Available online at www.sciencedirect.com
Autoimmunity Reviews 7 (2007) 149 – 154 www.elsevier.com/locate/autrev
The paradox of CD5-expressing B cells in systemic lupus erythematosus Pierre Youinou, Yves Renaudineau ⁎ Brest University Medical School, Brest, France Available online 20 March 2007
Abstract The pathophysiological relevance of B cells for systemic lupus erythematosus (SLE), particularly those expressing the T-cell marker CD5, raises the question as to how they operate upon autoimmune processes. Based on their production of low-affinity multispecific antibodies (Abs), CD5+ B lymphocytes, also referred to as B1 cells, have originally been endowed with the autoAb making. It has since been established that high-affinity Abs to double-stranded DNA are not generated by these cells, but rather by B2 cells. It does not appear that they have the exclusive rights to the production of pathogenic autoAbs. In the light of recent findings, CD5 plays a paradoxical role in preventing autoimmunity. Hence, misguided signaling through CD5 could lead to autoimmunity. This provocative view differs from the naïve interpretation that the increased levels of B1 cells in SLE represent a direct source of autoAbs responsible for damaging organs. © 2007 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; B lymphocyte; CD5; Chronic lymphocytic leukemia
Contents 1. 2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . The original interpretation . . . . . . . . . . . . . . . . . . . 2.1. CD5 B cells and disease . . . . . . . . . . . . . . . . 2.2. Separate lineage or activation marker? . . . . . . . . . 2.3. Function of CD5 in B cells . . . . . . . . . . . . . . . 2.4. CD5+ B cells as the source of autoantibodies . . . . . New findings on the CD5 molecule . . . . . . . . . . . . . . 3.1. CD5 revisited . . . . . . . . . . . . . . . . . . . . . . 3.2. Increased CD5+ B cells in systemic lupus erythematosus . Current interpretation . . . . . . . . . . . . . . . . . . . . . 4.1. Recent clues . . . . . . . . . . . . . . . . . . . . . . 4.2. The emerging picture . . . . . . . . . . . . . . . . . . Conclusions and perspectives . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
150 150 150 150 151 151 151 151 151 152 152 152 153
⁎ Corresponding author. Laboratory of Immunology, Brest University Medical School Hospital, BP 824, F 29609 Brest, France. Tel.: +33 298 22 33 84; fax: +33 298 22 38 47. E-mail address:
[email protected] (Y. Renaudineau). 1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2007.02.016
150
P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Systemic lupus erythematosus (SLE) is a complex illness hallmarked by increased antinuclear antibody (Ab) titers and widespread organ involvement [1]. Investigation into this jumble of immunological disorders continues to be an extremely active area of research [2], all the more because the central stage has recently shifted from T to B cells. Although our early concepts focused on the ability of B lymphocyte to produce autoAbs, it has become clear that they accomplish various other tasks. Any of them may be faulty in nonorgan-specific autoimmune diseases (NOSAIDs). These include [3–5] SLE, rheumatoid arthritis (RA) and primary Sjögren's syndrome (SS). Accumulating evidence points to disruption of B-cell tolerance [6], and offers a rationale for B-cell depletion as a therapeutic strategy [7]. The complexity inherent in the B-cell compartment dictates a thorough reappraisal of models based on the concept of a single B-cell population. It has indeed been two decades since CD5, first described as a T-cell marker, was identified in malignant human B cells [8] and later shown to mark a minority of B lymphocytes in the normal blood [9]. A new nomenclature has subsequently been set up [10] referring to CD5-negative conventional B cells as B2, and to CD5-positive distinctive B cells as B1. The latter subpopulation was further divided into B1a which express CD5, and B1b which do not but share many of the characteristics of their B1a counterpart. By nature, B1 and B2 lymphocytes mediate different functions. Those B cells expressing the T-cell marker CD5 have long been suspected to play a role in the development of autoimmunity for umpteen years. In the light of recent findings, they might rather act to prevent this damaging condition. The interplay between serum interleukin (IL)6 levels and IL-10-producing B-cell numbers might tune this cunning balance. Yet, the mechanisms involved in the loss of B-cell tolerance to nuclear antigens (Ags) remain elusive. 2. The original interpretation 2.1. CD5 B cells and disease Since T lymphocyte-associated Ags have unexpectedly been detected in chronic lymphocytic leukemia (CLL) B cells [11], there have been claims that the
