- Email: [email protected]
A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity
Autoimmunity Reviews 10 (2011) 218–221
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity Isabelle Segalen a,b, Tinhinane Fali a, Jacques-Olivier Pers a,b, Yann Le Meur b, Pierre Youinou a,b,⁎, Séverine Loisel a,b a b
EA 2216 "Immunology and Pathology" and IRF148 ScInBioS, European University of Brest, France Brest University Medical School Hospital, Brest, France
a r t i c l e
i n f o
Article history: Received 12 September 2010 Accepted 7 October 2010 Available online 16 October 2010 Keywords: B lymphocyte Graft-versus-host disease Regulatory B cell Antibody Autoimmunity Rituximab Stem cell transplantation BAFF (BLyS)
a b s t r a c t Following allogenic hematopoietic stem cell transplantation (HSCT), patients with autoimmune disease or hematopoietic malignancy may develop acute or chronic graft-versus-host (GvH) disease. B lymphocytes, from the recipient as well as from the donor, have recently been implicated in the pathogenesis of such disturbances. Their deleterious effects are accounted for by other tasks B lymphocytes accomplish than the antibody production. We highlight herein some recent observations in the context of B cells in the GvH disease. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . B lymphocytes perform multiple functions . . . B lymphocytes in acute GvH disease . . . . . . 3.1. B lymphocytes of the recipient . . . . . 3.2. B lymphocytes of the donor . . . . . . 4. B lymphocytes in chronic GvH disease . . . . . 4.1. B lymphocytes of the recipient . . . . . 4.2. B lymphocytes of the donor . . . . . . 5. B lymphocytes interact with other immune cells 6. Conclusion . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
1. Introduction Although potentially curative for autoimmune diseases [1], allogenic hematopoietic stem cell transplantation (HSCT) has been limited for fear of raising troublesome complications [2]. Not only does this practice [3] proceed from the stem cells to refill the blood ⁎ Corresponding author. Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest, France. E-mail address: [email protected] (P. Youinou). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.10.005
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
218 219 219 219 219 219 219 219 220 220 220 220 220
compartment with hematological cells, but it exerts as well antileukemia effects. These are achieved by the donor's alloreactive T lymphocytes (TLs), and referred to as graft-versus-leukemia reaction. Paradoxically, the consequences of this beneficial activity cannot be distinguished from those of the unwanted graft-versus-host (GvH) disease. For this to occur, the recipient's tissues (most notably skin, liver and intestine) must be targeted, and hence damaged by the donor's TLs. Arbitrarily, GvH-derived disorders have been categorized as acute GvH disease which takes place within the first three months after the HSCT, and chronic GvH disease which develops beyond the
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221
third month. These two models differ with respect to their clinical manifestations and the ensuing prognosis. In point of fact, the patients are at risk of developing either form, or successively both of them. On the basis that TLs used to occupy central stage in the interpretation of GvH responses, considerable research has long focused on abnormalities in this cell compartment, so that B lymphocytes (BLs) have received limited support as candidate causal agents. Since then, there have been major insights in the parameters that influence the behavior of BLs, and therefore the outcome of diseases possibly mediated by BLs [4]. Following this breakthrough in the understanding of GvH reaction, some investigators suspected BLs of the host, while others believed that those of the donor were the culprit. Furthermore, both approaches have been sparked off by the recent success of treatment of GvH disease with B cell depleting agents. Our main thrust was to discuss the real supportive evidence for BLs in the GvH disease, and thus to update the T cell proponents with the benefits and damages to BLs, not only from the host, but also from the donor. Although there is still some way to go before a unifying model can be proposed to explain how B cells and T cells interact to generate such disorders, we think that B cells should plead guilty and the GvH disease serves as a model for B cell-mediated autoimmunity. 2. B lymphocytes perform multiple functions Although the role of BLs was recognized early through the role played by antibodies (Abs) and immune complexes (ICs), in more recent years, various other aspects of their biology have been acknowledged to be relevant. For example, their ability to capture and present antigens (Ags) to cognate TLs and their ability to produce disease-promoting cytokines are now viewed as instrumental in a number of pathological settings. BLs take up, process and present Ags to TLs, and to other BLs. This process amplifies the responses by bringing up other lymphocytes or by activating bystander lymphocytes. Polyreactive Ab-bearing BLs act as particularly efficient Ag-presenting cells (APCs). Thus, Roosnek and Lanzavecchia have demonstrated that BLs bind IgG-containing ICs through their polyreactive Abs present the Ag and activate TLs [5]. It is interesting in this