Disease relevance of C1qa

• Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies [1].
• Moreover, the autoimmune disease was accelerated in wild-type mice given C1qa(-/-) BMC compared to animals transplanted with wild-type cells [2].
• These data imply that not only C1q deficiency but also regulatory region polymorphisms down-regulating C1q levels may confer the risk for lupus nephritis by reducing IC clearance and thus promoting IC deposition in glomeruli [3].
• C1q regulatory region polymorphism down-regulating murine c1q protein levels with linkage to lupus nephritis [3].
• Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q [4].

Psychiatry related information on C1qa

• Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease [5].

High impact information on C1qa

• These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells [1].
• The phenotype associated with C1q deficiency was modified by background genes [1].
• Similarly, no IL-4 response or CD8(+) T-cell priming was seen in C1qa(-/-) mice [6].
• However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions [7].
• Thus, in the early stages of infection, C3 and perhaps C1q contribute to the localization of TSE infectivity in lymphoid tissue and may be therapeutic targets [8].

Chemical compound and disease context of C1qa

• Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation [9].
• Gastrointestinal ischemia (20 min), followed by 3-h reperfusion, induced intestinal and lung injury in C1q KO and WT mice, but not in C2/fB KO mice [4].
• Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains [10].
• C1q was isolated from mouse serum and ascites fluid by absorption onto human IgG-coated latex beads followed by separation on 3-10% exponential gradient sodium dodecyl sulfate (SDS) polyacrylamide gels [11].
• A large proportion of systemic lupus erythematosus (SLE) patients develop glomerulonephritis, coincident with the appearance of autoantibodies to C1q, the Fc-recognizing collagen-like subcomponent of the first component of complement, C1 [12].

Biological context of C1qa

• To assess the contribution of background genes in the expression of the autoimmune phenotype, the disrupted C1qa gene was backcrossed for seven generations onto C57BL/6 and MRL/Mp(+/+) strains [13].
• Here, we studied the effect of BMT on autoimmunity in C1qa(-/-) mice [2].
• Remarkably, this up-regulation did not occur in mice that lack an early factor of the complement cascade, C1q, a component which has been shown previously to facilitate early prion pathogenesis [14].
• In this work we addressed the issue of whether genetic polymorphisms affecting C1q levels may predispose to SLE, using the (NZB x NZW)F(1) model [3].
• Sequence analysis of the C1q gene in New Zealand Black (NZB), New Zealand White (NZW), and BALB/c mice showed no polymorphisms in exons and introns of three genes [3].

Anatomical context of C1qa

• B cell tolerance was intact in C1qa-/- mice [15].
• Following irradiation, young C1qa(-/-) or wild-type MRL/Mp mice received bone marrow cells (BMC) from strain-matched wild-type or C1qa(-/-) animals [2].
• The frequency of anti-HEL-producing plasma cells and serum levels of anti-HEL immunoglobulin were comparably reduced in control and C1qa-/- double-transgenic mice compared to control Ig(HEL) and C1qa-/- Ig(HEL) mice [15].
• C1q levels in sera and culture supernatants of LPS-stimulated peritoneal macrophages and C1q messages in spleen cells were all lower in disease-free young NZB and (NZB x NZW)F(1) mice than in age-matched non-autoimmune NZW and BALB/c mice [3].
• GI/R significantly increased serum alanine aminotransferase, gastrointestinal barrier dysfunction, and neutrophil infiltration into the lung and gut in C1q KO and WT, but not C2/fB KO, mice [4].

Associations of C1qa with chemical compounds

• IgG was detected in the glomeruli of diseased C1qa/H2-Bf/C2-/- kidneys [9].
• These findings support the hypothesis that C1q may play a role in the clearance of apoptotic cells without the necessity for C3 activation and demonstrate that the activation of C3 is not essential for the development of GN in this spontaneous model of lupus-like disease [9].
• Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components [16].
• We now report that the alpha2beta1 integrin is a novel receptor for multiple collectins and the C1q complement protein [17].
• The multiple Fcs present in a single molecule apparently allow for more efficient interactions with the multiple C1q heads present in C1, the first component of the classical C cascade [18].

Physical interactions of C1qa

• Under low ionic strength conditions, this mutant was found to be approximately 50 and 75% as active as wild-type IgG1 in the C1q binding and C4b deposition assays, respectively [19].
• In this configuration, C1q bound avidly to PrP, with a K(D) of 5.4 nM (k(on) = 2.4 x 10(5) M(-1) s(-1); k(off) = 1.3 x 10(-3) s(-1)) [20].
• gC1qBP is a 33 kDa glycoprotein that binds to the globular 'heads' of C1q [21].
• In addition, we mutated the Glu 333, which resides in close proximity to the postulated C1q-binding site of mouse IgG2b, as well as Leu 235 in the lower hinge region [22].

Other interactions of C1qa

• Lung injury in mice after GI/R is MBL and C1q independent, but C2 dependent, suggesting a potential role for ficolins in this model [4].
• We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls [23].
• C4 binding studies, however, revealed that the observed difference in antibody and C1q binding has no influence on the complement resistance of SK-MEL-170 cells: significantly more C4b was bound to complement-resistant (1565 +/- 92 fg/cell) as compared to susceptible cells (715 +/- 31 fg/cell) [24].
• Activation of human microglia by fibrillar prion protein-related peptides is enhanced by amyloid-associated factors SAP and C1q [25].
• Characterisation of the rat and mouse homologues of gC1qBP, a 33 kDa glycoprotein that binds to the globular 'heads' of C1q [21].

Analytical, diagnostic and therapeutic context of C1qa

• C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months [1].
• However, Southern blot analysis revealed unique insertion polymorphism of a total of approximately 3.5 kb in the C1qa upstream region of NZB mice [3].
• We studied the contribution of the different complement activation pathways in the host defense against experimental polymicrobial peritonitis induced by cecal ligation and puncture by using mice deficient in either C1q or factors B and C2 [26].
• C1q or C2/factor B knockout mice, however, were not protected by passive immunization [27].
• An immunoblot of murine serum C1q separated by SDS-PAGE was detected with an A-chain specific antibody that had been affinity purified on recombinant mouse C1q A-chain expressed in Escherichia coli [28].

References