153 153 153
CD5+ B-cell subset is expanded in numerous NOSAIDs, such as SLE, RA and primary SS. At that time, the physiological role of such cells was likely, through a framework of self-reactivities, to be involved in the setting up of the immunoglobulin (Ig) repertoire, including the idiotypic (Id) network. Then, evidence has accumulated for a close relationship between CLL and NOSAIDs. Autoimmune traits were observed in more than 8% of patients with B lymphoproliferation, compared with less than 2% of those with myeloproliferation. Reciprocally, monoclonal Igs have been detected in the serum of patients with NOSAID. To come full circle, CLL B cells are skewed towards the production of multispecific autoAbs [13]. 2.2. Separate lineage or activation marker? A flurry of findings is consistent with the lineage model, particularly in the mouse model. For example, irradiated mice could be supplied with B1 cells, provided that the graft contained not only bone marrow (BM) stem cells, but also peritoneal cells. In addition, mice with severe combined immune deficiency fail to develop either T or B cells because of a genetic deficiency in the enzyme required for rearrangements of B-cell receptor (BCR) genes, and their B1 cells are reconstituted by fetal liver cells, but not by adult BM cells. Recently, a B1 cell-specified progenitor has been unravelled in the murine BM [13]. The crucial criteria for determining whether human B-cell subsets are homologous to the mouse B1a, B1b and B2 lineages remain, nonetheless, to be met [14]. Arguments against this view support, as a result, that B1 cells are activated. Human CD5-negative B cells can indeed be turned into CD5-positive by incubation with phorbol-myristic acetate (PMA) or EL4 thymoma cells. For this reason, we have proposed that there may be discrete B1 populations which depend on the consequence of CD5 ligation on their surface [15]. If proved correct, our hypothesis would raise the possibility of differences in CD5+ B cells arising during early ontogeny (innate B1a cells) and those whereby CD5 expression is induced by various stimuli (acquired B1a cells). These two families of CD5+ B cells would coexist in normal individuals. Endogenously carrying CD5 B1 cells may have a different function from those B cells induced to express CD5 following activation. Consequently, signaling via CD5
P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154
occurs through different ligands in innate than in acquired CD5+ B-cell populations. 2.3. Function of CD5 in B cells CD5 is associated with the BCR, since it co-caps and co-modulates with surface IgM [16]. A number of data establish that induction of proliferative or apoptosis responses to anti-CD5 depends on the activation state of the cells. The physiological relevance of CD5-mediated apoptosis mediated is unclear, although it is known that the molecule precludes the production of autoAbs in certain NOSAIDs. In addition, its defective regulation might favor the development of CD5+ B-cell tumors. 2.4. CD5+ B cells as the source of autoantibodies The question as to whether B1a cells are the source of autoAbs has been discussed for ages. Some experiments have yielded data suggesting that they make a number of autoAbs, including anti-double-stranded (ds) DNA Abs and rheumatoid factor (RF). Our own studies on CLL showed that cells from 12 out of 14 patients could be driven by PMA to release multispecific Abs, some of which bound to dsDNA and displayed RF activity [12]. It has subsequently been proven that highaffinity Abs to dsDNA in SLE [17] and RF in RA [18] derive from B2 cells and not from B1. In addition, CLL patients' cells express dominant cross-reactive Ids (CRIs) which have been associated with specific gene usage. This might be associated exclusively with CD5+ B cells [19]. Earlier experiments had approached this question using immortalised cord blood clones: 53 clones were derived from CD5+ cells and 49 from CD5− cord blood B cells. Using mAbs to the mutually exclusive 9G4 Id of the Ig products of the 34 + VH4 gene, and the LC1 Id of the Ig products of the 34 − VH4 genes, we found that the former predominated in CD5+ clones, whereas it was the latter in the CD5− B-cells clones [20]. This clear-cut distinction suggested that CD5 skewed the 9G4encoding gene usage. By re-evaluating the expression of CRI in sorted CD5+ and CD5− B cells from normal blood, CD5+ cells from CLL patients and CD5− cells from patients with Burkitt's lymphoma, neither of the VH4 CRI appeared to be associated exclusively with CD5+ B cells. Furthermore, it was clear that, when the IgM was tested with 20 Ags, the Abs bound to either none, one or two Ags, irrespective of CD5 expression of the cells [21]. Consistent with this result is the lack of CRI with RF activity in CLL patients shared by in RA