respect that these splenic polyreactive BLs induce two-fold greater levels of interferon (IFN)-γ than other BLs in lupusprone mice. The role of BLs in sustaining chronic inflammation is also supported by the data showing that TL activation is highly dependent on BLs. There is indeed evidence to suggest that Ag presentation by BLs involves extraction of intact Ag from APCs leading to peptidemajor histocompatibility complex (MHC) processing and immunological synapse formation [6,7]. Other results indicate that parts of disease mechanisms enacted by excessive cytokines are effected through BLs. For example, interleukin (IL)-6 which is copiously produced [8] in patients hastens the final stages of BL maturation and differentiation. In addition to the cooperation between cytokine and BLs in pathogenesis, naïve BLs differentiate into two polarized subpopulations with different cytokine profiles. These latter depend on the nature of the Ag and effector TLs in the immediate microenvironment of the BLs. Polarized subsets of B cells have been coined B-effectors Be1 and Be2, respectively [9], and shown to impart functional effects on TL polarization. Thus, Be1 cells produce IFN-γ and favors T helper (Th)1 expansion, while IL-4 produced by Be2 cells promotes Th2-cell development. The cross-regulation between Th1/Th2 and Be1/Be2 cells should represent a sequential amplifying circuit, that involves chemokines [10]. The concept of regulatory BLs (Breg) has just been launched. It was first suggested by the observation that spontaneous ulcerative colitis in TL receptor-knockout (KO) mice was worsened when the latter mice were made deficient in BLs [11]. Studies using mice transgenic for genes encoding anti-double-stranded DNA Abs could not produce
219
such Abs on a normal background, but did so when bred onto an autoimmune background. This suggests that autoreactive BLs stimulate autoreactive TLs in lupus mice, but not in their normal counterparts in which autoreactive TLs were suppressed by Breg cells. Members of the tumor necrosis factor (TNF) family of ligands and receptors are dominant players in lymphoid organogenesis of secondary lymphoid organs. Thus, early studies showed that TNFα, lymphotoxin (LT)-α, LTβ and TNF- α receptor I-deleted mice display abnormal architecture. 3. B lymphocytes in acute GvH disease 3.1. B lymphocytes of the recipient The activity of the BLs left in the host remains to be investigated. Evidence has been provided that they are pathogenic. For example, it has been claimed [12] that BL-depleted hosts had a decreased rate of acute GvH disease compared to BL-nondepleted hosts. Perplexingly, the opposite has also been described, and a beneficial role attributed to the recipient's BLs in acute GvH manifestations. It has thus been established that these BLs can be protective by amending the GvH disease in an IL-10-dependent manner [13]. The disease is more severe in BL-deficient mice, where IL-10 should be critical, since mutations of its gene increases the levels of IL-10, and decreases the frequency of acute GvH disease [14]. Furthermore, patients with a small amount of precursor BLs are at increased risk of acute GvH disease [15]. 3.2. B lymphocytes of the donor Accumulating evidence suggests that BLs of the donor, as well, are involved in the acute GvH disease. For example, donor's BLs promote acute GvH disease by acting as APCs [12]. It has even been reported [16] that a large number of BLs in the graft are associated with a great incidence of acute GvH disease. This observation is at odd with others [17] where CD34+CD19+ pro-B progenitors improve the fate of the graft. A significant number of pro-B cells in the graft, and a low ratio of TLs to BLs rarefy acute GvH disease. Such differences may simply be due to the use of blood stem cells in the first study, compared with bone marrow cells in the second. 4. B lymphocytes in chronic GvH disease 4.1. B lymphocytes of the recipient Rather, BLs of the host may be responsible for chronic GvH diseaseassociated autoimmune disorders [18]. While the consensus is that the offender cells derive from the donor, the recipient TLs have become a prerequisite to its induction. One hypothesis relies on the stimulation of the recipient's BLs via the MHC molecules by alloreactive TLs of the donor, followed by activation of those TLs of the recipient. Furthermore, high levels of pathogenic anti-self Abs are associated to the development of chronic GvH disease-like lesions [19,20]. The implication of BLs of the host was confirmed by a host origin of autoAbs, thus contributing to the severity of the GvH disease [21]. Recent studies have indeed established that BL-depletion of the donor hinders chronic GvH manifestations. Rituximab (RTX) therapy prior to or after HSCT protects the host from extensive chronic GvH disease, inhibiting APCs and thereby limiting donor's TL activation [22]. However, a recent study has shown that autoAb production was not associated with the persistence of BLs in the host [23]. 4.2. B lymphocytes of the donor High numbers of mature BLs brought about with the graft are associated with autoimmune traits in chronic GvH disease. Serum
220
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221
CD40L
Treg
IL-2 IL-10
TL
BL
Activation Expansion Différenciation
TL
Fig. 1. The multifaceted effects of B lymphocyte in graft-versus-host disease.
