The Role of the Complement System in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) MAT-GLB-2102239 v1 05/2021 Learning Objectives • At the conclusion of this slide set, the learner should be able to… • Have an overview of the role of the complement system in normal function and in the pathogenesis of disease • Understand how the complement system is activated and the possible outcomes of this activation • Describe how humoral factors and complement activation may underpin the pathogenesis of CIDP CIDP=chronic inflammatory demyelinating polyneuropathy. 2 Complement Plays a Critical Role in the Nervous System • The complement system can play both protective and detrimental roles toward peripheral nerves1 • Protective effects include immune surveillance and regulation of energy metabolism in the microenvironment • Role in early axon loss and regeneration after injury may mediate peripheral nerve damage • The complement system also plays an important role in the maintenance of the uninjured brain, protecting it from infection and inflammation, eliminating damaged cells, and supporting regeneration2 1. Ramaglia V et al. Mol Immunol 2008;45:3865-77; 2. Magdalon J et al. Front Neurosci 2020;14:23. 3 Overview of the Complement System ClassicalClassical Pathway LectinClassical Pathway AlternativeClassical Pathway • Network of >30 soluble and membrane-bound plasma proteins that underpins innate immune surveillance and adaptive immunity1 • Complement activation starts an enzymatic cascade that can C1q, C1r, C1s MBL/ficolin, MASP-2 Factor D, factor B C4 C4 properdin culminate in a variety of physiologic responses, including C2 C2 C3 chemoattraction, cell lysis, and the elimination of pathogens1 C3a, C3b • There are 3 primary pathways in the complement system; all enter a common C3 convertase terminal pathway that ends with formation of the cytolytic membrane attack C3 2 complex (MAC), which destroys bacterial and viral pathogens C3a C3b Classical Pathway2,3 Lectin Pathway2,3 Alternative Pathway2,3 • Triggered by a structural • Triggered mainly by • No specific initiating molecule change in the initiating binding of specific lectins • Instead, low-level constitutive Inflammation Opsonization Cell Lysis molecule C1q after binding circulating in the blood activation of C3 occurs (“tick- of target molecules, (MBL, ficolins) to over”) including immune carbohydrates on the • Sialic acid-rich surfaces, eg, complexes (IgM, surface of microbial host cell membranes inhibit this complement-fixing isotypes of pathogens process, while sialic acid-poor IgG), CRP, serum amyloid P surfaces, eg, foreign or altered protein, and pentaxins cell membranes, promote it CRP=C-reactive protein; Ig=immunoglobulin; MBL=mannose-binding lectin. 1. Sarma JV, Ward PA. J Immunol 2006;176:1305-10; 2. Shih AR, Murali MR. Am J Hematol 2015;90:1180-6; 3. Thurman JM, Holers VM. J Immunol 2006;176:1305-10; Figure adapted from Murphy K, Weaver C. Janeway’s Immunobiology (9th edition), Garland Science, 2016. 4 Antibody Binding Can Activate the Classical Complement Pathway ClassicalClassical Pathway • The classical pathway acts as a bridge between the innate and adaptive immune systems, which are critical for establishing a humoral response1 • Antibodies/autoantibodies bind antigen (IgG1, IgG2, IgG3, and IgM, but not IgG4, can trigger the classical pathway)2 • This initiates the proteolytic cascade3 C1q, C1r, C1s • The classical pathway can link to the lectin and alternative pathways C4 C2 C3a, C3b C3 convertase C3a,C5a, C3bC5b • The classical complement pathway (as well as the lectin C3C5 convertase and alternative pathways) all generate C3 convertase, C3 C5 which cleaves C3, and C5 convertase, which cleaves C53 C3a C5a • Cleavage of C3 and C5 produces inflammatory mediators C3b C5b (C3a, C5a) and enzymatic cleavage components (C3b, C5b) C3b facilitates opsonization C5 enables formation Inflammation C3a/C5a recruit Opsonization Cell Lysis of antigens responsible for of the MAC, which phagocytic cells to costimulation and activation disrupts the cell the site of infection of B cells; phagocytes with membrane and and promote C3b receptors then engulf causes cell lysis inflammation3 and destroy the pathogen3 of the pathogen3 Ig=immunoglobulin; MAC=membrane attack complex. 1. Nikitin PA et al. J Immunol 2019;202:1200-09; 2. Goldberg BS, Ackerman ME. Immunol Cell Biol 2020;98:305-17; 3. Murphy K, Weaver C. Janeway’s Immunobiology (9th edition), Garland Science, 2016; Figure adapted from reference 3. 