151
patients [17]. Increases in autoAbs in SLE and RA would thus not be directly due to CD5+ B cells. Still, from the 9G4 CRI studies in the cord blood cells was the specificity of the positive clones for the carbohydrate erythrocyte Ags Ii (Mageed et al., submitted). This observation indicates that the CD5+ clones had been Agdriven and, therefore, selected in vivo. Likewise, at least in the influenza model, innate CD5+ B cells and acquired CD5− B cells are mediated by distinct arms of the immune system [22]. 3. New findings on the CD5 molecule 3.1. CD5 revisited B1a lymphocytes could rather act as Ag presenting cells (APCs). Due to their association with multispecific Abs, they appear to be particularly appropriate to the presentation of Ags, and able to present self-components to other B1, B2 or T cells. It is thus of no surprise that splenic B1a lymphocytes are so potent APCs that they induce twofold greater levels of lymph-node T-cell interferon-γ production than that produced by B2 in the NZBM 2410 lupus-prone mouse [23]. Interestingly, Roosnek and Lanzavecchia have demonstrated that B cells binding IgG Ab complexes via membrane RF, primarily B1a cells, process and present Ag very efficiently [24]. B cell-derived IL-10 is a common finding in RA, SLE and primary SS [25]. This encourages Ag presentation by B1a cells. Relevant to this issue, we have sorted B1a, B1b and B2 cells from the peritoneal cavity and spleen of normal mice and identified the message for IL-10 by reverse transcriptase-polymerase chain transcription, particularly within the peritoneal B1a cells [26]. 3.2. Increased CD5+ B cells in systemic lupus erythematosus Hardly any B cell of the B1a phenotype arises during BM development in adult animals. Their increased numbers might thus reflect defective regulation of Bcell function through CD5 itself. Moreover, there is much evidence that CD5 is essential in modulating signals downstream from the BCR. Ligation of CD5 or IgM on tonsil B but not blood T cells results in apoptosis [27], whereas anti-CD5 sustains the proliferation of tonsil B cells pre-activated with anti-IgM and IL-2 [28]. This contrasts with the finding that cord blood CD5+ B cells do not apoptose in response to anti-CD5 (our unpublished results), but reflect the fact that they are continuously exposed to autoAg in vivo. CD5 is associated, both physically and functionally with the BCR, of which the
152
P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154
Igα, Igβ chains are constitutively linked to the NH2terminal Src-homology 2 domain-containing protein tyrosine phosphatase (SHP-1) through their immunoregulatory tyrosine based inhibitory motif of CD5 [29]. Such an interaction with CD5 sequesters the SHP-1, and limits its effects with important molecules in positive signaling through the BCR. The role of CD5 in the maintenance of clonal anergy has been addressed by the hen egg lysozyme (HEL)-Ig transgenic (Tg) mouse model [30]. Mice Tg for HEL-Ig and the membrane-bound form of HEL present with apoptotic anti-HEL B cells, while those Tg for HEL-Ig and the soluble form of HEL initiate anergy via SHP-1. Breeding of the latter anergic mice onto a CD5−/− background results in such a loss of tolerance, that antiHEL Abs are released. In other words, the presence of CD5 raises the threshold required for activation of selfreactive B cells, and thereby determines their ultimate fate. Consistent with this role for CD5 is another recent model in which CD5− spleen cells from anti-RNP Ab Tg mice were injected into irradiated naïve mice. They migrated to the peritoneal cavity (the site where most of the CD5+ B cells reside) and began to express CD5 which prevented their production of anti-RNP [31]. Other molecules than CD5 are important in the regulation of autoreactive B cells. For example, CD19 amplifies BCR signaling by facilitating the activity of tyrosine kinases, such that a modest increase in CD19 expression is sufficient to shift the balance between tolerance and immunity to autoimmunity [32]. In contrast, CD22 dampens down the signals by recruiting SHP-1, which is the reason why deficiency in CD22 induces autoimmunity [33]. In this respect, defective signaling through the BCR has been demonstrated for B cells from patients with SLE [34].