autoAb production leads to cutaneous sclerosis and glomerulonephritis [23]. In humans also, these are detectable in patients with chronic GvH disease [24]. We know that disturbed BL [25] and TL [26] homeostasis is associated with chronic GvH disease, but we do not know what generates and maintains such autoreactive BLs. Patients with chronic GvH disease raise their serum levels of B cell-activating factor of the TNF family (BAFF) which rescues activated BLs from apoptosis [27–29]. Furthermore, the elevated level of BAFF correlate with high number of activated CD27+ memory BLs [25]. Clinical observers have highlighted improvement in some cases of chronic GvH disease by BL-depleting RTX [30,31]. In sex-mismatched HSCT, Abs to Y chromosome-encoded minor histocompatibilty Ags (MHA) correlate with chronic GvH disease [32]. The use of RTX in steroid-refractory chronic GvH disease has induced a fall in the Ab titers against MHA, whereas those of Abs against infectious Ags, such as tetanus toxoid, persist [30]. H–Y Abs stem from the donor's BLs, whereas patients' protective Abs may result from long-lived plasma cells (PCs) and donor-derived memory BL maturation into PCs. This development requires coordinate interactions between BLs and TLs. 5. B lymphocytes interact with other immune cells BLs promote GvH disease in some models, but are preventive in others. Couldn't this paradox be accounted for by differences between transplants, regimens, and functions of the BL subsets involved in the two opposite processes? The depletion of BLs induces all the more a remission of GvH disease [22] that BLs act as APCs. Supporting this concept is that, in alloimmunity, autoAg presentation by the recipient's BLs is key in the progression of acute vascularized allograft rejection. Accordingly, the distribution of circulating BL subsets might be disturbed with, viz, an augmentation of transitional CD19+CD21- BLs in those patients who develop chronic GvH disease, compared to others. One is struck by the Breg nature of these transitional BLs, which are CD24highCD38high in humans [33,34], and CD5highCD1d+ BLs in mice [35]. The causes of this perturbation are unknown. Clearly, cytokines (most notably IL-10) are involved in these events. In some studies, IL-10 lowers the incidence of the disease. CD5highCD1d+ BL-derived IL-10 could thus derive differentiation of TLs towards regulatory TLs [36,37], yet this BL subset has never been examined in GvH disease. 6. Conclusion In sum, BLs play so many roles (Fig. 1), that their effects in the GvH disease are contrasted. BL involvement is an area worthy of pursuit, to delineate why and when they interact with other cells, particularly with TLs and alternatively-activated macrophages [38]. To conclude,
predominance of TLs in GvH disease does not negate a role for BLs. These prevent or induce GvH disease. Improved understanding of their role of BLs in GvH disease may ultimately prove amenable to therapeutic intervention. To this end MicroRNA [39] and proteomic [40] are required. Take-home messages • B cells from the donor, as well as from the host, are involved in GvH disease. • Interleukin-10 is a critical modulator of GvH disease. • High levels of anti-self antibodies (Ab) may be encountered. • B cells act as efficient antigen-presenting cells to autoAb-producing B cells. • B cell-depletion might be used to prevent the disease.
Acknowledgements Thanks are due to Geneviève Michel and Simone Forest for their help with the typing of this manuscript. References [1] Burt RK, Testori A, Craig R, Cohen B, Suffit R, Barr W. Hematopoietic stem cell transplantation for autoimmune diseases: what have we learned? J Autoimmun 2008;30:116–20. [2] Ichiki Y, Bowlus CL, Shimoda S, Ishibashi H, Vierling JM, Gershwin ME. T cell immunity and graft-versus-host disease. Autoimmun Rev 2006;5:1–9. [3] Horowitz M, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versusleukemia reactions after bone marrow transplantation. Blood 1990;75:555–62. [4] Korganow AS, Knapp AM, Nehme-Schuster H, Soulas-Sprauel P, Poindron V, Pasquali JL, et al. Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase:decreased memory B cells and membrane CD19 expression. J Autoimmun 2010;34:426–34. [5] Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen antibody complexes by rheumatoid factor B cells. J Exp Med 1991;173:487–9. [6] Batista FD, Iber D, Neuberger MS. B cells acquire antigen from target cells after synapse formation. Nature 2001;411:489–94. [7] Dustin ML, Dustin LB. The immunological relay race: B cells take antigen by synapse. Nat Immunol 2001;2:480–2. [8] Youinou P, Jamin C. The weight of interleukin-6 in B cell-related autoimmune disorders. J Autoimmun 2009;32:206–10. [9] Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000;1:475–82. [10] Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun 2010;34:45–54. [11] Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of TCR mutant mice. J Exp Med 1997;186:1749–56. [12] Schultz KR, Paquet J, Bader S, HayGlass KT. Requirement for B cells in T cell priming to minor histocompatibility antigens and development of GvH disease. Bone Marrow Transplant 1995;16:289–95. [13] Rowe V, Banovic T, MacDonald KP, Kuns R, Don AL, Morris ES, et al. Host B cells produce IL-10 following TBI and attenuate acute GvH disease after allogeneic bone marrow transplantation. Blood 2006;108:2485–92.
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221 [14] Lin MT, Storer B, Martin PJ. Genetic variation in the IL-10 pathway modulates severity of acute GvH disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor beta genotype of donor. Blood 2005;106:3995–4001. [15] Storek J, Wells D, Dawson MA, Storer B, Maloney DG. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001;98: 489–91. [16] Iori AP, Torelli GF, De Propris MS, Milano F, Pupella S, Gozzer M, et al. B-cell concentration in the apheretic product predicts acute GvH disease and treatmentrelated mortality of allogeneic peripheral blood stem cell transplantation. Transplantation 2008;85:386–90. [17] Michonneau D, Peffault de Latour R, Porcher R, Robin M, Benbunan M, Rocha V, et al. Influence of bone marrow graft B lymphocyte subsets on outcome after HLAidentical sibling transplants. Br J Haematol 2009;145:107–14. [18] Chen F, Maldonado MA, Madaio M, Eisenberg RA. The role of host T cells in chronic GvH autoimmune disease. J Immunol 1998;161:5880–5. [19] Bohgaki T, Atsumi T, Koike T. Autoimmune disease after autologous hematopoietic stem cell transplantation. Autoimmun Rev 2008;7:198–203. [20] Lister J, Messner H, Keystone E, Miller R, Fritzler MJ. Autoantibody analysis of patients with GvH disease. J Clin Lab Immunol 1987;24:19–23. [21] Perruche S, Marandin A, Kleinclauss F, Angonin R, Fresnay S, Baron MH, et al. Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic GvH disease occurrence. Transplantation 2006;81:573–82. [22] Ratanatharathorn V, Logan B, Wang D, Horowitz M, Uberti JP, Ringden O, et al. Prior rituximab correlates with less acute GvH disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation. Br J Haematol 2009;145:816–24. [23] Zorn E, Miklos DB, Floyd BH, Mattes-Ritz A, Guo L, Soiffer RJ, et al. Minor histocompatibility antigen BDY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J Exp Med 2004;199:1133–42. [24] Rouquette-Gally AM, Boyeldieu D, Prost AC, Gluckman E. Autoimmunity after allogeneic bone marrow transplantation. A study of 53 long-term-surviving patients. Transplantation 1988;46:238–40. [25] Greinix HT, Pohlreich D, Kouba M, Körmöczi U, Lohmann I, Feldmann K, et al. Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic GvH disease. Biol Blood Marrow Transplant 2008;14:208–19. [26] Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S, et al. Donor CD4+ T and B cells in transplants induce chronic GvH disease with autoimmune manifestations. Blood 2006;107:2993–3001.
