Page 335 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 21 The Human Complement System: Basic Concepts and Clinical Relevance 315

enhanced by inflammatory cytokines, such as IL-6. There is oN tHE HorIZoN
evidence both from human multiple sclerosis (MS) (Chapter
66) and the animal model, experimental allergic encephalitis Future Directions in Complement Research
(EAE), that complement activation with the generation of the Functional analysis of polymorphisms and rare variants in complement
MAC contributes to the demyelination in these diseases. Genera- proteins identified in genome-wide association studies (GWAS) and
tion of the MAC can lead to oligodendrocyte death, generation by next generation sequencing of inflammatory and autoimmune
of inflammatory mediators, or a repair process in which myelin diseases will be functionally characterized to provide insight into
pathogenesis and treatment.
synthesis is decreased. Complement activation on myelin and Genetic sequencing of entire complement activation pathways and their
oligodendrocytes is initiated by antimyelin Ab or directly by regulators and receptors in patients with inflammatory and autoimmune
myelin through the CP. There is evidence of MAC formation in diseases will reveal novel pathogenic mechanisms and approaches
the cerebrospinal fluid of patients with MS, and complement to diagnosis and therapy.
depletion, inhibition, and genetic deficiency are protective in rat RNA sequence analysis will identify “up and down” regulation of comple-
and mouse models of EAE. ment proteins in human disease.
There is also evidence of complement activation in degenerative Structural analysis of complement protein complexes will lead to targeted
small molecules to inhibit or enhance complement activation.
neurological conditions, such as Alzheimer disease. In Alzheimer Therapeutic trials of existing agents and those in development will dramati-
disease, neurofibrillary tangles and senile plaques composed of cally refine therapy of complement-mediated diseases.
β-amyloid and other proteins develop, resulting in neuronal loss Proteome studies in patients with infectious, inflammatory, and auto-
and dementia with progressive loss of cognitive function. Comple- immune diseases will reveal patterns of complement activation and
ment activation products C1q, C4, C3, and MAC components, biomarkers for diagnosis, disease activity, and monitoring responses
as well as clusterin (ApoJ) and vitronectin (S40), are found to therapy.
deposited in areas of β-amyloid, suggesting CP activation. Peptides
derived from β-amyloid were shown to activate C1 directly by
binding to the collagen-like domain. SAP, a component of all
types of amyloid, including β-amyloid, activates the CP as well.
There are limited data on the role of complement in the patho- cascade have many beneficial effects in host defense and the
genesis of Alzheimer disease, with some studies reporting adaptive immune response. The detrimental effects of complement
enhanced disease following complement inhibition and another activation are, for the most part, associated with C5a and the
finding decreased inflammatory changes and neuronal degenera- MAC. Thus targeting either the generation of C5a or its association
tion in C1q deficiency. Finally, excessive complement activity, with C5aR might be expected to control inflammation while
notably C4, has been implicated in the development of schizo- maintaining other important functions, such as opsonization.
phrenia and has been associated with reduced numbers of An anti-C5 mAb that prevents C5 cleavage (eculizumab) has
70
synapses. This suggests that the role of complement proteins in been approved for human use in the treatment of PNH and
neuropsychiatric illness extends beyond inflammation-mediated atypical HUS. It is also being evaluated for treatment of refractory
tissue damage. 69,70 glomerulonephritides with C3 deposition and severe Ab-mediated
rejection after organ transplantation. Other drugs targeting the
Ischemia/Reperfusion Injury C5 pathway, as well as mAb directed to components of the AP
I/R injury refers to injury induced by inflammatory mediators, (e.g., factor D), are under investigation for ARMD. Peptides and
such as reactive oxygen intermediates produced by activated mAb directed at the C5aR, as well as upstream of C3 convertase
neutrophils, following the reperfusion of hypoxic tissue. Different production, have shown promise in a number of inflammatory
pathways of complement activation may be important in different models in animals and are being evaluated for the treatment of
sites of injury, probably because of differences in expression of sepsis, reperfusion injury, and asthma. Other approaches that
complement regulatory proteins and the nature of the tissue are being developed will target complement regulatory proteins
damage and the antigens exposed to the innate immune system. to specific cell or tissue targets. As the importance of this system
The primary complement mediators of tissue injury are C5a is clarified in a variety of inflammatory diseases, it is likely that
and the MAC acting locally and, in some cases, C5a acting systemi- further research will establish new complement-based therapeutic
cally. In experimental renal I/R injury and in human tubular agents for additional applications.
necrosis, the AP appears to be directly activated and neither Ab
nor the CP is required. However, in intestinal I/R injury, the CP Please check your eBook at https://expertconsult.inkling.com/
as well as the AP are required, and a natural IgM Ab to a newly for self-assessment questions. See inside cover for registration
exposed antigen on damaged endothelium initiates complement details.
activation. In coronary artery ligation/reperfusion models, innate
recognition of epitopes of ischemic tissue by MBL and CRP
leads to lectin and CP activation, respectively. REFERENCES/BIBLIOGRAPHY
With a few exceptions, the citations for the basics of complement
COMPLEMENT-BASED THERAPEUTICS biology are reviews related to the sections on the role of comple-
ment in human disease; few references are noted because of
The multiple roles of complement in inflammatory and space limitations, but each topic is covered in other chapters (as
autoimmune diseases make it an attractive target for therapeutic noted for the reader).
intervention. Recombinant complement inhibitors, inhibitory 1. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for
mAb, and peptide-based receptor inhibitors have been developed immune surveillance and homeostasis. Nat Immunol 2010;11:785–97.
to block the detrimental effects of the complement activation 2. Atkinson JP. Complement system in disease. In: Goldman-Cecil Medicine,
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fragments. As described above, products of the complement vol. 1. 25th ed. 2015. p. 240–6.