment and adhesion of CD4⁺ T cells primed in the periphery against a CNS antigen. On the abluminal surface of endothelial cells, CXCR7 binds to CXCL12 to reduce T cell sequestration in the perivascular space. Within the perivascular space, activated T cells produce chemokines and cytokines (such as TNFα and GM-CSF) that promote the recruitment of myeloid cells from the blood. Matrix metalloproteinases (MMP-2 and MMP-9) are produced and selectively cleave dystroglycan in the astrocytic foot processes, allowing penetration of T cells, B cells, monocytes, and complement into the CNS parenchyma. Within the CNS, encephalitogenic T cells re-encounter their specific antigen and are re-activated, producing inflammatory cytokines. T cells can also bind directly to myelin epitopes producing cytotoxic mediators and leading to activation of macrophages. Infiltrating B cells transition into antibody-producing plasma cells perhaps in situ. Autoantibodies can also enter the CNS through a breached BBB. Complement components enter the CNS via a breached BBB and are activated either by the recognition of antigen/antibody complexes or directly by “altered self” myelin epitopes. Complement-tagged myelin is then phagocytosed by phagocytes expressing complement receptors (macrophages and microglia). Activated complement components can also bind T cells and B cells via their complement receptor modulating their function (see details in text). Abbreviations: CNS, central nervous system; TNFα, tumor necrosis factor α; GM-CSF, granulocyte-macrophage colony-stimulating factor; CR, complement receptor.

Figure 5

A role for complement in the “inside-out” paradigm of demyelination and synapse loss in MS. (A) The “inside-out” model argues that a so far unknown primary cytodegenerative event leads to myelin changes or Wallerian degeneration or retrograde degeneration which exposes altered highly antigenic myelin epitopes. In this scenario, the complement system would participate in the secondary autoimmune and inflammatory response by tagging myelin and promoting its clearance by phagocytes. (B) In the normal-appearing white matter, complement (particularly activated C3) tags axons that may be damaged as a result of Wallerian degeneration or retrograde degeneration. C3-tagged altered myelin is then removed by clusters of microglia (also called microglial nodules). (C) In the gray matter, neurons and synapses could be potential hotspots of complement-mediated primary cytodegeneration. (C’) Synapses (of the visual thalamus) are tagged by C3b and engulfed by microglia. Tagging of synapses by C1q has also been reported in the MS hippocampus but its role in the early engulfment of synapses has not yet been investigated. Also, microglia-derived C1q (together with IL-1α and TNF) induces a subtype of C3⁺ reactive astrocytes, termed A1 astrocytes, which are neurotoxic. (C”) Neurons upregulate C1q by an unknown trigger. C1q can then potentially bind to its receptor (gC1qR) on the surface of mitochondria triggering the production of ROS which in turn can induce myelin and neuronal damage. Abbreviations: ROS, reactive oxygen species.