Complement in Lupus Nephritis: The Good, the Bad, and the Unknown
Section snippets
Why Complement in Human SLE?
Initially, complement caught people’s attention based on the observations of hypocomplementemia in patients with active SLE. Low total complement hemolytic activity and decreased C3 and C4 levels have been found in about 75% of SLE patients with focal nephritis and in 90% of patients with diffuse nephritis.24 The colocalization of immunoglobulin isotypes IgG, IgA, and IgM with C1q, C4, and C3 (and C5b-9) is called a full house, which is present almost exclusively in glomeruli of patients with
Mouse Models of Human SLE
There are several murine models that spontaneously develop lupus-like syndromes. Two of the best studied models are the F1 cross between New Zealand Black and New Zealand White mice (NZB/W) and the MRL/MpJ-Tnfrsf6lpr/lpr/J (MRL/lpr) strain.44 Similar to the female predominance in human beings, only female NZB/W mice develop SLE. MRL/lpr mice are on the autoimmune MRL/Mp background with a retrotransposon in the Tnfrsf6 (Fas) gene leading to nearly complete absence of the proapoptotic Fas protein.
Functional Studies of Complement in Experimental Lupus Models
The manipulation of individual complement proteins through genetic techniques in lupus mouse strains has provided considerable insight into how complement is involved in this disease. In addition, functional inhibition through the use of specific antibodies or antagonists using recombinant or transgenic techniques can be extremely illuminating. Given that C3 is the common point connecting all 3 pathways in complement activation, there are more naturally occurring proteins regulating its
What We have Learned from Animals Can be Used in the Treatment of Human Beings
Strategies to manipulate the complement system in different human diseases have followed from successful animal studies, including through the use of recombinant intrinsic complement regulators and blocking antibodies. In addition to the treatment approaches indicated in studies using experimental models as we discussed earlier, we focus on therapeutic approaches that have been used in the treatment of human diseases, which potentially may extend to the treatment of human SLE and lupus
References (108)
- et al.
cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro
Immunity
(1997) - et al.
Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR
Mol Immunol
(2006) - et al.
Cell signals transduced by complement
Mol Immunol
(2004) - et al.
The regulators of complement activation (RCA) gene cluster
Adv Immunol
(1989) - et al.
Physiological and pathological aspects of circulating immune complexes
Kidney Int
(1989) - et al.
Immune complex glomerulonephritis in C4- and C3-deficient mice
Kidney Int
(1998) - et al.
A protein with characteristics of factor H is present on rodent platelets and functions as the immune adherence receptor
J Biol Chem
(2001) - et al.
Systemic lupus erythematosus and complement deficiency: clues to a novel role for the classical complement pathway in the maintenance of immune tolerance
Immunopharmacology
(1999) - et al.
Induction of systemic lupus erythematosus in naive mice with T-cell lines specific for human anti-DNA antibody SA-1 (16/6 Id+) and for mouse tuberculosis antibody TB/68 (16/6 Id+)
Clin Immunol Immunopathol
(1991) - et al.
Localization of decay accelerating factor in normal and diseased kidneys
Kidney Int
(1989)
Decay-accelerating factor expression in the rat kidney is restricted to the apical surface of podocytes
Kidney Int
Expression of decay accelerating factor mRNA and complement C3 mRNA in human diseased kidney
Kidney Int
Deletion of decay-accelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice
Am J Pathol
Role of a rat membrane inhibitor of complement in anti-basement membrane antibody-induced renal injury
Kidney Int
A critical role for complement in maintenance of self-tolerance
Immunity
A protective role for innate immunity in autoimmune disease
Clin Immunol
Effects of complement factor D deficiency on the renal disease of MRL/lpr mice
Kidney Int
Targeting of functional antibody-decay-accelerating factor fusion proteins to a cell surface
J Biol Chem
Advances in immunology: complement
N Engl J Med
The complement system
Complement
Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q
J Immunol
Immunohistochemical study of the human glomerular C3b receptor in normal kidney and in seventy-five cases of renal diseases
J Clin Invest
Signaling through up-regulated C3a receptor is key to the development of experimental lupus nephritis
J Immunol
Renal expression of the C3a receptor and functional responses of primary human proximal tubular epithelial cells
J Immunol
The membrane attack complex of complement
Annu Rev Immunol
Inherited deficiency of C8 in a patient with recurrent meningococcal infections: further evidence for a dysfunctional C8 molecule and nonlinkage to the HLA system
J Clin Immunol
Paroxysmal nocturnal haemoglobinuria: nature’s gene therapy?