By raising the threshold of the BCR for the response, CD5 diminishes the signal down to a level [37] that triggers the expression of recombination activating genes (RAGs). Revision of variable genes (which has been shown to be instrumental in the prevention of autoimmune states) is launched this way. IL-10 that is synthesized by CD5+ B cells and involved in the control of autoimmunity [38], might be relevant to this issue. Also, IL-6 warrants to be mentioned, which contributes to the expression of RAGs in human mature B cells (Hillion et al., submitted) is currently being evaluated in SLE, RA and primary SS [39]. 4.2. The emerging picture A great deal of effort has been made into understanding the expression of CD5 at intracellular and cell surface levels. Shedding and internalization of the protein have been recognized to regulate the membrane expression level of CD5, and a third mechanism might operate through transcription of the gene. CD5-E1B transcripts are translated into a truncated variant of the CD5 molecule; truncated and, therefore, devoid of leader peptide. Hence, E1B tends to prevent the translocation of CD5, and to limit the amount of SHP-1, whereas E1A promotes its membrane expression (Fig. 1). When E1A is selected, the full-length CD5 protein which is synthesized carries SHP-1 to the membrane, increases the amount of phosphatase in the vicinity of the BCR, and makes tolerance easier in autoreactive B
4. Current interpretation 4.1. Recent clues A novel exon 1 for the CD5 gene has freshly been identified [35]. This is exclusively transcribed in B lymphocytes. It has been designated exon 1B (E1B), and the known exon 1 renamed E1A. Interestingly, E1B originates from a human endogenous retrovirus, at a time interval between the divergence of New World and Old World monkeys, and the divergence of humans from the apes [36]. This explains why E1B does not exist in the mouse. There is a reciprocal expression of the two exons 1. The balance might be key in the regulation of membrane expression of CD5.
Fig. 1. When exon 1A (E1A) is selected (left), the full-length CD5 protein is synthesized and translocated to the membrane, along with the src-homolog 2 domains-containing protein tyrosine phosphatase (SHP-1) to the vicinity of the B-cell antigen receptor (BCR), in order to dephosphorylate the CD79a and CD79b chains associated with the membrane immunoglobulin, and, thereby, diminish BCR signaling and raise its threshold. When it is (right) E1B, a truncated CD5 protein is synthesized and retained in the cytoplasm as well as SHP-1. The former scenario leads to anergy, and the latter to (auto)antibody production.
P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154
lymphocytes. Conversely, when E1B is selected, the truncated version of CD5 is synthesized, and SHP-1 blocked within the endoplasmic reticulum. In that case, the strength of the BCR-mediated signaling increases up to a level enabling the B lymphocyte expansion. Not only does the truncated CD5 protein not recruit SHP-1, but it also reduces the expression of the fulllength molecule in Jurkat T lymphocytes transfected with E1B-complementary DNA. As a consequence, folowing their shedding and internalization, CD5 molecules would not be replaced, and their membrane expression level of CD5 is doomed to decline. Our ongoing studies are focused on analyzing more accurately how this mechanism regulates the level of membrane CD5 expression. We know nothing about the basis for the selection of exons 1 for transcription. One mechanism for silencing a gene is through the transfer of methyl groups to the cytosine nucleotides of the CpG motifs by DNA methyl-transferases (DNMTs). These are, themselves, regulated through the ras-dependent pathway of the mitogen-activated protein and extracellular-regulated kinases. Three families of DNMTs have so far been delineated: DNMT1 which are maintenance methylases, DNMT2 of which the specificities are unclear, and DNMT3a and DNMT3b which are generated anew. Although being established during ontogeny and maintained by DNMT1, the DNA methylation patterns are not fixed forever. The selection of E1A or E1B might (also or rather?) be regulated through protein degradation. Consistent with this alternative pathway is the presence of two 9-amino acid peptide sequences, called destruction boxes in the N-terminus of CD5. One of these is required for ubiquitination by anaphase-promoting complex and proteasomic proteolysis. 5. Conclusions and perspectives Conventional therapy, although at times effective in SLE, brings it with a host of severe complications. The current revival of interest in B lymphocytes as contributors to the cause of NOSAIDs promotes B-cell depleting therapies. Although the last years have witnessed numerous initially promising drugs that proved disillusioning, anti-B-cell mAbs should now be used on a routine basis in adults [39] and children [40] with SLE. Acknowledgements We are grateful to Simone Forest and Cindy Séné for expert secretarial assistance.