221
[27] Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, et al. High levels of BAFF in patients with chronic GvH disease. Clin Cancer Res 2007;13: 6107–14. [28] Daridon C, Youinou P, Pers JO. BAFF, APRIL, TWE-PRIL: who's who? Autoimmun Rev 2008;7:267–71. [29] Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, et al. Altered B-cell homeostasis and excess BAFF in human chronic GvH disease. Blood 2009;113:3865–74. [30] Cutler C, Miklos D, Kim HT, Tresiter N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic GvH disease. Blood 2006;108:756–62. [31] Cornec D, Avouac J, Youinou P, Saraux A. Critical analysis of rituximab induced serological changes in connective tissue diseases. Autoimmun Rev 2009;8:515–9. [32] Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic GvH disease and disease remission. Blood 2005;105:2973–8. [33] Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CDC8(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematous patients. Immunity 2010;32:129–40. [34] Jamin C, Morva A, Lemoine S, Daridon C, de Mendoza AR, Youinou P. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthritis Rheum 2008;58:1900–6. [35] Yanaba K, Bouaziz JD, Haas K, Poe J, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1highCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 2008;28:639–50. [36] Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder F. Regulatory B cells inhibit EAE initiation in mice while others B cells promote disease progression. J Clin Invest 2008;118:3420–30. [37] Dalloul A. CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev 2009;8:349–53. [38] Fairweather D, Cihakova D. Alternatively activated macrophages in infection and autoimmunity. J Autoimmun 2009;33:222–30. [39] Alevizos I, Illei GG. MicroRNAs in Sjögren's syndrome as a prototypic autoimmune disease. Autoimmun Rev 2010;9:618–21. [40] Ferraccioli GF, de Santis M, Peluso G, Inzitari R, Fanali C, Bosello SL, et al. Proteomic approaches to Sjögren's syndrome: a clue to interpret the pathophysiology and organ involvement of the disease. Autoimmun Rev 2010;9:622–6.
Clinical analysis of systemic lupus erythematosus with gastro intestinal manifestations Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that may affect different organs or systems. Recently, Xu D et al (Lupus 2010; 19(7) 866-9) analyzed clinical characteristics of 177 hospitalized SLE patients in a Beijing China. Gastrointestinal involvement was documented in 39/177 (22%) SLE patients, in 12 of them (30%) gastrointestinal manifestations were the initial ones. In this cohort 25 patients presented with abdominal pain, 22 with nauseas and vomiting, 12 with diarrhea and 3 with gastrointestinal bleeding. Protein loosing enteroapthy and intestinal pseudo-obstruction were the most common complications of Gastrointestinal involvement in this cohort. Of note, in other studies mesenteric venous thrombosis, pancreatitis, peritonitis and liver impairment were also documented. In the current study gastrointestinal manifestations correlated with the presence of Raynaud’s phenomenon, decreased levels of complement, and positive serum anti-neutrophil cytoplasmic antibodies (ANCA). Hence, the authors conclude that gastrointestinal manifestations are common and may be the presenting symptom of SLE disease. Gastrointestinal involvement in SLE patients correlated with clinical and serological markers of diseases.
