The Role of Complement in Cryoglobulin-Induced Immune Complex Glomerulonephritis

Trendelenburg, Marten; Fossati-Jimack, Liliane; Cortés-Hernández, Josefina; Turnberg, Daniel; Lewis, Margarita; Izui, Shozo; Cook, H. Terence; Botto, Marina

doi:10.4049/jimmunol.175.10.6909

Cited by 58 publications

(43 citation statements)

References 20 publications

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“…In the present study, we found the complement component C1q to be dispensable for the induction of blisters by Abs against type VII collagen. In line with the present observations, C1q deficiency does not protect from autoantibody-induced tissue injury in cryoglobulin-induced immune complex glomerulonephritis (26). In addition, the blockade of the classical pathway in C4…”

Section: Discussionsupporting

confidence: 78%

“…This scenario bears similarities to the effector phase of other autoantibody-induced inflammatory diseases, including arthritis (24), vitiligo (25), cryoglobulinemia (26,27), bullous pemphigoid (28), and antiphospholipid syndrome (29). In contrast, the pathogenic effects of autoantibodies in other autoimmune diseases such as pemphigus (30) are mediated strictly by binding to their target Ag and do not involve the complement network.…”

Section: Discussionmentioning

confidence: 97%

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The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

Mihai

Chiriac

Takahashi

et al. 2007

The Journal of Immunology

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Epidermolysis bullosa acquisita is a subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against type VII collagen, a major constituent of the dermal-epidermal junction. The passive transfer of Abs against type VII collagen into mice induces a subepidermal blistering disease dependent upon activation of terminal complement components. To further dissect the role of the different complement activation pathways in this model, we injected C1q-deficient, mannan-binding lectin-deficient, and factor B-deficient mice with rabbit Abs against murine type VII collagen. The development and evolution of blistering had a similar pattern in mannan-binding lectin-deficient and control mice and was initially only marginally less extensive in C1q-deficient mice compared with controls. Importantly, factor B-deficient mice developed a delayed and significantly less severe blistering disease compared with factor B-sufficient mice. A significantly lower neutrophilic infiltration was observed in factor B-deficient mice compared with controls and local reconstitution with granulocytes restored the blistering disease in factor B-deficient mice. Our study provides the first direct evidence for the involvement of the alternative pathway in an autoantibody-induced blistering disease and should facilitate the development of new therapeutic strategies for epidermolysis bullosa acquisita and related autoimmune diseases.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 97%

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

Mihai

Chiriac

Takahashi

et al. 2007

The Journal of Immunology

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“…Efforts to interrupt the activation of complement have thus far not been successful in ameliorating the MPGN of TSLP transgenic mice (41), although such measures have been successful in other models of glomerulonephritis (34,36). A very recent and potentially important finding is the demonstration of upregulated expression of the Toll-like receptor 3 in human HCV-associated MPGN (42).…”

Section: Hepatitis C Virus-associated Glomerulonephritismentioning

confidence: 99%

Emerging Paradigms in the Renal Pathology of Viral Diseases

Alpers¹,

Kowalewska²

2007

Clinical Journal of the American Society of Nephrology

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This review considers recent information that illuminates pathogenetic mechanisms that involve three of the major viral infections that cause renal injury in the form of HIV-associated nephropathy, polyoma virus nephropathy, and hepatitis C virus-associated glomerulonephritis.Clin J Am Soc Nephrol 2: S6 -S12, 2007. doi: 10.2215/CJN.00280107 HIV-Associated NephropathyA nephropathy that is associated with HIV infection was identified soon after the epidemic of HIV/AIDS first became recognized in the early 1980s. HIV-associated nephropathy (HIVAN) is a combined glomerular and tubular injury that is characterized by a collapsing glomerulopathy (CG) with collapse of glomerular capillary structures and a striking hyperplasia of podocytes, microcystic transformation of renal tubules, and concomitant and likely nonspecific interstitial inflammation and fibrosis consequent to the glomerular and tubular injuries (Figure 1). From a pathology standpoint, three major areas of investigation have led to a deeper understanding of this lesion.The first of these addresses the issue of whether HIVAN is a direct consequence of viral infection of the renal parenchyma or is a secondary consequence of systemic infection. Cohen et al.(1) first reported the presence of HIV RNA in podocytes as revealed by in situ hybridization (ISH) in 1989, a finding that was supported by microdissection studies of Kimmel et al. (2). These studies were difficult to validate because of the failure of others to replicate these findings using conventional techniques of ISH, the inability to demonstrate the presence of viral peptides in renal parenchymal cells by immunohistochemistry, and the inability to demonstrate appropriate receptors for viral entry into cells, namely CD4 and the chemokine receptors CXCR4 or CCR5, on renal parenchymal cells (3). This created a conundrum in that a mechanism for viral entry into renal cells could not be defined. Some but not all of the difficulties were resolved by a more sophisticated form of ISH, which is based on a technique that detects forms of viral DNA that are characteristic of replicating virus (4 -6). With these techniques, it was possible to substantiate the findings of Cohen et al. and convincingly demonstrate HIV infection of podocytes and tubular epithelial cells.A second key development concomitant with the demonstration of HIV infection of human renal epithelial cells was the development of murine models of HIVAN. The best studied of these involves the Tg26 mouse: Mice are made transgenic for a nearly whole-length HIV virus but with a deletion of HIV gag and pol genes to render the virus nonreplicative (7). Studies of these mice, largely by the group of Klotman and their collaborators, have established that expression of HIV genes, presumably modeling the events of renal HIV infection, is sufficient to produce a renal injury in the mouse that is similar to HIVAN in humans. Studies in which kidneys from transgenic mice were transplanted into wild-type controls demonstrated that renal expression of HIV gene...

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“…49 NeuT male mice 28 from Biogem (Ariano Irpino, Italy) were crossed with BALB-C1KO and with BALB-C3KO females in order to obtain neuT C C1 C/¡ and neuT C C3 C/¡ heterozygous male mice, respectively. These heterozygous male mice were then crossed with BALB-C1KO and BALB-C3KO females; the progeny was genotyped in order to identify neuT C C1 ¡/¡ (neuT-C1KO) and neuT C C3 ¡/¡ (neuT-C3KO) female mice that were then used in the experiments.…”

Section: Methodsmentioning

confidence: 99%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

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There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

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The Role of Complement in Cryoglobulin-Induced Immune Complex Glomerulonephritis

Cited by 58 publications

References 20 publications

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

Emerging Paradigms in the Renal Pathology of Viral Diseases

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

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