Table 1.
Overview of complement-related diseases.
| Disease | Mechanism | Recommended analysis | Ref. |
|---|---|---|---|
| Age-related macular degeneration (AMD) | Genetic variants in complement genes C3, CFB CFH, and CD46 (MCP). | Genetic analysis of the genes C3, CFB, CFH, CD46 | (19) |
| Alzheimer disease (AD) | Local generation of C3a and C5a creating an inflammatory environment. Altered levels of C1q, FB, C4, C4a, TCC. Deposition of TCC on neuronal cells may be responsible for neuritic loss. | Analysis of complement components C1q, FB, C4, C4a and TCC | (20, 21) |
| Amyotrophic lateral sclerosis (ALS) | Dysregulation of complement, complement activation in the spinal cord, C5aR1-C5a signalling during progression suggests that the terminal complement pathway contributes to the pathogenesis of ALS. | Analysis of terminal pathway components, such as TCC | (22) |
| ANCA-associated vasculitis | Signalling through the C5a-C5a receptor, contributes to the immunopathology of ANCA-associated vasculitis | ELISA for C5a | (23, 24) |
| Anti-glomerular basement membrane (anti-GMB) disease | Autoantibodies- or immune complexes-induced complement activation | ELISA for anti-C1q antibodies | (25, 26) |
| Angioedema | Genetic variants in C1-INH (Hereditary angioedema; HAE), autoantibodies against C1-INH (acquired angioedema) | C1-INH, C4, C1q, anti-C1-INH autoantibodies, molecular analysis C1-INH. | (27) |
| Atypical haemolytic uremic syndrome (aHUS) | Genetic variants in C3, CFB, CFH, CFI, CD46 (MCP) genes. | CH50, AH50, functional ELISA for CP, AP, ELISA for C3, FB, C3a, C3d, TCC, FH, FI, anti-FH autoantibodies, molecular analysis CFH, CFI, C3, CFB, CD46 (MCP) | (28) |
| Cancer | Complement-induced inflammation leading to tumour growth and metastasis. | Analysis of terminal pathway components, such as TCC | (29) |
| Cold agglutinin disease | Cold agglutinin (CA) IgM immune complexes bind C1q and thereby initiates the classical complement pathway | CH50 | (30) |
| Diabetes | Increased levels of complement activation in plasma. | Analysis of terminal pathway components, such as C3d and TCC | (31) |
| Epilepsy | Deposition of C1q, C3b and TCC in affected brain tissue. | Analysis of components such as C1q, C3, C5 and TCC | (32) |
| Glomerulopathies (C3G) | Genetic variants in C3, CFB CFH, CFI and CFHR5; presence of autoantibodies (C3NeF) preventing AP regulation. | CH50, AH50, functional ELISA for CP, AP, ELISA for C3, C4, C3a, C3d, TCC, FH, FI, C3 and C4 nephritic factor, autoantibodies to FH and FB, C3 convertase, molecular analysis of CFH, CFI, C3, FB, MCP (CD46) | (33–35) |
| Guillain–Barré Syndrome (GBS) | IgG anti-ganglioside antibodies that lead to GBS cause complement-mediated disruption of interactions between Schwann cells and axon. Terminal complement activation and TCC deposition on Schwann cell. Elevated levels C3a and C5a in the CSF of patients | ELISA for C3a, C5a, TCC. Measurement of anti-ganglioside antibodies | (36) |
| Henoch-Schoenlein purpura [Immunoglobulin A vasculitis (IgAV)] | Most common form of childhood vasculitis, characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Autoantibodies- or immune complexes-induced complement activation via the alternative and lectin pathway. Levels of TCC in the urine might be a useful indicator of renal injury | Analysis of terminal pathway component TCC | (37, 38) |
| Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS) | Exact pathophysiology unknown. Rare immune complex-mediated small vessel vasculitis characterized by urticaria, hypocomplementemia (low C1q, C3, and C4), and systemic manifestations, and it is also associated with circulating anti-C1q autoantibodies | ELISA for C1q, C3, C4, autoantibodies against C1q | (39, 40) |
| Huntington’s disease | Autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene. Upregulation of complement components C7 and C9 in HD, increased levels of clusterin are associated with disease progression. Upregulation of C5a-C5aR axis. | ELISA for C5a, C7, C9, TCC | (36, 41) |
| Infection disorders | Pathogens trigger innate immune responses and activate the complement pathway either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. | CH50, AH50, functional ELISA for CP, AP, LP. ELISA for C3, C4, C1q, C3a, C3d, TCC, C5-C9, Properdin, MBL | (42, 43) |
| Inflammatory bowel disease | Appropriate activation of the intestinal complement system seems to play an important role in the resolution of chronic intestinal inflammation, while over-activation and/or dysregulation may worsen intestinal inflammation. C3 and C4a are suggested as diagnostic markers | ELISA for C3 and C4a | (44, 45) |
