the late news on baff in autoimmune diseases
TRANSCRIPT
Autoimmunity Reviews 9 (2010) 804–806
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Review
The late news on baff in autoimmune diseases
Pierre Youinou ⁎, Jacques-Olivier PersDepartment of “Immunology and Pathology”, European University of Brest, Brest, FranceIFR 148 “Scin Bios”, European University of Brest, Brest, FranceBrest University Medical School Hospital (CHU Augustin Morvan), Brest, France
⁎ Corresponding author. Laboratory of ImmunologyFrance. Tel.: +33 298 22 33 84; fax: +33 298 22 38 47
E-mail address: [email protected] (P. Youinou)
1568-9972/$ – see front matter © 2010 Elsevier B.V. Adoi:10.1016/j.autrev.2010.06.011
a b s t r a c t
a r t i c l e i n f oArticle history:Received 4 June 2010Accepted 17 June 2010Available online 23 July 2010
The B cell-activating factor of the tumor-necrosis factor family (BAFF) plays a dominant role in the B cellhomeostasis. By rescuing autoreactive B cells, excessive BAFF favors the development of autoimmunediseases. Given the numbers of variants of this B cell-specific cytokine, caution must be exercized whendetermining its serum level. Alternate splice isoforms, such as Δ3 BAFF and Δ4 BAFF, have been identified.They raise the possibility that their overproduction impact the synthesis of full-length BAFF.
, CHU, BP824, F-29609, Brest,..
ll rights reserved.
© 2010 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8042. Setting the scene for BAFF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
2.1. Where is BAFF coming from and going to? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8042.2. The variants of BAFF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8052.3. Assessment of BAFF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
3. The known activites of BAFF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8053.1. The effects on B lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8053.2. The impact of BAFF on T lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8053.3. Various activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
4. Controversy over the regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8054.1. Alternate splice isoforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8054.2. The transcription factors for BAFF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
1. Introduction
Beyond the paradigm that T lymphocytes hold strict control over Blymphocytes, the activities of the latter cells are orchestrated byrepresentatives of the tumor-necrosis factor (TNF) group [1]. Threemembers come forth in this large family [2]: the TNF-like weakinducer of apotosis (TWEAK), a proliferation-inducing ligand (APRIL),and the B cell-activating factor of the TNF family (BAFF). The thirdcytokine, described in the late 90s [3], favors the growth ofautoimmune disorders [4–6], including systemic lupus erythematosus(SLE), primary Sjögren's syndrome (SS) and rheumatoid arthritis (RA)
in BAFF transgenic (Tg) and humans. As such, BAFF might become atherapeutic target [7], although the process of drug development isparticularly difficult in autoimmune diseases [8]. For now, given theamount of new insight into the mechanisms of tolerance breach, theneed is great for a synthesis of current discoveries in the field.
2. Setting the scene for BAFF
2.1. Where is BAFF coming from and going to?
Multiple cell lineages are supposed to produce BAFF (reviewed in[9]). Among them, emerge all sorts of monocytes, activated Tlymphocytes, neutrophils, synoviocytes, astrocytes, epithelial cellsand those B lymphocytes infiltrating the salivary glands (SGs) ofpatients with primary SS [10]. There is indeed evidence that local
Take-home messages
• BAFF is produced by multiple cell lineages, including B lymphocytes.• There are numerous variants of BAFF in the circulations.• The dominant role of BAFF is to sustain the B cell survival.• Several transcription factors are involved in the regulation.• BAFF will most probably, be a therapeutic target in the future.
805P. Youinou, J.-O. Pers / Autoimmunity Reviews 9 (2010) 804–806
production of the cytokine contributes to the deleterious effects ofactivated B lymphocytes. BAFF (which preserves autoreactive B cellsfrom apoptosis) and APRIL (which regulates B cell activation) share thetransmembrane activator and calcium modulator ligand interactor(TACI) and the B cell maturation antigen receptors, while BAFF, but notAPRIL, binds to the BAFF-receptor 3 (BR-3), and APRIL, but not BAFF,binds to heparan sulfate proteoglycans (reviewed in [11]).
2.2. The variants of BAFF
Excessive quantities of BAFF were found in the sera and cerebro-spinal fluids of SLE patients [12], sera and SGs of SS patients [5], andsera and synovial fluids of RA patients [13]. But, in fact, BAFF offers abunch of variants: membrane-bound or soluble, monomer or trimers,homotrimers or heterotrimers, herotrimers with APRIL or hetero-trimerswith TWEAK, or evenvirus-like aggregates of 60monomers [2].
2.3. Assessment of BAFF
There exists the issue of why the serum concentrations of BAFFremain within, or below, normal range in a proportion of patients.Also intriguing is that raised serum concentrations of BAFF have beenassociated with anti-self antibody (Ab) production by some [14], butnot all investigators [15]. Thus, receptor occupancy B cells by BAFF[16], its urinary excretion in case of renal failure [15] andsequestration in these immune complexes [17], all hinder assessmentof BAFF. In this respect, it is interesting that intravenous immunoglu-blin contains natural anti-BAFF Abs [18]. Furthermore, on the basisthat flaws in an enzyme-linked immunosorbent assay (ELISA) mightexplain such variations, we have set an in-house ELISA, as a reliabletool in the management of diseases [19].