Clinical course of high-risk patients diagnosed with antiphospohlipid syndrome The concomitant presence of three anti-phospholipids antibodies (i.e. lupus anti coagulants, anti cardiolipin and anti-β2GPI antibodies) has been recently recognized as a characteristic of high risk anti-phospholipids syndrome. In a current study Pengo V et al (J thrombosis Haemost. 2010; 8 (2) 237-242) analyzed data of 160 patients that were referred to thrombosis centers in Italy with the diagnosis of the anti-phospholipids syndrome and the presence of all three related autoantibodies. In this cohort, at study entry, venous thromboembolism was documented in 76 (47%) patients, arterial thromboenbolism in 69 (43%), pregnancy morbidity in 11 (9.7%) patients and catastrophic anti-phospholipids syndrome was diagnosed in 4(2.5%) patients. In the follow-up period 10 patients died, 7 of which from cardiovascular disease. The cumulative incidence of thromboemblic events was 12.2% in the first year, 26.1% during the first 5 years and 44.2% after 10 years of follow-up. The incidence of these thrombotic events correlated with the lack oral anti-coagulants therapy (p<0.003). In contrast the risk of major bleeding associated with oral anticoagulants therapy was low (0.8% patients/years). Thus, the authors concluded that patients with APS and triple positivity for anti-phospholipids antibodies are at a higher risk of recurrent thromboembolic events. Treatment with oral anti coagulants significantly reduces this risk.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity Isabelle Segalen a,b, Tinhinane Fali a, Jacques-Olivier Pers a,b, Yann Le Meur b, Pierre Youinou a,b,⁎, Séverine Loisel a,b a b
EA 2216 "Immunology and Pathology" and IRF148 ScInBioS, European University of Brest, France Brest University Medical School Hospital, Brest, France
a r t i c l e
i n f o
Article history: Received 12 September 2010 Accepted 7 October 2010 Available online 16 October 2010 Keywords: B lymphocyte Graft-versus-host disease Regulatory B cell Antibody Autoimmunity Rituximab Stem cell transplantation BAFF (BLyS)
a b s t r a c t Following allogenic hematopoietic stem cell transplantation (HSCT), patients with autoimmune disease or hematopoietic malignancy may develop acute or chronic graft-versus-host (GvH) disease. B lymphocytes, from the recipient as well as from the donor, have recently been implicated in the pathogenesis of such disturbances. Their deleterious effects are accounted for by other tasks B lymphocytes accomplish than the antibody production. We highlight herein some recent observations in the context of B cells in the GvH disease. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . B lymphocytes perform multiple functions . . . B lymphocytes in acute GvH disease . . . . . . 3.1. B lymphocytes of the recipient . . . . . 3.2. B lymphocytes of the donor . . . . . . 4. B lymphocytes in chronic GvH disease . . . . . 4.1. B lymphocytes of the recipient . . . . . 4.2. B lymphocytes of the donor . . . . . . 5. B lymphocytes interact with other immune cells 6. Conclusion . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
1. Introduction Although potentially curative for autoimmune diseases [1], allogenic hematopoietic stem cell transplantation (HSCT) has been limited for fear of raising troublesome complications [2]. Not only does this practice [3] proceed from the stem cells to refill the blood ⁎ Corresponding author. Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest, France. E-mail address: [email protected] (P. Youinou). 1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2010.10.005
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
218 219 219 219 219 219 219 219 220 220 220 220 220
compartment with hematological cells, but it exerts as well antileukemia effects. These are achieved by the donor's alloreactive T lymphocytes (TLs), and referred to as graft-versus-leukemia reaction. Paradoxically, the consequences of this beneficial activity cannot be distinguished from those of the unwanted graft-versus-host (GvH) disease. For this to occur, the recipient's tissues (most notably skin, liver and intestine) must be targeted, and hence damaged by the donor's TLs. Arbitrarily, GvH-derived disorders have been categorized as acute GvH disease which takes place within the first three months after the HSCT, and chronic GvH disease which develops beyond the
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221
third month. These two models differ with respect to their clinical manifestations and the ensuing prognosis. In point of fact, the patients are at risk of developing either form, or successively both of them. On the basis that TLs used to occupy central stage in the interpretation of GvH responses, considerable research has long focused on abnormalities in this cell compartment, so that B lymphocytes (BLs) have received limited support as candidate causal agents. Since then, there have been major insights in the parameters that influence the behavior of BLs, and therefore the outcome of diseases possibly mediated by BLs [4]. Following this breakthrough in the understanding of GvH reaction, some investigators suspected BLs of the host, while others believed that those of the donor were the culprit. Furthermore, both approaches have been sparked off by the recent success of treatment of GvH disease with B cell depleting agents. Our main thrust was to discuss the real supportive evidence for BLs in the GvH disease, and thus to update the T cell proponents with the benefits and damages to BLs, not only from the host, but also from the donor. Although there is still some way to go before a unifying model can be proposed to explain how B cells and T cells interact to generate such disorders, we think that B cells should plead guilty and the GvH disease serves as a model for B cell-mediated autoimmunity. 2. B lymphocytes perform multiple functions Although the role of BLs was recognized early through the role played by antibodies (Abs) and immune complexes (ICs), in more recent years, various other aspects of their biology have been acknowledged to be relevant. For example, their ability to capture and present antigens (Ags) to cognate TLs and their ability to produce disease-promoting cytokines are now viewed as instrumental in a number of pathological settings. BLs take up, process and present Ags to TLs, and to other BLs. This process amplifies the responses by bringing up other lymphocytes or by activating bystander lymphocytes. Polyreactive Ab-bearing BLs act as particularly efficient Ag-presenting cells (APCs). Thus, Roosnek and Lanzavecchia have demonstrated that BLs bind IgG-containing ICs through their polyreactive Abs present the Ag and activate TLs [5]. It is interesting in this respect that these splenic polyreactive BLs induce two-fold greater levels of interferon (IFN)-γ than other BLs in lupusprone mice. The role of BLs in sustaining chronic inflammation is also supported by the data showing that TL activation is highly dependent on BLs. There is indeed evidence to suggest that Ag presentation by BLs involves extraction of intact Ag from APCs leading to peptidemajor histocompatibility complex (MHC) processing and immunological synapse formation [6,7]. Other results indicate that parts of disease mechanisms enacted by excessive cytokines are effected through BLs. For example, interleukin (IL)-6 which is copiously produced [8] in patients hastens the final stages of BL maturation and differentiation. In addition to the cooperation between cytokine and BLs in pathogenesis, naïve BLs differentiate into two polarized subpopulations with different cytokine profiles. These latter depend on the nature of the Ag and effector TLs in the immediate microenvironment of the BLs. Polarized subsets of B cells have been coined B-effectors Be1 and Be2, respectively [9], and shown to impart functional effects on TL polarization. Thus, Be1 cells produce IFN-γ and favors T helper (Th)1 expansion, while IL-4 produced by Be2 cells promotes Th2-cell development. The cross-regulation between Th1/Th2 and Be1/Be2 cells should represent a sequential amplifying circuit, that involves chemokines [10]. The concept of regulatory BLs (Breg) has just been launched. It was first suggested by the observation that spontaneous ulcerative colitis in TL receptor-knockout (KO) mice was worsened when the latter mice were made deficient in BLs [11]. Studies using mice transgenic for genes encoding anti-double-stranded DNA Abs could not produce