| Kidney ischemia/reperfusion (I/R) injury | Complement molecules influence function of factors such as free radicals, neutrophils, and the products of activated endothelium. Complement activation releases biologically active, proinflammatory products. C4a, C3a, and C5a can induce smooth muscle contraction, increase vascular permeability, and cause the release of histamine. C5a acts on neutrophils, promoting chemotaxis and activation and acts on neutrophils and endothelium to upregulate cell adhesion molecules such as CD11b/CD18 and the intercellular adhesion molecule (ICAM-1). C5b-9 inserts into the membrane of target cells, inducing cell injury and necrosis. C5b-9 also activates neutrophils and endothelium by upregulating adhesion molecules and promoting the release of cell stimulants such as hydrolytic enzymes, reactive oxygen species, arachidonic acid metabolites, and cytokines. In addition, C5b-9 can enhance the procoagulant properties of the endothelium | ELISA for C3/C3 split products, C4/C4 split products, C5/C5a split products, TCC, FH, properdin. C4d staining of kidney biopsies | (46–49) |
| Kidney transplant injury | Antibody-mediated renal injury; individuals with pre-existing circulating antibodies are at high risk to develop complement-dependent reaction against transplanted kidney; local synthesis of complement components together with loss of regulatory mechanisms for complement activation, especially of C3, C5 and TCC. | ELISA for C3/C3 split products, C4/C4 split products, C5/C5a split products, TCC, FH, properdin. C4d staining of kidney biopsies | (47, 49, 50) |
| Multiple sclerosis | Inflammatory, demyelinating disease of the central nervous system that leads to variable axonal and neuronal damage. Causes are largely unknown. Depositions of C1q, C3d, and C5b-9 in white matter lesions of MS. Complement proteins, activation products and inhibitors were found at MS plaques. Astrocyte-enriched extracellular vesicles derived from the plasma of MS patients contained high levels of C1q, C3, C3b, iC3b, C5, and C5a. C3a in CSF at baseline assessment of patients with clinically isolated syndrome and newly diagnosed relapsing-remitting MS could be a promising prognostic marker of disease activity Also genetic variants were identified, for instance in MASP1 and C2 to be associated with the disease. | ELISA for C3 and C3 activation products such as C3a | (32, 36) |
| Myasthenia gravis (MG) | MG is an antibody-mediated autoimmune disease of the postsynaptic neuromuscular junction presenting with a fluctuating degree of weakness in ocular, bulbar, limb, and respiratory muscles. Activation of complement via disease-specific autoantibodies to the acetylcholine receptor (AChR). Inhibition of C5 or TCC could be beneficial in refractory MG | ELISA for C5/C5a, TCC | (36, 51) |
| Myocardial infarction | Complement activation is an important factor for inflammation and injury of ischemic and infarcted myocardial tissue. Lectin pathway main driver in myocardial reperfusion injury. Complement-derived effector molecules as described above are involved in producing the inflammation, tissue injury, and necrosis of the heart tissue during reperfusion | Analysis of terminal pathway component C3/C3 split products, C5/C5 split products and TCC | (52) |
| Neuromyelitis optica | Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4) | Anti-AQP4 autoantibodies | (53) |
| Organ transplantation | C3 is activated during transplant and is associated with late allograft damage and rejection. C5a and C3a anaphylatoxins increase the inflammatory response. C5a fragment serves as a chemotactic agent for neutrophils and macrophages, there is also evidence that C3a induced chemotaxis of monocytes and mast cells. In Antibody-mediated rejection (AMR), donor-specific antibodies (DSAs) form immune complexes on the surface of (kidney) allograft endothelium bind C1q complement component, leading to the activation of the classical complement pathway. The C4d fragment formed following this activation, and deposited in the peritubular capillaries of the kidney allograft, is an important biomarker of antibody-mediated rejection | ELISA for C3/C3 split products, C4/C4 split products, C5/C5a split products, TCC, FH, properdin. C4d staining of kidney biopsies | (29, 47, 54) |
| Parkinson disease (PD) | PD is characterized by dopamine deficiency at the basal ganglia and deposition of a-synuclein that forms Lewy bodies. However, the exact neuropathologic mechanisms remain elusive. Studies regarding the role of complement in PD are controversial. Some reported the involvement of the classical complement pathway by recognizing anti C3d, C4d, C7 and C9 antibodies in substantia nigra or by the aggregation of iC3b and C9 in Lewy bodies of PD patients. Other studies failed to correlate complement activation with cortical Lewy Bodies. Clusterin and complement C1r were decreased compared to controls and have been proposed as useful biomarkers of disease progression | ELISA for clusterin and C1r | (36, 55–58) |
