Disease relevance of C2

• Genetic deficiency of the second component of complement (C2) is the most common complement-deficiency state among Western Europeans and is frequently associated with autoimmune diseases [1].
• A variable number of tandem repeats locus within the human complement C2 gene is associated with a retroposon derived from a human endogenous retrovirus [2].
• Incubation of different astrocytic cell lines and primary astrocytes with HIV-1 induced a marked upregulation of the expression of the complement factors C2 and C3 [3].
• We have studied the expression of the complement components C2, C3, factor B, C1 inhibitor (C1-inh), C4-binding protein (C4-bp) and factor H in human peripheral blood monocytes, skin fibroblasts, umbilical vein endothelial cells (HUVEC) and the human hepatoma cell line G2 (Hep G2) in the absence and the presence of interferon-gamma (IFN-gamma) [4].
• The family members had an equal distribution of rheumatic disease and antinuclear antibody in the C2 deficient and C2 normal groups [5].

Psychiatry related information on C2

• Genetic association study between senile dementia of Alzheimer's type and APOE/C1/C2 gene cluster [6].

High impact information on C2

• Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls [7].
• Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration [7].
• We screened factor B (BF) and complement component 2 (C2) genes, located in the major histocompatibility complex class III region, for genetic variation in two independent cohorts comprising approximately 900 individuals with AMD and approximately 400 matched controls [7].
• The human complement protein Factor B is encoded by a single gene in the major histocompatibility complex and is closely linked to the gene encoding the second component of complement C2 [8].
• DNA sequencing, S1 mapping, and primer extension experiments have established that the transcription initiation site of the Factor B gene lies only 421 bp from the poly(A) site of the C2 gene [8].

Chemical compound and disease context of C2

• Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin [9].
• Overall, both C2 and C5 gene expression was increased by about three-fold in skeletal muscle of cachectic cancer patients (average weight loss 14.5+/-2.5%), compared with that in patients without weight loss, with or without cancer [10].
• Development and use of PCR primers for the investigation of C1, C2 and C3 enterotoxin types of Staphylococcus aureus strains isolated from food-borne outbreaks [11].
• Effects of vitamin D3 and IFN-gamma on the synthesis of the second complement component, C2, by a human myeloid leukemia (HL-60) cell line [12].
• The most prominent association of rheumatic diseases with hereditary complement deficiency is systemic lupus erythematosus (SLE) and discoid lupus erythematosus with homozygous C2 deficiency in females [13].

Biological context of C2

• The complete genomic DNA sequence between C2 and TNX is now available [14].
• Deficiencies in complement C2 are either due to abolition of C2 protein synthesis by mini-deletions that caused frameshift mutations, or blocked secretion of the C2 protein by single amino acid substitutions [14].
• Two cDNA clones for complement component C2 have been isolated from a high-complexity human liver cDNA library by using a mixture of 64 synthetic oligonucleotides as a probe [15].
• In studies of eight kindred, the 28-base pair deletion was observed in all C2Q0 alleles associated with the common type I deficient complotype/haplotype; this deletion was not present in normal C2 nor in type II C2-deficient genes [16].
• Human complement proteins D, C2, and B. Active site mapping with peptide thioester substrates [17].

Anatomical context of C2

• To examine the molecular basis of this deficiency, we established cultures of blood monocytes from four families with C2-deficient members [1].
• Pulse-chase biosynthetic labeling experiments indicated that the C111Y mutant C2 was retained by transfected COS cells and secreted only in minimal amounts [18].
• As a result Sh-TOR-ed1 pre-incubated with C2 inhibits classical pathway (CP)-mediated haemolysis of sheep erythrocytes in a dose-dependent manner [19].
• Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis, we examined the effects of LPS on synthesis of C3 by human mononuclear phagocytes as well as synthesis of the second component of complement (C2), factor B, lysozyme, and total protein [20].
• The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement (C2) was studied in families of patients with connective tissue disorders [21].

Associations of C2 with chemical compounds

• MASP-2 is the protease responsible for activating C4 and C2 to generate the C3 convertase, C4bC2b [22].
• The binding of MBL to microbial carbohydrates activates the MBL-associated serine proteases (MASPs), which recruit the complement factors, C4 and C2, to generate the C3 convertase or directly activate C3 [23].
• This part of C2 is 34% homologous to the corresponding region of the related serine protease factor B and additional similarity is evident from a number of conservative amino acid replacements in this region [15].
• C2 and fragment C2a had comparable reactivities and hydrolyzed peptides containing Leu-Ala-Arg and Leu-Gly-Arg, which have the same sequence as the cleavage sites of C3 and C5, respectively [17].
• Two clusters of acidic amino acids near the NH2 terminus of complement component C4 alpha'-chain are important for C2 binding [24].

Enzymatic interactions of C2

• MASP-3 downregulate the C4 and C2 cleaving activity of MASP-2 [23].
• MASP-1 can cleave C2, and with low efficiency also C3, and may serve a function through direct C3 activation [25].

Regulatory relationships of C2

• Mannan-binding lectin (MBL) activates the complement system through cleavage of C4 and C2 [26].
• Recombinant IFN-gamma in concentrations ranging from 0.1 to 300 U/ml (0.003 to 8.8 ng/ml) stimulates C2 production by both cell populations [27].
• The ability of gold sodium thiomalate to inhibit production of the second complement component (C2) by monocytes stimulated by a lymphokine (monocyte complement stimulator is demonstrated [28].
• In contrast to PBL, lymphocytes isolated from the synovial membranes (SML) of patients with rheumatoid arthritis and their culture supernatants were able to stimulate C2 synthesis without exposure to mitogens or antigens [29].

Other interactions of C2

• Design, synthesis and biological activity of novel C2-C3' N-Linked macrocyclic taxoids [30].
• IFN-gamma produced dose-dependent stimulation of C2, factor B, C1-inh, C4-bp and factor H synthesis by all cell types expressing these proteins, but decreased C3 synthesis in all four cell types [4].
• The addition of lymphoblastoid interferon alpha, fibroblast interferon beta and recombinant interferon gamma to in vitro monocyte cultures produced dose-dependent increases in transcription rates of the genes encoding the second component of complement (C2), factor B (B) and C1 inhibitor, and the abundance of their respective mRNA [31].
• A lod score of 13 was calculated for linkage between C2 deficiency and HLA-B at a maximum likelihood value of the recombinant fraction of 0.04 [21].
• Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes [32].

Analytical, diagnostic and therapeutic context of C2

• Southern blot analysis of genomic DNA of unrelated individuals identified a single C2 locus and showed no cross-hybridization with the factor B locus [15].
• Western blot analysis indicated that secreted rC2 had the same apparent m.w. as C2 in human serum [33].
• Site-directed mutagenesis experiments revealed that replacing subsets of the charged residues by their isosteric amides within either acidic cluster resulted in molecules having reduced C2 binding activity [24].
• Northern blot analysis of total RNA isolated from transfected COS cells showed two bands of C2 mRNA, both of which were longer than human liver C2 mRNA and represent transcripts generated by the vector-C2 construct [33].
• Subsequent molecular biology, biosynthetic, and immunofluorescence studies demonstrated that C2 secretion is impaired in Type II C2 deficiency because of different missense mutations at highly conserved residues in each of the C2Q0 alleles [34].

References