153
Take-home messages • CD5+ B cells are associated with autoimmune diseases and B lymphoproliferative disorders. • These B1 cells do not generate pathogenic autoantibodies. • Due to its association with the B-cell antigen receptor (BCR) and a protein tyrosine phosphatase, CD5 raises the threshold of the BCR response. • A reciprocal expression of two exons 1 for CD5 regulates the membrane expression level of the protein. • These findings offer a rationale for B-cell-targeted therapies. References [1] Cervera R, Font J, Shoenfeld Y. European Working Party on Systemic Lupus Erythematosus: a 15-year report. Autoimmun Rev 2006;5:549–53. [2] Fairhurst AM, Wandstrat AE, Wakeland EK. Systemic lupus erythematosus: multiple immunological phenotypes in a complex genetic disease. Adv Immunol 2006;92:1–69. [3] Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001;2:764–6. [4] Youinou P, Saraux A, Jamin C. B cell: a logical target for treatment of rheumatoid arthritis. Clin Exp Rheumatol 2006:491–2. [5] Youinou P, Daridon C, Steinfeld S, Pers JO. A case for B cells in the pathogenesis of Sjögren's syndrome. Trends Immunol in press. [6] La Cava A, Fang CJ, Singh RP, Ebling F, Hahn BH. Manipulation of immune regulation in systemic lupus erythematosus. Autoimmun Rev 2005;4:515–9. [7] Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmun Rev 2006;5:18–24. [8] Boumsell L, Bernard A, Lepage V, Degos L, Lemerle J, Dausset J. Some chronic lymphocytic leukemia cells bearing surface immunoglobulins share determinants with T cells. Eur J Immunol 1976;8:900–4. [9] Caligaris-Cappio F, Gobbi M, Bofill M, Janossy G. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia. J Exp Med 1982;155:623–8. [10] Kantor A. A new nomenclature for B cells. Immunol Today 1991;12:388–90. [11] Boumsell L, Bernard A, Lepage V, Degos L, Lemerle J, Dausset J. Some chronic lymphocytic leukemia cells bearing surface immunoglobulins share determinants with T cells. Eur J Immunol 1978;8:900–4. [12] Bröker BM, Klajman A, Youinou P, Jouquan J, Worman CP, Murphy J, et al. Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies. J Autoimmun 1988;1:469–81. [13] Montecino-Rodriguez E, Leathers H, Dorshkind K. Identification of a B-1 B cell-specified progenitor. Nat Immunol 2006;7:293–301. [14] Hardy RR. B-1 B cell development. J Immunol 2006;177:2749–54. [15] Youinou P, Jamin C, Lydyard PM. CD5 expression in human B-cell populations. Immunol Today 1999;20:312–6. [16] Jamin C, Lydyard PM, Le Corre R, Youinou PY. CD5 + B cells: differential capping and modulation of IgM and CD5. Scand J Immunol 1996;43:73–80. [17] Casali P, Burastero SE, Balow JE, Notkins AL. High-affinity antibodies to ssDNA are produced by CD5-B cells in systemic lupus erythematosus patients. J Immunol 1989;143:3476–83.
