Citrullination, a possible functional link between susceptibility genes and rheumatoid arthritis

Abstract

Antibodies directed to citrullinated proteins (anti-cyclic citrullinated peptide) are highly specific for rheumatoid arthritis (RA). Recent data suggest that the antibodies may be involved in the disease process of RA and that several RA-associated genetic factors might be functionally linked to RA via modulation of the production of anti-cyclic citrullinated peptide antibodies or citrullinated antigens.

Figure 1

Summary of the four exonal single nucleotide polymorphisms (SNPs) in PADI4. The actual SNP is indicated in bold. The amino acid that shows most conservation with other known peptidylarginine deiminases [4] is shaded gray. SNP ID* according to Suzuki and colleagues as padi4_x [7].

Figure 2

Multiple alignment of partial peptidylarginine deiminase (PAD) protein sequences based on a large full alignment described in [4] (available online: ). Shown are segments of all five isotypes from the human (Homo sapiens [Hs], PAD1 NP_037490, PAD2 NP_031391, PAD3 NP_057317, PAD4 NP_036519 and PAD6 XP_210118) and segments of PAD4 from the mouse (Mus musculus [Mm], NP_035191), the rat (Rattus norvegicus [Rn], NP_058923) and the cow (Bos taurus [Bt], based on BG364988). Conserved residues that are identical in more than 50% of all known PAD sequences are shaded black; fully conserved residues are shaded cyan. Conserved charged residues are also indicated (shaded light gray). Exon boundaries, based on PAD1 sequences, are annotated above the alignment. The monopartite nuclear localization signal (NLS) of PAD4 is shaded green, and conserved NLS residues are bold [8]. The four exonal single nucleotide polymorphisms are shaded pink. The nonsusceptible haplotype (S A A L) is shown in the alignment, and the susceptible (G V G L) haplotype is indicated below it. a.a., amino acid.

Figure 3

Correlation between the PADI4 haplotype and autoantibodies to citrullinated proteins (anti-filaggrin antibodies [AFA]). Homozygous susceptible (homo suscept.) rheumatoid arthritis (RA) patients (n = 30) are significantly more often AFA-positive than homozygous nonsusceptible (homo non-suscept.) RA patients (n = 33) or heterozygous (hetero) RA patients (n = 66) [7].

Figure 4

Possible links between rheumatoid arthritis (RA) specific anti-cyclic citrullinated peptide (anti-CCP) antibodies and RA-associated genetic factors (see text for details). (a) PADI4 single nucleotide polymorphisms (SNPs) may lead to elevated PAD4 expression and to increased citrullination of proteins [7]. (b) RA-associated HLA-DR4 molecules (DR4) can bind and present citrullinated peptides much more efficiently than noncitrullinated peptides [17]. (c) IL-10 promoter SNPs are associated with increased anti-CCP antibody production and severity of the disease [19]. (d) Various cytokine polymorphisms are associated with RA and may lead to stronger effects of immune complex activated cells. Abs, antibodies; DC, dendritic cell; Fcγ, Fcγ receptor; IC, immune complex; mφ, macrophage; PAD, peptidylarginine deiminase.