Editorial

Is the celiac disease model relevant to rheumatoid arthritis?

Keywords: Rheumatoid arthritis; Citrulline; Autoimmunity

Rheumatoid arthritis (RA) in adults has benefited fromnew knowledge acquired in many fields including inflamma-tion and innate immunity [1], specific or adaptive immunity,genetics, and biochemistry. In addition to the classic arthritismodels in rodents, other sources of knowledge may shedlight on the pathophysiology of RA. The pathogenesis ofceliac disease related to gluten intolerance was elucidatedrecently. I will review the mechanisms underlying celiacdisease and examine their possible relevance to RA.

The prevalent pathophysiological concept involves a spe-cific CD4+ T-cell immune response to one or more peptidespresented by Class II HLA molecules carrying the sharedepitope QKRAA, which is located in the third hypervariableregion of the HLA DRB1* chains (0101, 0401, 0404, 0405)[2]. The antigen or antigens that trigger the immune responsehave not been identified and may be self-antigens or environ-mental antigens. Strong experimental evidence incriminatespeptides containing citrullinated residues, which are pro-duced when arginine is converted to citrulline by the enzymepeptidyl-arginine-deiminase (PAD) [3,4].

The interest generated by citrullinated peptides is a longEuropean saga that started in The Netherlands with the de-scription of antiperinuclear factor [5] and continued to unfoldin Toulouse, where antistratum corneum antibodies (antik-eratin antibodies) were first identified [6]. Antistratum cor-neum antibodies, which are highly specific of RA, recognizea filamentous protein or group of proteins called filaggrin (ortheir precursor, profilaggrin) [7,8]. Filaggrin is an epithelialprotein that undergoes posttranslational changes [3]; PADincreases its content in citrullinated residues. Several PADisoforms exist, of which four have been identified and clonedin humans and rodents [9–11]. One or several PAD isoformshave been found in a variety of tissues, although their target isnot always known. Filaggrin is found only in epithelia andconsequently cannot play a direct role in the connectivesynovial tissue. However, among the other citrullinated pro-teins identified to date, fibrin with its a and b chains is apossible candidate in the synovium [12]; a role for vimentin,the Sa protein [13] (identified as vimentin-related in somestudies), or nuclear proteins has also been suggested. Citrul-linated peptides have been identified in 50% of rheumatoidsynovium specimens [14]. Studies are under way to deter-

mine whether this phenomenon is specific of rheumatoidinflammation [15].

The groups headed by Guy Serre in Toulouse and VanVenrooij in Nijmegen identified the PAD isoforms II and V inrheumatoid synovial tissue, but not the isoforms I and III[11]. The messenger RNA for PAD V is expressed bymonocyte-derived macrophages. Although citrullinated pro-teins are not detectable in monocytes, citrullinated vimentinis found in monocyte-derived macrophages [10]. PAD II, incontrast, is expressed by monocytes and by monocyte-derived macrophages. The PAD V gene has been mapped tochromosome 1 and, of the several variants identified to date,one was found in 38% of RA patients overall, as compared toonly 17% of controls in the ECRAF European study(P < 0.007); among patients with RA and antikeratin antibod-ies, 41% had this variant (P < 0.03) [16]. A specific genehaplotype that encodes PAD14 is strongly associated withRA [17]. This establishes that protein citrullination is undergenetic control.

In addition to self-proteins, bacterial proteins may un-dergo citrullination [18], either spontaneously or when theypenetrate into the body. Whether PAD activity in mammali-ans is spontaneous or induced remains unclear; if it is in-duced, the preferential triggers would need to be identified[19]. Conceivably, triggers for RA may cause cell apoptosiswith citrullination of self-proteins [19]. PADs are also stimu-lated by estrogens. Citrullinated proteins are degraded bycalpains, which are calcium-dependent cysteine proteasesnormally neutralized by calpastatin [20,21].

The link between Class II HLA molecules and citrulli-nated peptides remains speculative. An appealing hypothesisis that citrullinated peptides have higher affinity for Class IIHLA molecules that share the QKRAA sequence, as com-pared to similar noncitrullinated peptide sequences. Thishypothesis was tested by Hill et al. [22], who used T epitopescontaining either arginine or citrulline in the lateral section ofthe molecule that usually binds to the P4 part of the peptidegroove, which is the HLA DRB1* zone containing the sharedepitope. Using transgenic HLA-DR4-IE mice (whose cellsexpress DRB1*0401 but not class II murine molecules),these researchers showed that citrullinated vimentin peptidesexhibited stronger affinity for DRB1*0401 than did the same

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noncitrullinated peptides. Similar results were obtained forthe 0404 and 0101 molecules. In addition, the citrullinatedvimentin peptide triggered activation of a CD4+ T-cell re-sponse in transgenic mice (proliferation and IFNc produc-tion).

These data outline a scenario involving several steps.First, an environmental agent may penetrate within the body,activating pattern recognition receptors (PRR), such as theToll receptors on monocytes and type A synoviocytes [23].Then, NF-kB pathway activation may enhance the produc-tion of cytokines such as IL-15, IL-18, IL-1, and TNFa [24].Finally, monocytes and immature dendritic cells may differ-entiate into antigen-presenting cells [1].