5 Role of the Complement System in the Pathogenesis of Disease • Proinflammatory peptides and complexes are generated during complement activation1 • Aberrant complement activation is often observed in autoimmune diseases, in which C3 deposition on self-antigens may activate self-reactive B-cell clones2 • Studiesa have implicated the complement system in the pathogenesis of several ischemic, inflammatory, autoimmune, and neurologic disorders,3 including: Peripheral4 CNS4 Neuromuscular4 Other1 • CIDP • Multiple sclerosis • Myasthenia gravis • Rheumatoid • Guillain-Barré • Neuromyelitis • Lambert-Eaton arthritis syndrome optica myasthenic • Asthma • IgM neuropathy • Alzheimer’s disease syndrome • Spontaneous fetal • Dermatomyositis loss aIncluding genetic and epidemiologic studies, cerebrospinal fluid and plasma biomarker measurements, and pathologic analysis of postmortem tissues. CIDP=chronic inflammatory demyelinating polyneuropathy; CNS=central nervous system; Ig=immunoglobulin. 1. Thurman JM, Holers VM. J Immunol 2006;176:1305-10; 2. Nikitin PA et al. J Immunol 2019;202:1200-09; 3. Carpanini SM et al. Front Immunol 2019;10:362; 4. Dalakas MC et al. Nat Rev Neurol 2020;16:601-17. 6 Humoral Factors Play a Fundamental Role in the Pathogenesis of CIDP CIDP • Rare, acquired, immune-mediated neuropathy that causes Healthy CIDP loss of the myelin sheath in peripheral nerves and nerve roots1 • Typically can be progressive or relapsing-remitting, and is characterized by a symmetric, motor-predominant peripheral neuropathy that causes both proximal and distal weakness, and sensory impairment1,2 • Due to the speed of response to plasmapheresis in CIDP patients, it is thought that a circulating factor, likely an as-yet unidentified antibody, is responsible for demyelination and conduction block in CIDP3 • Evidence that antibodies may be involved in CIDP • Presence of complement-fixing IgG and IgM deposits on patients’ myelin sheath and in sural nerve biopsy samples3,4 • Induction of conduction block and demyelination after passive transfer of serum or purified IgG from patients with CIDP into rats1 • Presence of a band after gel electrophoresis of patients’ cerebrospinal fluid with a molecular weight that corresponds to IgG3 • In 10% of patients, autoantibodies against nodal and paranodal proteins have been identified, which are considered pathogenic1 CASPR1=contactin-associated protein 1; CIDP=chronic inflammatory demyelinating polyneuropathy; CNTN1=contactin 1; Ig=immunoglobulin; NF=neurofascin; MAG= myelin-associated glycoprotein; NrCAM, neuronal cell adhesion molecule. 1. Lewis RA. Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis. In UpToDate, Post TW (ed), Waltham MA, 2020; 2. Bowley MP, Chad DA. Handb Clin Neurol 2019;161:241-68; 3. Dalakas MC. Biochimica et Biophysica Acta 2015;1852:658-66; 4. Querol L et al. Nat Rev Neurol 2017;13:533-47; Figure adapted from reference 4. 7 Complement Activation in Patients With CIDP CIDP vs Control serum • CIDP patients show increased terminal complement activation (with level of activation correlating to disease severity) compared with control patients with noninflammatory neurologic diseases CIDP Disease Severity CIDP=chronic inflammatory demyelinating polyneuropathy; INCAT=Inflammatory Neuropathy Cause and Treatment scale; sTCC=soluble terminal complement complex. Quast I et al. Ann Clin Transl Neurol 2016;3:730-5. 8 Complement Activation Is Involved in the Pathogenesis of CIDP Preclinical Data • Sera/IgG from patients with CIDP cause nerve conduction impairment and demyelination if injected into rat nerves, and conduction impairment if injected into marmosets1,2 • Complement depletion restores nerve function and limits disease progression in experimental autoimmune neuritis (EAN), an animal model with features that resemble CIDP3–5 Human Studies • Complement deposition is observed on nerve myelin in patients with CIDP6,7 • Serum and CSF levels of C5a and the MAC are elevated in treatment-naive patients with CIDP, and MAC activation correlates with clinical disease severity8 • Rare missense mutations in CD59 (a cell-surface glycoprotein that inhibits the MAC) cause excessive complement activation and CIDP-like neuropathy with onset in infancy9 CIDP=chronic inflammatory demyelinating polyneuropathy; CSF=cerebrospinal fluid; Ig=immunoglobulin; MAC=membrane attack complex. 1. Heininger K et al. J Neurol Sci 1984;66:1-14; 2. Yan WX et al. Ann Neurol 2000;47:765-75; 3. Feasby TE et al. Brain Res 1987;419:97-103; 4. Jung S et al. Neurosci Lett 1995;200:167-70; 5. Vriesendorp FJ et al. Acta Neuropathol 1998;95:297-301; 6. Hays AP et al. J Neuroimmunol 1988;18:231-44; 7. Dalakas MC et al. Neurology 1980;30:864-7; 8. Quast I et al. Ann Clin Transl Neurol 2016;3:730-5; 9. Nevo Y et al. Blood 2013;121:129-35. 9 Summary • The complement system is a proteolytic cascade that underpins innate and adaptive immunity, and has a role in a variety of physiologic processes, including chemoattraction, cell lysis,