Citrullination is an inflammation-dependent process

Makrygiannakis, Dimitrios; Klint, Erik af; Lundberg, IE; Löfberg, Robert; Ulfgren, A-K; Klareskog, Lars; Catrina, Anca I.

doi:10.1136/ard.2005.049403

Cited by 268 publications

(219 citation statements)

References 16 publications

(10 reference statements)

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“…This suggests that this process is inflammationdependent rather than disease-dependent (22,23). Moreover, the presence of anti-CCP antibody has been reported, in low prevalence, in association with systemic lupus erythematosus, systemic sclerosis, polymyositis (24), Sjö gren syndrome (25) and psoriasis (26,27).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of anti-cyclic citrullinated peptide antibodies in Egyptian patients with chronic hepatitis C virus genotype IV infection

Bassyouni

Ezzat

Hamdy

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Section: Discussionmentioning

confidence: 99%

Clinical significance of anti-cyclic citrullinated peptide antibodies in Egyptian patients with chronic hepatitis C virus genotype IV infection

Bassyouni

Ezzat

Hamdy

et al. 2009

Clinical Chemistry and Laboratory Medicine

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“…In addition, the accumulation of citrullinated proteins has been described at sites of inflammation, including the joints of patients with all forms of arthritis (17), the brains of patients with multiple sclerosis (18) or Alzheimer's disease (19), and in the muscle fibers of patients with myositis (20). Hence, citrullinated proteins are present in the setting of both health and disease, while tolerance to citrullinated proteins appears to be selectively lost in patients with RA.…”

mentioning

confidence: 99%

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

Lundberg

Kinloch

Fisher

et al. 2008

Arthritis & Rheumatism

339

313

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Objective. To map the antibody response to human citrullinated ␣-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine crossreactivity with bacterial enolase.Methods. Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated ␣-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting.Results. An immunodominant peptide, citrullinated ␣-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated ␣-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r 2 ‫؍‬ 0.803, P < 0.0001). Affinitypurified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.Conclusion. We have identified an immunodominant epitope in citrullinated ␣-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

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“…PAD4, unlike other PADs, can translocate into the nucleus (Vossenaar et al, 2003), in which it deiminates histones Nakashima et al, 2002;Cuthbert et al, 2004;Sarmento et al, 2004;Wang et al, 2004). The association of PAD4 activity with a number of inflammatory diseases (Nissinen et al, 2003;Lundberg et al, 2005;Makrygiannakis et al, 2006) may be an indicator of the involvement of this enzyme in cellular stress mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

Mastronardi¹,

Wood²,

Jiang³

et al. 2006

J. Neurosci.

228

175

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Modification of arginine residues by citrullination is catalyzed by peptidylarginine deiminases (PADs), of which five are known, generating irreversible protein structural modifications. We have shown previously that enhanced citrullination of myelin basic protein contributed to destabilization of the myelin membrane in the CNS of multiple sclerosis (MS) patients. We now report increased citrullination of nucleosomal histones by PAD4 in normal-appearing white matter (NAWM) of MS patients and in animal models of demyelination. Histone citrullination was attributable to increased levels and activity of nuclear PAD4. PAD4 translocation into the nucleus was attributable to elevated tumor necrosis factor-␣ (TNF-␣) protein. The elevated TNF-␣ in MS NAWM was not associated with CD3 ϩ or CD8 ϩ lymphocytes, nor was it associated with CD68 ϩ microglia/macrophages. GFAP, a measure of astrocytosis, was the only cytological marker that was consistently elevated in the MS NAWM, suggesting that TNF-␣ may have been derived from astrocytes. In cell cultures of mouse and human oligodendroglial cell lines, PAD4 was predominantly cytosolic but TNF-␣ treatment induced its nuclear translocation. To address the involvement of TNF-␣ in targeting PAD4 to the nucleus, we found that transgenic mice overexpressing TNF-␣ also had increased levels of citrullinated histones and elevated nuclear PAD4 before demyelination. In conclusion, high citrullination of histones consequent to PAD4 nuclear translocation is part of the process that leads to irreversible changes in oligodendrocytes and may contribute to apoptosis of oligodendrocytes in MS.

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Citrullination is an inflammation-dependent process

Abstract: Citrullination is present in a wide range of inflammatory tissues, suggesting that this process is inflammation dependent rather than disease dependent.

Cited by 268 publications

References 16 publications

Clinical significance of anti-cyclic citrullinated peptide antibodies in Egyptian patients with chronic hepatitis C virus genotype IV infection

Clinical significance of anti-cyclic citrullinated peptide antibodies in Egyptian patients with chronic hepatitis C virus genotype IV infection

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

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