DOI 10.1002/art.22428

Epigenetic considerations in investigating the cause ofsystemic lupus erythematosus: comment on the articleby Chagnon et al

To the Editor:Findings reported by Chagnon et al (1) represent an

important contribution to efforts to determine the causes ofsystemic lupus erythematosus (SLE). Their report suggeststhat the distal end of the X chromosome short arm is involvedin SLE events. In support of this, they mention the possibleincreased incidence of SLE among patients with Klinefelter’ssyndrome. Reports of discoid and systemic lupus erythemato-sus occurring in association with X-linked chronic granuloma-tous disease (X-CGD) in carriers (mothers) and patients(sons) (2–5) provide further support for this contention.X-CGD is a recessive disease attributed to mutations in thecytochrome heavy-chain gene, encoded by a locus at Xp21.1.The result is an inability of lymphocytes to generate an“oxygen burst” when attacking bacteria, leading to life-threatening infections. These reports of an association be-tween lupus and X-CGD hint at a culprit gene or genes distalto Xp21.1, supporting the findings of Chagnon et al.

Epigenetic interpretations of Chagnon and colleagues’observations in the XX male patient should also be considered.Overexpression of genes distal to Xp22.33 could disrupt Xinactivation, leading to loss of dosage compensation andincreased expression of other genes in the area, both distaland proximal to Xp22.33. Loss of epigenetic control couldextend for megabases in either direction as chromatin higher-order domains are disrupted. In particular, 2 polyamine genesat Xp22.1, spermine synthase and spermidine/spermine N1-acetyltransferase, could be suspect in the development oflupus. Increased activity of these genes in a cell would in-crease polyamine synthesis. This increase would reduce levelsof ornithine, which is needed for synthesis of proline, a keyamino acid in collagen formation in connective tissue. In addi-tion, increased polyamine synthesis would divert S-adenosyl-methionine into decarboxylated S-adenosylmethionine used inpolyamine synthesis. This diversion of S-adenosylmethioninecould hamper the cell’s normal use of S-adenosylmethionine inDNA and protein methylation. There would most likely beother detrimental consequences of this change in polyaminesynthesis since polyamine levels are normally tightly controlled.

I look forward to reports on the lines of furtherresearch into the causes of SLE suggested by Chagnon et al.

Wesley H. Brooks, MBA, PhDMoffitt Research InstituteTampa, FL

1. Chagnon P, Schneider R, Hebert J, Fortin PR, Provost S, Belisle C,et al. Identification and characterization of an Xp22.33;Yp11.2translocation causing a triplication of several genes of the pseudo-autosomal region 1 in an XX male patient with severe systemiclupus erythematosus. Arthritis Rheum 2006;54:1270–8.

2. Schaller J. Illness resembling lupus erythematosus in mothers ofboys with chronic granulomatous disease. Ann Intern Med 1972;76:747–50.

3. Manzi S, Urbach AH, McCune AB, Altman HA, Kaplan SS,Medsger TA Jr, et al. Systemic lupus erythematosus in a boy with

chronic granulomatous disease: case report and review of theliterature. Arthritis Rheum 1991;34:101–5.

4. Hafner J, Enderlin A, Seger RA, Wuthrich B, Bruckner-Tuder-mann L, Panizzoni P, et al. Discoid lupus erythematosus-like lesionsin carriers of X-linked chronic granulomatous disease. Adv DentRes 1996;10:57–61.

5. Brandrup F, Koch C, Petri M, Schiodt M, Johansen KS. Discoidlupus erythematosus-like lesions and stomatitis in female carriers ofX-linked chronic granulomatous disease. Br J Dermatol 1981;104:495–505.

DOI 10.1002/art.22438

The existence of human TII B cells remains unproven:comment on the article by Daridon et al

To the Editor:Recently, Daridon et al proposed that B cells infiltrat-

ing the minor salivary glands of patients with primary Sjogren’ssyndrome (SS) fulfilled the criteria for transitional type II(TII) B cells and also resembled marginal-zone B cells (1). Amajor area of concern relates to the nature of human transi-tional B cells. In mice, immature CD93� splenic B cells can bedivided into 2 or more transitional subsets based on phenotypeand functional characteristics, as follows: more immature TI Bcells and more mature TII B cells.

