Anti-DNA autoreactivity in C4-deficient mice

Paul, Elahna; Pozdnyakova, Olga; Mitchell, Elizabeth; Carroll, Michael

doi:10.1002/1521-4141(200209)32:9<2672::aid-immu2672>3.0.co;2-x

Cited by 72 publications

(31 citation statements)

References 21 publications

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“…Interestingly, ablation of the C4 gene, located at the peak marker used in the original linkage studies describing Sles1, has been demonstrated to alter negative selection of immature self-reactive B cells in both the double-transgenic hen egg lysosome and the lpr null models (4,50). Furthermore, unlike other complement deficiencies (C1qa, C3, and Cr1/2), the lack of C4 appears less dependent on a mixed 129 ϫ B6 background for the manifestation of some degree of autoimmunity (7). However, serum levels of this complement component are equivalent in young, preautoimmune B6, B6.Sle1 and B6.Sle1 Sles1 mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping ofSles1to Less Than 1 Mb

Subramanian

Yim

Liu

et al. 2005

The Journal of Immunology

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Sle is a susceptibility locus for systemic autoimmunity derived from the lupus-prone NZM2410 mouse. The New Zealand White-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of IgG anti-chromatin autoantibodies mediated by Sle1 on the C57BL/6 (B6) background. Fine mapping of Sles1 with truncated congenic intervals localizes it to a ∼956-kb segment of mouse chromosome 17. Sles1 completely abrogates the development of activated T and B cell populations in B6.Sle1. Despite this suppression of the Sle1-mediated cell surface activation phenotypes, B6.Sle1 Sles1 splenic B cells still exhibit intrinsic ERK phosphorylation. Classic genetic complementation tests using the nonautoimmmune 129/SvJ mouse suggests that this strain possesses a Sles1 allele complementary to that of New Zealand White, as evidenced by the lack of glomerulonephritis, splenomegaly, and antinuclear autoantibody production seen in (129 × B6.Sle1 Sles1)F1s. These findings localize and characterize the suppressive properties of Sles1 and implicate 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene.

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Section: Discussionmentioning

confidence: 99%

Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping ofSles1to Less Than 1 Mb

Subramanian

Yim

Liu

et al. 2005

The Journal of Immunology

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“…The deficiency of classical complement pathway factors has been most strongly related with systemic lupus erythematosus (20,21) and other immune complex-mediated diseases (22). C4 deficiency could thus be expected to increase EAMG incidence rather than decreasing it.…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Tüzün

Scott

Goluszko

et al. 2003

The Journal of Immunology

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Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3−/−, C4−/−, C3+/−, and C4+/− mice and their control littermates (C3+/+ and C4+/+ mice) with AChR in CFA. C3−/− and C4−/− mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3−/− and C4−/− mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3−/− mice was significantly suppressed. Both C3−/− and C4−/− mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3−/− and C4−/− mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

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“…This hypothesis is supported by the clinical observation that deficiency of the early complement components, particularly of the classical pathways, such as C1q, C4, and C2, is a high-penetrance risk factor for developing systemic lupus erythematosus (SLE) (Walport 2001a(Walport , 2001b. Furthermore, mice deficient in C1q and C4 also developed autoimmune diseases resembling human SLE with characteristic findings such as glomerulonephritis and appearance of high titer autoantibodies (Botto et al 1998;Chen, Koralov, and Kelsoe 2000;Paul et al 2002).…”

Section: Complementmentioning

confidence: 99%

Crosstalk between Complement and Toll-Like Receptors

Song

2011

Toxicol Pathol

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The complement system and toll-like receptors (TLRs) are two components of innate immunity that are critical for first-line host defense. Many pathogen-associated molecular patterns activate both complement and TLRs, and recent studies in animal models have revealed a marked synergistic interaction between the two systems. In mice deficient in a membrane complement regulator, prototypical TLR ligands such as LPS, zymosan, and polyI:C caused increased systemic complement activation, which in turn led to a profound elevation of proinflammatory cytokine biosynthesis. This phenotype required interaction between complement and TLRs because complement activation alone by cobra venom factor without TLR engagement did not lead to appreciable cytokine production. The regulatory effect of complement on TLR signaling was mediated by the anaphylatoxins C5a and C3a through a receptor-dependent mechanism and involved increased mitogen-activated protein kinase and nuclear factor B activation. The crosstalk between complement and TLRs may also impact adaptive immunity, for example, the differentiation of T helper 17 (Th-17) cells. Given that excessive activation of either TLR or complement has been associated with inflammatory tissue injury as occurs in sepsis and autoimmune diseases, the new insight on complement and TLR crosstalk may have therapeutic implications.

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Anti-DNA autoreactivity in C4-deficient mice

Cited by 72 publications

References 21 publications

Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping ofSles1to Less Than 1 Mb

Epistatic Suppression of Systemic Lupus Erythematosus: Fine Mapping ofSles1to Less Than 1 Mb

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

Crosstalk between Complement and Toll-Like Receptors

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