219
such Abs on a normal background, but did so when bred onto an autoimmune background. This suggests that autoreactive BLs stimulate autoreactive TLs in lupus mice, but not in their normal counterparts in which autoreactive TLs were suppressed by Breg cells. Members of the tumor necrosis factor (TNF) family of ligands and receptors are dominant players in lymphoid organogenesis of secondary lymphoid organs. Thus, early studies showed that TNFα, lymphotoxin (LT)-α, LTβ and TNF- α receptor I-deleted mice display abnormal architecture. 3. B lymphocytes in acute GvH disease 3.1. B lymphocytes of the recipient The activity of the BLs left in the host remains to be investigated. Evidence has been provided that they are pathogenic. For example, it has been claimed [12] that BL-depleted hosts had a decreased rate of acute GvH disease compared to BL-nondepleted hosts. Perplexingly, the opposite has also been described, and a beneficial role attributed to the recipient's BLs in acute GvH manifestations. It has thus been established that these BLs can be protective by amending the GvH disease in an IL-10-dependent manner [13]. The disease is more severe in BL-deficient mice, where IL-10 should be critical, since mutations of its gene increases the levels of IL-10, and decreases the frequency of acute GvH disease [14]. Furthermore, patients with a small amount of precursor BLs are at increased risk of acute GvH disease [15]. 3.2. B lymphocytes of the donor Accumulating evidence suggests that BLs of the donor, as well, are involved in the acute GvH disease. For example, donor's BLs promote acute GvH disease by acting as APCs [12]. It has even been reported [16] that a large number of BLs in the graft are associated with a great incidence of acute GvH disease. This observation is at odd with others [17] where CD34+CD19+ pro-B progenitors improve the fate of the graft. A significant number of pro-B cells in the graft, and a low ratio of TLs to BLs rarefy acute GvH disease. Such differences may simply be due to the use of blood stem cells in the first study, compared with bone marrow cells in the second. 4. B lymphocytes in chronic GvH disease 4.1. B lymphocytes of the recipient Rather, BLs of the host may be responsible for chronic GvH diseaseassociated autoimmune disorders [18]. While the consensus is that the offender cells derive from the donor, the recipient TLs have become a prerequisite to its induction. One hypothesis relies on the stimulation of the recipient's BLs via the MHC molecules by alloreactive TLs of the donor, followed by activation of those TLs of the recipient. Furthermore, high levels of pathogenic anti-self Abs are associated to the development of chronic GvH disease-like lesions [19,20]. The implication of BLs of the host was confirmed by a host origin of autoAbs, thus contributing to the severity of the GvH disease [21]. Recent studies have indeed established that BL-depletion of the donor hinders chronic GvH manifestations. Rituximab (RTX) therapy prior to or after HSCT protects the host from extensive chronic GvH disease, inhibiting APCs and thereby limiting donor's TL activation [22]. However, a recent study has shown that autoAb production was not associated with the persistence of BLs in the host [23]. 4.2. B lymphocytes of the donor High numbers of mature BLs brought about with the graft are associated with autoimmune traits in chronic GvH disease. Serum
220
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221
CD40L
Treg
IL-2 IL-10
TL
BL
Activation Expansion Différenciation
TL
Fig. 1. The multifaceted effects of B lymphocyte in graft-versus-host disease.
autoAb production leads to cutaneous sclerosis and glomerulonephritis [23]. In humans also, these are detectable in patients with chronic GvH disease [24]. We know that disturbed BL [25] and TL [26] homeostasis is associated with chronic GvH disease, but we do not know what generates and maintains such autoreactive BLs. Patients with chronic GvH disease raise their serum levels of B cell-activating factor of the TNF family (BAFF) which rescues activated BLs from apoptosis [27–29]. Furthermore, the elevated level of BAFF correlate with high number of activated CD27+ memory BLs [25]. Clinical observers have highlighted improvement in some cases of chronic GvH disease by BL-depleting RTX [30,31]. In sex-mismatched HSCT, Abs to Y chromosome-encoded minor histocompatibilty Ags (MHA) correlate with chronic GvH disease [32]. The use of RTX in steroid-refractory chronic GvH disease has induced a fall in the Ab titers against MHA, whereas those of Abs against infectious Ags, such as tetanus toxoid, persist [30]. H–Y Abs stem from the donor's BLs, whereas patients' protective Abs may result from long-lived plasma cells (PCs) and donor-derived memory BL maturation into PCs. This development requires coordinate interactions between BLs and TLs. 5. B lymphocytes interact with other immune cells BLs promote GvH disease in some models, but are preventive in others. Couldn't this paradox be accounted for by differences between transplants, regimens, and functions of the BL subsets involved in the two opposite processes? The depletion of BLs induces all the more a remission of GvH disease [22] that BLs act as APCs. Supporting this concept is that, in alloimmunity, autoAg presentation by the recipient's BLs is key in the progression of acute vascularized allograft rejection. Accordingly, the distribution of circulating BL subsets might be disturbed with, viz, an augmentation of transitional CD19+CD21- BLs in those patients who develop chronic GvH disease, compared to others. One is struck by the Breg nature of these transitional BLs, which are CD24highCD38high in humans [33,34], and CD5highCD1d+ BLs in mice [35]. The causes of this perturbation are unknown. Clearly, cytokines (most notably IL-10) are involved in these events. In some studies, IL-10 lowers the incidence of the disease. CD5highCD1d+ BL-derived IL-10 could thus derive differentiation of TLs towards regulatory TLs [36,37], yet this BL subset has never been examined in GvH disease. 6. Conclusion In sum, BLs play so many roles (Fig. 1), that their effects in the GvH disease are contrasted. BL involvement is an area worthy of pursuit, to delineate why and when they interact with other cells, particularly with TLs and alternatively-activated macrophages [38]. To conclude,
predominance of TLs in GvH disease does not negate a role for BLs. These prevent or induce GvH disease. Improved understanding of their role of BLs in GvH disease may ultimately prove amenable to therapeutic intervention. To this end MicroRNA [39] and proteomic [40] are required. Take-home messages • B cells from the donor, as well as from the host, are involved in GvH disease. • Interleukin-10 is a critical modulator of GvH disease. • High levels of anti-self antibodies (Ab) may be encountered. • B cells act as efficient antigen-presenting cells to autoAb-producing B cells. • B cell-depletion might be used to prevent the disease.