3. The known activites of BAFF
3.1. The effects on B lymphocytes
Above all, BAFF mediates survival of peripheral immature Blymphocytes [20] that may evolve into marginal zone B cells [21].Given the reduced competitiveness of autoantigen-engaged B cells, dueto increased dependence on BAFF [22], its pathological excess rescuesautoreactive B cells from peripheral deletion and allows them to enterforbidden follicular andMZniches [23]. BAFF has thus been castwith theleading part in this play because MZ B cells are particularly prone toactivation. The implication is that preventing autoreactive B cells fromcolonizing this area is paramount, and the abundance of BAFF becomes aserious threat in thepatients. Then, BAFFactivates theB cells via thePax-5 transcription factor [24] and substitutes for CD40 ligand in the classswitch [25]. Finally, BAFF encourages infiltration of lymphoid tissuesalongwith T-lymphocyte-derivedTNF. This help has longbeen regardedas necessary. Were that to be the case, no tissue infiltration should beobserved in the progeny of BAFF-Tg mice and TNF-deleted mice [26].
3.2. The impact of BAFF on T lymphocytes
Surprisingly, aberrant expression of BAFF in T cells of patients withSLE [27] or RA [28] may engender some T helper-1 responses [29] andan anti-inflammatory regulatory T cell expansion [30]. Theseobservations indicate that BAFF has a dichotomous role in immunity.
3.3. Various activities
Not only is BAFF produced by astrocytes [31], but its serum levels areelevated in myasthenia gravis [32], multiple sclerosis [33] and neuro-Behçet [34]. Furthermore, altered emotional behaviors in autoimmuneBAFF-Tg mice [35] suggest that anxiety associated with SLE, primary SSand RA can be linked to BAFF-induced brain inflammation.
4. Controversy over the regulation
4.1. Alternate splice isoforms
Alternative splicing generates proteomic diversity. A novel exon3-lacking isoform of BAFF, referred to as ΔBAFF, has been identified inmany mouse and human myeloid cells [36]. Based on its ability tomultimerize with full-length BAFF, this truncated variant mightrestrain the effects of the full-length-cytokine, and thereby regulateB lymphocyte homeostasis [37].
4.2. The transcription factors for BAFF
Since 2000, we know that the CD40 receptor behaves as atranscription factor for BAFF [38]. Other factors may be operating.The use of new primers allowed us to detect an additional transcript(Le Pottier, Tobón, Youinou and Pers, unpublished observations). Thebandwas devoid of the 114 base pair segment encoded by exon 4, andthis new variant referred to as Δ4BAFF, as opposed to the formerΔ3BAFF. The chromosome immunoprecipitation technology unveiledthat the protein was associated with DNA, and, to our surprise, actedas a transcription factor for the full-length form of BAFF.
5. Conclusion
Treatments that eliminate the abnormal B cells (rituximab) seem tobe effective in preventing progression towardmalignancies [39] and inimproving the severe extra-glandular manifestations that are relatedto B-cell overstimulation in SS [40]. There are claims for an increase inthe BAFF level by approximately 2.5 to 3-fold at 3–4months after B-celldepletion, and a return to pre-treatment value at 8–12 months.Rituximab-induced changes in the serum bring about new insightsinto mechanisms of action [41]. Thus BAFF is possibly (likely) a noveltherapeutic target for autoimmune diseases. Anti-BAFF or anti-BR3monoclonal Abs [42], as well as BR3 or TACI decoy fusion proteins [43],are currently being evaluated in SLE. By inhibiting the BAFF-mediatedsurvival of autoreactive B cells, might prove effective in monorgan-specific autoimmune diseases.
Acknowledgements
Thanks are due to Geneviève Michel and Simone Forest forcheerful and expert assistance with the typing of this manuscript.
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Topoisomerase I inhibitor in experimental lupus reverses proteinuria
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CD19 and B10 cell deficiency exacerbates systemic autoimmunity
nce of B cells on disease pathogenesis in amurine lupusmodel, NZB/Wa B cell-specific cell surfacemolecule that is essential for optimal B cellhe emergence of anti-nuclear Abs was significantly delayed in CD19-/-ologic manifestations of nephritis appeared significantly earlier, andild typemice. These results demonstrate both disease-promoting andified a potent regulatory B cell subset (B10 cells) within the rare CD1dnd autoimmunity through theproduction of IL-10. Inwild typeNZB/Wncreasedby2.5-foldduring thedisease course,whereas CD19-/-NZB/Wsfer of splenic CD1d (hi) CD5+B cells fromwild typeNZB/Wmice intoore, regulatory T cells were significantly decreased in CD19-/- NZB/Wtory cell expansion in CD19-/- NZB/Wmice. These results demonstratemmune disease.
er, and experimentally this drugpreventeddeath ofmice injectedwith010;184:2175–82)have injectedNZBxNZWF1micewith irinotecanathe authors observed that all treated mice survived until the end of theto control group in which all animals had proteinuria by week 42. Asecan was infused, proteinuria was reduced, the disease entered into airinotecan seem to be promising as lupus treatment agent.