For reasons possibly related in part to the triggering factor(which induces apoptosis) and in part to the genetic back-ground [25], PAD activation may occur in a subset ofmonocyte/macrophages, leading to citrullination of self pro-teins including vimentin. Degradation of these citrullinatedpeptides by calpains may release immunogenic peptides,which may be presented to CD4+ T-cells with high affinityfor Class II HLA molecules containing the shared epitopeQKRAA. Activation of these T cells specific of citrullinatedepitopes may lead to the production of antibodies to citrulli-nated peptides and to a specific cellular response contributingto the development of the synovial pannus. Plasma cells [26]and B cells producing antibodies to citrullinated peptideshave been identified within the synovium, confirming thelocal nature of the phenomenon [27].

The reason this reactivity against citrullinated peptides isspecific of RA probably lies in the genetic control of PADproduction or activation. The same applies to the possibleresistance of some citrullinated peptides to calpains. Calp-

astatin is a naturally occurring calpain inhibitor. Acquiredmechanisms such as autoantibody production may play arole.Antibodies to calpastatin have been identified in patientswith RA [21], although they do not seem specific of thisdisease.

This hypothetical scenario is supported by a number ofarguments. A similar chain of events has been shown to causeceliac disease [28]: a 33-amino acid gliadine peptide pen-etrates within the gut mucosa cells without being degradedby the gut enzymes. This “villain” (this is the word used byauthors) [29] undergoes active transglutamination and multi-merization that makes it susceptible to endocytosis andcleavage into three epitopes exhibiting high affinity for theHLA DQ1 and DQ8 molecules. Closely intertwined innateand adaptive immune responses lead to the intestinal lesionscharacteristic of celiac disease. Thus, the transglutaminated“villain” stimulates various functions related to innate immu-nity, causing increased production of IL-15, stimulation ofCOX-2, expression of CD83 receptors (markers for maturedendritic cells), expression of CD25 (the IL-2 receptor) byCD3+ T cells, and apoptosis of enterocytes [30]. Similarly,RA might be triggered by an environmental protein thatescapes complete degradation by the nonspecific defensesystems. This protein, or a fragment resistant to degradationby monocytes/macrophages, may undergo citrullination [18]or may activate the PADs causing citrullination of a variety ofproteins. The result may be release of citrullinated peptideswith high affinity for HLA DRB1*0401, 0101, 0405, 0408,0410, 1001, and others (Fig. 1). Whether citrullinated pep-tides play a role in innate immunity is unknown. The highspecificity of anticitrulline antibodies for RA and the asso-ciation between these antibodies and bone erosions [31]

Fig. 1

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suggest an urgent need for investigating interactions with theRANK–RANK-L cytokine system.

“Comparison is not reason”. Nevertheless, the hypothesisoutlined above deserves investigation, and several groups areworking on the genetics and biochemical regulation of PADsand their substrates. The recent elucidation of the patho-physiology of celiac disease suggests that this approach maybe a rich source of information.

References

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[15] Smeets TJM, Vossenaar ER, van Venrooij WJ, Tak PP. Is expression ofintracellular citrullinated proteins in synovial tissue specific for rheu-matoid arthritis? Arthritis Rheum 2002;46:2824–6 Comment on thearticle by Baeten et al.

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[26] Masson-Bessière C, Sebbag M, Durieux JJ, Nogueira L, Vincent C,Girbal-neuhauser E. In the rheumatoid pannus, anti-filaggrin autoan-tibodies are produced by local plasma cells and constitute a higherproportion of IgG than in synovial fluid and serum. Clin Exp Immunol2000;119:544–52.

[27] Reparon-Schuijt CC, van Esch WJE, van Kooten C, Schellekens GA,de Jong BAW, van Venrooij WJ, et al. Secretion of anti-citrullinecontaining peptide antibody by B lymphocytes in rheumatoid arthritis.Arthritis Rheum 2001;44:41–7.

[28] Schuppan D, Esslinger B, Dieterich W. Innate immunity and coeliacdisease. Lancet 2003;362:3–4.

[29] McManus R, Kelleher D. Celiac disease. The villain unmasked? NewEngl J Med 2003;348:2573–4.

[30] Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al.Association between innate response to gliadin and activation ofpathogenic T cells in coeliac disease. Lancet 2003;362:30–7.

[31] Meyer O, Labarre C, Dougados M, Goupille PH, Cantagrel A,Dubois A, et al. Anticitrullinated protein/peptide antibody assays inearly rheumatoid arthritis for predicting 5-year radiographic damage.Ann Rheum Dis 2003;62:120–6.

Olivier MeyerRheumatology department, Hôpital Bichat,

46, rue Henri Huchard, 75018 Paris, FranceE-mail address: olivier.meyer@bch.ap-hop-paris.fr

(O. Meyer).

Received 2 September 2003; accepted 9 October 2003

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