Acknowledgements Thanks are due to Geneviève Michel and Simone Forest for their help with the typing of this manuscript. References [1] Burt RK, Testori A, Craig R, Cohen B, Suffit R, Barr W. Hematopoietic stem cell transplantation for autoimmune diseases: what have we learned? J Autoimmun 2008;30:116–20. [2] Ichiki Y, Bowlus CL, Shimoda S, Ishibashi H, Vierling JM, Gershwin ME. T cell immunity and graft-versus-host disease. Autoimmun Rev 2006;5:1–9. [3] Horowitz M, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versusleukemia reactions after bone marrow transplantation. Blood 1990;75:555–62. [4] Korganow AS, Knapp AM, Nehme-Schuster H, Soulas-Sprauel P, Poindron V, Pasquali JL, et al. Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase:decreased memory B cells and membrane CD19 expression. J Autoimmun 2010;34:426–34. [5] Roosnek E, Lanzavecchia A. Efficient and selective presentation of antigen antibody complexes by rheumatoid factor B cells. J Exp Med 1991;173:487–9. [6] Batista FD, Iber D, Neuberger MS. B cells acquire antigen from target cells after synapse formation. Nature 2001;411:489–94. [7] Dustin ML, Dustin LB. The immunological relay race: B cells take antigen by synapse. Nat Immunol 2001;2:480–2. [8] Youinou P, Jamin C. The weight of interleukin-6 in B cell-related autoimmune disorders. J Autoimmun 2009;32:206–10. [9] Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000;1:475–82. [10] Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun 2010;34:45–54. [11] Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of TCR mutant mice. J Exp Med 1997;186:1749–56. [12] Schultz KR, Paquet J, Bader S, HayGlass KT. Requirement for B cells in T cell priming to minor histocompatibility antigens and development of GvH disease. Bone Marrow Transplant 1995;16:289–95. [13] Rowe V, Banovic T, MacDonald KP, Kuns R, Don AL, Morris ES, et al. Host B cells produce IL-10 following TBI and attenuate acute GvH disease after allogeneic bone marrow transplantation. Blood 2006;108:2485–92.
I. Segalen et al. / Autoimmunity Reviews 10 (2011) 218–221 [14] Lin MT, Storer B, Martin PJ. Genetic variation in the IL-10 pathway modulates severity of acute GvH disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor beta genotype of donor. Blood 2005;106:3995–4001. [15] Storek J, Wells D, Dawson MA, Storer B, Maloney DG. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001;98: 489–91. [16] Iori AP, Torelli GF, De Propris MS, Milano F, Pupella S, Gozzer M, et al. B-cell concentration in the apheretic product predicts acute GvH disease and treatmentrelated mortality of allogeneic peripheral blood stem cell transplantation. Transplantation 2008;85:386–90. [17] Michonneau D, Peffault de Latour R, Porcher R, Robin M, Benbunan M, Rocha V, et al. Influence of bone marrow graft B lymphocyte subsets on outcome after HLAidentical sibling transplants. Br J Haematol 2009;145:107–14. [18] Chen F, Maldonado MA, Madaio M, Eisenberg RA. The role of host T cells in chronic GvH autoimmune disease. J Immunol 1998;161:5880–5. [19] Bohgaki T, Atsumi T, Koike T. Autoimmune disease after autologous hematopoietic stem cell transplantation. Autoimmun Rev 2008;7:198–203. [20] Lister J, Messner H, Keystone E, Miller R, Fritzler MJ. Autoantibody analysis of patients with GvH disease. J Clin Lab Immunol 1987;24:19–23. [21] Perruche S, Marandin A, Kleinclauss F, Angonin R, Fresnay S, Baron MH, et al. Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic GvH disease occurrence. Transplantation 2006;81:573–82. [22] Ratanatharathorn V, Logan B, Wang D, Horowitz M, Uberti JP, Ringden O, et al. Prior rituximab correlates with less acute GvH disease and better survival in B-cell lymphoma patients who received allogeneic peripheral blood stem cell transplantation. Br J Haematol 2009;145:816–24. [23] Zorn E, Miklos DB, Floyd BH, Mattes-Ritz A, Guo L, Soiffer RJ, et al. Minor histocompatibility antigen BDY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J Exp Med 2004;199:1133–42. [24] Rouquette-Gally AM, Boyeldieu D, Prost AC, Gluckman E. Autoimmunity after allogeneic bone marrow transplantation. A study of 53 long-term-surviving patients. Transplantation 1988;46:238–40. [25] Greinix HT, Pohlreich D, Kouba M, Körmöczi U, Lohmann I, Feldmann K, et al. Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic GvH disease. Biol Blood Marrow Transplant 2008;14:208–19. [26] Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S, et al. Donor CD4+ T and B cells in transplants induce chronic GvH disease with autoimmune manifestations. Blood 2006;107:2993–3001.