Mol Pathol
Effects of the membrane attack complex of complement on nucleated cells
Curr Top Microbiol Immunol
The role of C5b-9 terminal complement complex in activation of the cell cycle and transcription
Immunol Res
Organization of the genes encoding complement receptors type 1 and 2, decay-accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1
J Exp Med
Structural gene for human membrane cofactor protein (MCP) of complement maps to within 100 kb of the 3′ end of the C3b/C4b receptor gene
J Exp Med
p65: a C3b-binding protein on murine cells that shares antigenic determinants with the human C3b receptor (CR1) and is distinct from murine C3b receptor
J Immunol
The murine complement receptor gene family. I.Analysis of mCRY gene products and their homology to human CR1
J Immunol
The beta-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells
J Immunol
Regulation in the terminal pathway
The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus
Arthritis Rheum
Complement in the pathophysiology and diagnosis of human diseases
Crit Rev Clin Lab Sci
Sensitivity and specificity of plasma and urine complement split products as indicators of lupus disease activity
Arthritis Rheum
Complement deficiency and immune complex disease
Springer Semin Immunopathol
Mechanisms of immune-deposit formation and the mediation of immune renal injury
Clin Exp Nephrol
The clearance of immune complexes from the circulation of man and other primates
Am J Kidney Dis
The role of complement and its receptor in the elimination of immune complexes
N Engl J Med
Disease-associated loss of erythrocyte complement receptors (CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activation
J Immunol
C3b receptor (CR1) expression of the polymorphonuclear leukocytes from patients with systemic lupus erythematosus
Clin Exp Immunol
The role of complement in the development of systemic lupus erythematosus
Annu Rev Immunol
Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus
Lupus
High levels of antibodies against Clq are associated with disease activity and nephritis but not with other organ manifestations in SLE patients
Clin Exp Rheumatol
Antibodies against C1q in patients with systemic lupus erythematosus
Springer Semin Immunopathol
Cited by (57)
Esculetin alleviates murine lupus nephritis by inhibiting complement activation and enhancing Nrf2 signaling pathway
2022, Journal of EthnopharmacologyCitation Excerpt :Besides of renal local over-oxidation, renal local complement activation is another key mediator for LN initiation and progression. Immune complex-mediated activation of complement in affected kidney is clearly evident in both experimental and human SLE along with pathologic features (Bao and Quigg, 2007). One study reported that long-term treatment with anti-C5 monoclonal antibody had impressive effects on lupus nephritis in NZB/W lupus mice (Bao and Quigg, 2007).
Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice
2016, ImmunobiologyCitation Excerpt :On one hand, the complement system appears to have protective features as evidenced by the observation that hereditary homozygous deficiencies of classic pathway components are associated with an increased risk for SLE. On the other hand, immune complex-mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathologic features that are direct consequences of complement activation (Bao and Quigg, 2007). Complement factor B protein (FB) is one of the proteins required for activation of the alternative pathway.
Association study of TRAF1/C5 polymorphism (rs10818488) with susceptibility to rheumatoid arthritis and systemic lupus erythematosus: A meta-analysis
2013, GeneCitation Excerpt :The TRAF1 gene encodes an intracellular protein member of the TNF receptor-associated factor family involved in TNFα signaling (Wajant et al., 2001), which is considered to be associated with the activation and proliferation of T cells (Sabbagh et al., 2006; Tsitsikov et al., 2001). C5 is a pivotal member of the complement system, and unregulated complement activation is likely to play a crucial role in the pathogenesis of several autoimmune diseases (Allegretti et al., 2005; Bao and Quigg, 2007). Therefore, TRAF1/C5 might possibly contribute to the pathogenesis of both autoimmune diseases RA and SLE.
Complement: Functions, location and implications
2023, ImmunologyGenetic analysis of CFH and MCP in Egyptian patients with immune-complex proliferative glomerulonephritis
2022, Frontiers in Immunology
Supported by a grant from the National Institutes of Health (R01DK055357).