154
P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154
[18] Victor KD, Randen I, Thompson K, Forre O, Natvig JB, Fu SM, et al. Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes. J Clin Invest 1991;87:1603–13. [19] Kipps TJ, Robbins BA, Tefferi A, Meisenholder G, Banks PM, Carson DA. CD5-positive B-cell malignancies frequently express cross-reactive idiotypes associated with IgM autoantibodies. Am J Pathol 1990;136:809–16. [20] Mageed RA, MacKenzie LE, Stevenson FK, Yuksel B, Shokri F, Maziak BR, et al. Selective expression of a VHIV subfamily of immunoglobulin genes in human CD5+ B lymphocytes from cord blood. J Exp Med 1991;174:109–13. [21] Deane M, Mackenzie LE, Stevenson FK, Youinou PY, Lydyard PM, Mageed RA. The genetic basis of human VH4 gene familyassociated cross-reactive idiotype expression in CD5+ and CD5-cord blood B-lymphocyte clones. Scand J Immunol 1993;38:348–58. [22] Baumgarth N, Herman OC, Jager GC, Brown L, Herzenberg LA, Herzenberg LA. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc Natl Acad Sci U S A 1999;96:2250–5. [23] Mohan C, Morel L, Yang P, Wakeland EK. Accumulation of splenic B1a cells with potent antigen-presenting capability in NZM2410 lupus-prone mice. Arthritis Rheum 1998;41:1652–62. [24] Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med 1991;173:487–9. [25] Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier BM, et al. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum 1994;37:1647–55. [26] Pers JO, Jamin C, Youinou P, Charreire J. Role of IL-10 in the distribution of B cell subsets in the mouse B-1 cell population. Eur Cytokine Netw 2003;14:178–85. [27] Pers JO, Jamin C, Le Corre R, Lydyard PM, Youinou P. Ligation of CD5 on resting B cells, but not on resting T cells, results in apoptosis. Eur J Immunol 1998;28:4170–6. [28] Jamin C, Le Corre R, Lydyard PM, Youinou P. Anti-CD5 extends the proliferative response of human CD5+ B cells activated with anti-IgM and interleukin-2. Eur J Immunol 1996;26:57–62.
[29] Sen G, Bikah G, Venkataraman C, Bondada S. Negative regulation of antigen receptor-mediated signaling by constitutive association of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells. Eur J Immunol 1999;29:3319–28. [30] Hippen KL, Tze LE, Behrens TW. CD5 maintains tolerance in anergic B cells. J Exp Med 2000;191:883–90. [31] Qian Y, Santiago C, Borrero M, Tedder TF, Clarke SH. Lupusspecific antiribonucleoprotein B cell tolerance in nonautoimmune mice is maintained by differentiation to B-1 and governed by B cell receptor signaling thresholds. J Immunol 2001;166:2412–9. [32] Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000;165:6635–43. [33] Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT. Inhibition of the B cell by CD22: a requirement for Lyn. J Exp Med 1998;187:807–11. [34] Liossis SN, Kovacs B, Dennis G, Kammer GM, Tsokos GC. B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest 1996;98:2549–57. [35] Renaudineau Y, Hillion S, Saraux A, Mageed RA, Youinou P. An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes. Blood 2005;106:2781–9. [36] Renaudineau Y, Vallet S, Le Dantec C, Hillion S, Saraux A, Youinou P. Characterization of the human CD5 endogenous retrovirus-E in B lymphocytes. Genes Immun 2005;6:663–71. [37] Hillion S, Saraux A, Youinou P, Jamin C. Expression of RAGs in peripheral B cells outside germinal centers is associated with the expression of CD5. J Immunol 2005;174:5553–61. [38] Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002;3:944–50. [39] Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 2003;149:1–38. [40] Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004;50:2580–9.
Autoantibodies in breast cancer: their use as an aid to early diagnosis There is increasing evidence that the immune system produces a humoral response to cancer-derived antigens. In this study, Chapman C. et. al. (Ann Oncology 2007; 18: 868-73) assessed the diagnostic potential of autoantibodies to multiple known tumor-associated proteins. Sera from 94 normal controls, primary breast cancer patients (n = 97) and patients with ductal carcinoma in situ (DCIS) (n = 40) were investigated for the presence of autoantibodies to p53, cmyc, HER2, NY-ESO-1, BRCA1, BRCA2, and MUCI antigens by ELISA. Reproducibility elevated levels of autoantibodies were seen in at least one of the six antigens in 64% of primary breast cancer patient sera and 45% of patients with DCIS at a specificity of 85%. No significant differences were seen when patients were subdivided by age, tumor size, histological grade, and lymph node status or detection methodology. Autoantibodies against one or more of these tumor-associated antigens appear to indicate the presence of early-stage breast cancers. Autoantibody assays against a panel of antigens could be used as an aid to mammography in the detection and diagnosis of early primary breast cancer, especially in younger women at increased risk of breast cancer were mammography is known to have reduced sensitivity and specificity.