| Paroxysmal nocturnal haemoglobinuria (PNH) | PNH is a rare disease that presents clinically with a variety of symptoms, the most prevalent of which are hemolytic anemia, hemoglobinuria, and somatic symptoms including fatigue and shortness of breath. In patients with PNH, CD55 and CD59 are lacking, and RBCs undergo excessive complement-mediated hemolysis leading to hemolytic anemia, thrombosis, renal dysfunction, and pulmonary hypertension | CD55, CD59, fluorescently labeled aerolysine (FLAER) test | (59) |
| Periodontitis | Inflammatory disease in tooth-supporting tissues, induced by bacteria growing in a biofilm on tooth surfaces. Components of the complement system are present in the periodontal tissue leading to local induced complement activation. C1q, factor B, factor Bb, C3, C3a, C3b, C3c, C3d, C4, C5, C5a, C5b and C9 have all been detected in diseased periodontal tissue | ELISA for C1q, factor B, factor Bb, C3, C3a, C3b, C3c, C3d, C4, C5, C5a, C5b and C9 | (60) |
| Polytrauma | Evidence of systemically increased complement activation: C3a, C5a, high C3a/C3 ratio in case of organ dysfunction after trauma. Predominance of alternative pathway activation. C5a is seen to delay the fracture healing by delaying neutrophil apoptosis and delaying recruitment of osteoblast and osteoclast progenitors. | CH50, MBL, C3a, C5a, SC5b-9, C4BP total, C4BP-β, and factor I by ELISA | (61–63) |
| Refractory generalized myasthenia gravis (gMG). See also myasthenia gravis | gMG is a rare autoimmune disorder characterized by skeletal muscle weakness caused by disrupted neurotransmission at the neuromuscular junction. Autoantibodies attack acetylcholine receptors, which are essential in facilitating muscle contraction and movement. | ELISA for C5/C5a, TCC | (29, 36) |
| Rheumatoid arthritis | Evidence suggesting complement activation in synovial tissue. Increased levels of C2, C3 and C3a in RA patients |
C2, C4b, C5a, FD, MBL, FI, C1q, C3,C3a, C3b C4, FB, FH, properdin, TCC | (64) |
| Schizophrenia | Genetic variant in C4A associated with increased risk. Increased copy number of C4A | Genetic variant analysis C4A | (65) |
| Sepsis/multi-organ dysfunction | Hyperinflammatory response after infection (cytokine storm). Increased levels of C3a, C5a and TCC. Excessive complement activation and consumption during septic shock. | ELISA for C3, C3a,C3c, C5, C5a, and TCC (sC5b-9), CH50 | (66–68) |
| Skin diseases | Excessive complement activation, may be caused by autoantibody-induced cytotoxic effects of TCC on epidermal or vascular cells thereby causing inflammation. | Analysis of terminal pathway components, such as TCC | (69) |
| Systemic lupus erythematosus (SLE) | Genetic variants in C1Q, C2, C4, CR2, CR3; impairment of complement-mediated clearance of immune complexes and apoptotic cells. Autoantibodies against C1q. | CH50, functional ELISA for CP. ELISA for C4 (C4a/b), C1q, C3, C3a, C3d, TCC, anti-C1q autoantibodies | (39, 40) |
| Thrombotic thrombocytopenic purpura (TTP) | Excessive AP activation. Functional deficiency of ADAMTS13 plays a substantial role in the development of TTP. Increased complement activation, increased levels of complement activation markers C4d, C3bBbP and C3a. | C3, Factors H, I, B and total alternative pathway activity together with complement activation fragments (C3a) or complexes (C1rs-INH, C3bBbP, sC5b9) measured by ELISA or RID. | (70) |
| Trauma (see also polytrauma) | Evidence of systemically increased complement activation: C3a, C5a, high C3a/C3 ratio in case of organ dysfunction after trauma. Predominance of alternative pathway activation. C5a is seen to delay the fracture healing by delaying neutrophil apoptosis and delaying recruitment of osteoblast and osteoclast progenitors. | CH50, MBL, C3a, C5a, SC5b-9, C4BP total, C4BP-β, and factor I by ELISA | (61–63) |
| Urticarial vasculitis (see also Hypocomplementemic Urticarial Vasculitis Syndrome) | Exact pathophysiology unknown. Rare immune complex-mediated small vessel vasculitis characterized by urticaria, hypocomplementemia (low C1q, C3, and C4), and systemic manifestations, and it is also associated with circulating anti-C1q autoantibodies | ELISA for C1q, C3, C4, autoantibodies against C1q | (39, 40) |
| Uveitis | Inflammation of the uvea, the pigmented layer that lies between the inner retina and the outer fibrous layer composed of the sclera and cornea. Presence of autoantibodies activating complement. | Human C3a radioimmunoassay Immunoelectrophoresis (IEP) |
(71) |