In humans, identification of transitional B cells is moredifficult, because CD93 expression is not useful. Despite this,we recently characterized the phenotype and function ofhuman TI B cells from peripheral blood (2). Interestingly,there is an apparent continuum in function and surfaceexpression of a variety of markers between the TI B cells andnaive B cells, and we proposed that B cells with theseintermediate characteristics may represent the equivalent ofmouse TII B cells. If so, they would be quite different frommurine TII cells that reside uniquely in the spleen (1). Impor-tantly, however, there is no real evidence that an equivalent ofthe murine TII B cell exists in humans.

The major question, therefore, is whether Daridon etal identified TII cells in the salivary glands. They relied on aseries of markers that cannot clearly distinguish immature TIIcells from naive B cells. In this regard, it was surprising that noB cells in the salivary glands expressed CD38, because thismarker is expressed on TI, intermediate TII, and naive B cellsin peripheral blood, whereas the CD38� B cells are largelyCD27� memory B cells in humans. The fluorescence stainingin that study does indicate that the infiltrating IgD� B cellswere a homogeneous population with high expression of IgM,CD21, and CD23. This phenotype is reminiscent of murine TIIB cells, but it may also be induced by activation or exposure ofmature B cells to cytokines, such as BAFF (3). Indeed,Daridon et al clearly demonstrated that BAFF was abundant insalivary glands, as previously reported (4).

Murine studies have shown that BAFF is a survivalfactor for CD21high TII B cells (4). BAFF-transgenic mice haveincreased numbers of splenic CD21high marginal-zone and TIIcells, and the salivary glands have increased proportions ofinfiltrating marginal-zone–like B cells compared with age-matched wild-type mice (4,5). However, because mature Bcells in BAFF-deficient mice fail to up-regulate CD21 effec-tively (3), it remains plausible that the high expression of CD21associated with the TII B cell phenotype may be a consequence

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of BAFF and other inflammation mediators acting on matureB cells. Therefore, this phenotype may represent an activatedB cell rather than an immature developmental intermediate.

In summary, while the phenotypic analysis by Daridonet al is interesting, we believe that it is insufficient and theknowledge of human TII cells too incomplete to sustain anyconclusion about the possible appearance of these cells insalivary glands from patients with primary SS.

Gary Sims, MDPeter Lipsky, MDNational Institutes of HealthBethesda, MD

1. Daridon C, Pers JO, Devauchelle V, Martins-Carvalho C, Hutin P,Pennec YL, et al. Identification of transitional type II B cells in the

salivary glands of patients with Sjogren’s syndrome. ArthritisRheum 2006;54:2280–8.

2. Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE.Identification and characterization of circulating human transi-tional B cells. Blood 2005;105:4390–8.

3. Gorelik L, Cutler AH, Thill G, Miklasz SD, Shea DE, Ambrose C,et al. Cutting edge: BAFF regulates CD21/35 and CD23 expressionindependent of its B cell survival function. J Immunol 2004;172:762–6.

4. Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, SchneiderP, et al. Association of BAFF/BLyS overexpression and altered Bcell differentiation with Sjogren’s syndrome. J Clin Invest 2002;109:59–68.

5. Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J,et al. BAFF mediates survival of peripheral immature B lympho-cytes. J Exp Med 2000;192:1453–65.

DOI 10.1002/art.22359

Clinical Image: Intracardiac thrombosis in the antiphospholipid syndrome

The patient, a 36-year-old man, presented to the emergency department with severe dyspnea and digital gangrene affecting thehands and feet. Within a few hours his condition progressed to frank respiratory insufficiency, and he died. Laboratory studiesrevealed a prolonged activated partial thromboplastin time (70 seconds), positivity for lupus anticoagulant, and increased levels ofIgG and IgM anticardiolipin antibodies (87 IgG phospholipid units/ml, 34 IgM phospholipid units/ml). Postmortem examinationrevealed extensive intracardiac thrombosis. Intracardiac thrombosis is a potentially life-threatening complication of the antiphos-pholipid syndrome.

Luiz Sergio Guedes-Barbosa, MDDely Cristina Martins, MDAndrea Barros, MDHospital Universitario Julio Miller/UFMTCuiaba, Mato Grosso, Brazil

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