Complement in Lupus: Biomarker, Therapeutic Target, or a Little Bit of Both?
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ABSTRACT:
SUBMITTER: Cantarelli C
PROVIDER: S-EPMC8344109 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundScreening abnormal pathways and complement components in the kidneys of patients with lupus nephritis (LN) and NZB/W mice may help to identify complement-related therapeutic targets for LN.MethodsKEGG and GO enrichment assays were used to analyze kidney microarray data of LN patients and NZB/W mice. Immunohistochemistry and immunofluorescence assays were used to measure renal expression of complement-related proteins and TGFβ1. Cytokines were measured using RT-qPCR and ELISA.ResultsWe screened the renal pathogenic pathways present in LN patients and NZB/W mice and selected the complement activation pathway for further study. The results indicated greater renal expression of C1qa, C1qb, C3, C3aR1, and C5aR1 at the mRNA and protein levels. C3 appeared to be a key factor in LN and the renal signaling downstream of C1 was inhibited. There were significant correlations between the expression of TGFβ1 and C3. Analysis of primary cell cultures indicated that TGFβ1 promoted the expression of C3 and that a TGFβ1 antagonist decreased the levels of C3 and C3aR. TGFβ1 inhibition significantly inhibited the deposition of complement-related factors in the kidneys of NZB/W mice.ConclusionsAt the onset of LN, there are significant increases in the renal levels of C3 and other complement pathway-related factors in patients with LN and NZB/W mice. C3 may lead to albuminuria and participate in the pathogenesis of LN. TGFβ1 promotes C3 synthesis, and TGFβ1 inhibition may block the progression of LN by inhibiting the synthesis of C3 and other complement components.
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Project description:BackgroundIn the absence of sex and recombination, genomes are expected to accumulate deleterious mutations via an irreversible process known as Muller's ratchet, especially in the case of polyploidy. In contrast, no genome-wide mutation accumulation was detected in a transcriptome of facultative apomictic, hexaploid plants of the Ranunculus auricomus complex. We hypothesize that mutations cannot accumulate in flowering plants with facultative sexuality because sexual and asexual development concurrently occurs within the same generation. We assume a strong effect of purging selection on reduced gametophytes in the sexual developmental pathway because previously masked recessive deleterious mutations would be exposed to selection.ResultsWe test this hypothesis by modeling mutation elimination using apomictic hexaploid plants of the R. auricomus complex. To estimate mean recombination rates, the mean number of recombinants per generation was calculated by genotyping three F1 progeny arrays with six microsatellite markers and character incompatibility analyses. We estimated the strength of purging selection in gametophytes by calculating abortion rates of sexual versus apomictic development at the female gametophyte, seed and offspring stage. Accordingly, we applied three selection coefficients by considering effects of purging selection against mutations on (1) male and female gametophytes in the sexual pathway (additive, s = 1.000), (2) female gametophytes only (s = 0.520), and (3) on adult plants only (sporophytes, s = 0.212). We implemented recombination rates into a mathematical model considering the three different selection coefficients, and a genomic mutation rate calculated from genome size of our plants and plant-specific mutation rates. We revealed a mean of 6.05% recombinants per generation. This recombination rate eliminates mutations after 138, 204 or 246 generations, depending on the respective selection coefficients (s = 1.000, 0.520, and 0.212).ConclusionsOur results confirm that the empirically observed frequencies of facultative recombination suffice to prevent accumulation of deleterious mutations via Muller's ratchet even in a polyploid genome. The efficiency of selection is in flowering plants strongly increased by acting on the haplontic (reduced) gametophyte stage.
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