221
[27] Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, et al. High levels of BAFF in patients with chronic GvH disease. Clin Cancer Res 2007;13: 6107–14. [28] Daridon C, Youinou P, Pers JO. BAFF, APRIL, TWE-PRIL: who's who? Autoimmun Rev 2008;7:267–71. [29] Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, et al. Altered B-cell homeostasis and excess BAFF in human chronic GvH disease. Blood 2009;113:3865–74. [30] Cutler C, Miklos D, Kim HT, Tresiter N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic GvH disease. Blood 2006;108:756–62. [31] Cornec D, Avouac J, Youinou P, Saraux A. Critical analysis of rituximab induced serological changes in connective tissue diseases. Autoimmun Rev 2009;8:515–9. [32] Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic GvH disease and disease remission. Blood 2005;105:2973–8. [33] Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CDC8(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematous patients. Immunity 2010;32:129–40. [34] Jamin C, Morva A, Lemoine S, Daridon C, de Mendoza AR, Youinou P. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthritis Rheum 2008;58:1900–6. [35] Yanaba K, Bouaziz JD, Haas K, Poe J, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1highCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 2008;28:639–50. [36] Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder F. Regulatory B cells inhibit EAE initiation in mice while others B cells promote disease progression. J Clin Invest 2008;118:3420–30. [37] Dalloul A. CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev 2009;8:349–53. [38] Fairweather D, Cihakova D. Alternatively activated macrophages in infection and autoimmunity. J Autoimmun 2009;33:222–30. [39] Alevizos I, Illei GG. MicroRNAs in Sjögren's syndrome as a prototypic autoimmune disease. Autoimmun Rev 2010;9:618–21. [40] Ferraccioli GF, de Santis M, Peluso G, Inzitari R, Fanali C, Bosello SL, et al. Proteomic approaches to Sjögren's syndrome: a clue to interpret the pathophysiology and organ involvement of the disease. Autoimmun Rev 2010;9:622–6.
Clinical analysis of systemic lupus erythematosus with gastro intestinal manifestations Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that may affect different organs or systems. Recently, Xu D et al (Lupus 2010; 19(7) 866-9) analyzed clinical characteristics of 177 hospitalized SLE patients in a Beijing China. Gastrointestinal involvement was documented in 39/177 (22%) SLE patients, in 12 of them (30%) gastrointestinal manifestations were the initial ones. In this cohort 25 patients presented with abdominal pain, 22 with nauseas and vomiting, 12 with diarrhea and 3 with gastrointestinal bleeding. Protein loosing enteroapthy and intestinal pseudo-obstruction were the most common complications of Gastrointestinal involvement in this cohort. Of note, in other studies mesenteric venous thrombosis, pancreatitis, peritonitis and liver impairment were also documented. In the current study gastrointestinal manifestations correlated with the presence of Raynaud’s phenomenon, decreased levels of complement, and positive serum anti-neutrophil cytoplasmic antibodies (ANCA). Hence, the authors conclude that gastrointestinal manifestations are common and may be the presenting symptom of SLE disease. Gastrointestinal involvement in SLE patients correlated with clinical and serological markers of diseases.
Clinical course of high-risk patients diagnosed with antiphospohlipid syndrome The concomitant presence of three anti-phospholipids antibodies (i.e. lupus anti coagulants, anti cardiolipin and anti-β2GPI antibodies) has been recently recognized as a characteristic of high risk anti-phospholipids syndrome. In a current study Pengo V et al (J thrombosis Haemost. 2010; 8 (2) 237-242) analyzed data of 160 patients that were referred to thrombosis centers in Italy with the diagnosis of the anti-phospholipids syndrome and the presence of all three related autoantibodies. In this cohort, at study entry, venous thromboembolism was documented in 76 (47%) patients, arterial thromboenbolism in 69 (43%), pregnancy morbidity in 11 (9.7%) patients and catastrophic anti-phospholipids syndrome was diagnosed in 4(2.5%) patients. In the follow-up period 10 patients died, 7 of which from cardiovascular disease. The cumulative incidence of thromboemblic events was 12.2% in the first year, 26.1% during the first 5 years and 44.2% after 10 years of follow-up. The incidence of these thrombotic events correlated with the lack oral anti-coagulants therapy (p<0.003). In contrast the risk of major bleeding associated with oral anticoagulants therapy was low (0.8% patients/years). Thus, the authors concluded that patients with APS and triple positivity for anti-phospholipids antibodies are at a higher risk of recurrent thromboembolic events. Treatment with oral anti coagulants significantly reduces this risk.