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What is the role of HLA-B27 in spondyloarthropathies?
Autoimmunity Reviews 10 (2011) 464–468
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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
What is the role of HLA-B27 in spondyloarthropathies? Anthoula Chatzikyriakidou, Paraskevi V. Voulgari, Alexandros A. Drosos ⁎ Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece
a r t i c l e
i n f o
Article history: Received 13 January 2011 Accepted 28 January 2011 Available online 4 February 2011
a b s t r a c t HLA-B27 (Human Leukocyte Antigen-B27) accounts approximately for the one third of the overall genetic susceptibility to spondylorthropathies (SpAs). Up to 70 HLA-B27 subtypes have been reported all over the world with a decreasing north–south gradient of its frequency, which is reverse to that of endemic malaria. In an attempt to explain the possible role of HLA-B27 in SpAs pathogenesis, several theories have been suggested [1. Arthritogenic peptide, 2. Misfolding, 3. Cell surface HLA-B27 homodimers, 4. β2m (β2-microglobulin) deposition, 5. β2m-free/peptide free heavy chains of HLA-I, 6. Enhanced survival of some microbes in HLA-B27 cells, 7. ERAP1/ERAP2 (endoplasmic reticulum aminopeptidases 1 and 2) and Tapasin function, 8. β2m overexpression] each of which contributes up to a point to our understanding of HLA-B27 subtypes’ role in SpAs manifestation. However, reviewing all the suggested hypotheses it seems logical to pass from a puzzle of distinct hypotheses to a global theory. This review summarizes the current knowledge of HLA-B27 aiming to understand its potential use in clinical practice of SpAs diagnosis and to direct its future studies. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theories suggesting the role of HLA-B27 in SpAs’ pathogenesis . . . . . 2.1. Arthritogenic peptide hypothesis . . . . . . . . . . . . . . . . 2.2. Misfolding hypothesis . . . . . . . . . . . . . . . . . . . . . 2.3. Cell surface HLA-B27 homodimers hypothesis . . . . . . . . . . 2.4. β2m deposition hypothesis . . . . . . . . . . . . . . . . . . 2.5. β2m-free/peptide free heavy chains of HLA-I hypothesis . . . . 2.6. Enhanced survival of some microbes in HLA-B27 cells hypothesis . 2.7. ERAP1/ERAP2 aminopeptidase and Tapasin function hypothesis. . 2.8. β2m over-expression hypothesis . . . . . . . . . . . . . . . . 3. From a puzzle of distinct hypotheses to a global theory . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Spondyloarthropathies (SpAs) occur in 0.5–1% of the population and comprise several immune-mediated inflammatory disorders such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, and undifferentiated spondylorthropathy [1–3]. SpAs predominate on the axial skeleton (spinal, thoratic, and pelvic joints) ⁎ Corresponding author. Tel.: + 30 26510 07503; fax: + 30 26510 07054. E-mail address: [email protected] (A.A. Drosos). URL: http://www.rheumatology.gr (A.A. Drosos). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.01.011
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while peripheral arthritis and peripheral enthesitis also exist in a large subgroup of patients. Axial inflammation is fibrocartilaginous enthesitis in the attachment of tendons, ligaments and joint capsules to bone while inflammation may also cause extraarticular symptoms (psoriasis, anterior uveitis, urerthritis, and inflammatory bowel disease). The recurrence rate of SpAs among first degree relatives of patients is 12% [2]. Family studies have shown that SpAs are phenotypic variants of the same disease that can be distinguished in two major subtypes: a predominantly axial disease and a more diffuse pattern of articular and extraarticular manifestations [4]. Ankylosing spondylitis (AS), which is the prototype of SpAs, is largely known to be highly
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familial, with the sibling of a patient with AS may have 50 times higher risk developing the disease compared to the general population [5]. Today, it is well established that SpAs are complex disorders involving both environmental and genetic factors to their susceptibility. Major histocompatibility complex (MHC) genes confer the 40–50% of the genetic susceptibility to SpAs, with HLA-B27 accounting approximately for the 30% of the overall genetic susceptibility to SpAs [6,7]. Additionally, recently many non-MHC genes have also been implicated in SpAs susceptibility such as IL23R (interleukin 23 receptor), ERAP1 (endoplasmic reticulum aminopeptidase 1), IL1R2 (interleukin 1 receptor 2), ANTXR2 (anthrax toxin receptor 2), CARD9 (caspase recruitment domain family, member 9), TNFSF15 [tumor necrosis factor (ligand) superfamily, member 15], and KIR (killer immunoglobulin receptor) [8]. However, HLA-B27 still remains the cornerstone of the genetic factors related to SpAs (Table 1). Up to 70 HLA-B27 subtypes have been reported all over the world (http://hla.alleles.org/class1.html), with a decreasing north–south gradient of its frequency [9]. Specifically, HLA-B27 subtypes differ in one or more amino acid substitutions of the alpha 1 and alpha 2 domains (exons 2 and 3), which constitute the peptide binding cleft [10–12]. The binding cleft has six side pockets (A–F) that accommodate the side chains of the amino acids of the bound peptide. From the six side pockets side-pockets B (binds the P2 peptide residue) and F (binds the C-terminal P9 peptide residue) are the critical sites for the usual nine-residue HLA-B27 peptide [13–15]. The most widespread HLA-B2705 subtype is thought to be the ancestral subtype and it is common in Caucasians and American Indians. The HLA-B2704 is most frequent in Asians, while the HLA-B2702 in Mediterranean populations [16]. Interestingly, the geographic distribution of HLA-B27 seems to be the result of a negative selection induced by malaria endemic [17–20].
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The majority of HLA-B27 subtypes have been associated with AS. However, some of them are rare or for other the results are not univocal and therefore their association with AS is under consideration [21,22]. Up to date, there appears to be a hierarchy of HLA-B27 subtypes’ association with AS. HLA-B2704 shows the strongest association, followed by HLA-B2705, HLA-B2702, and HLA-B2707, while HLA-B2706 and HLA-B2709 show the weakest association with the disease [8]. Many reasons reveal difficulties to understand the potential HLAB27 association with SpAs. The extend linkage disequilibrium within the HLA region reveals the difficulty to discern the real disease related gene. In addition to this, the manifestation may be the result of the synergic role of many HLA or non-HLA genes. Furthermore, the autoimmune diseases are complex disorders with both genetic and environmental factors contributing to their manifestation which is also extremely heterogenic [23]. On the other hand, many points support the association of HLA-B27 with SpAs [24,25]. First of all, HLA-B27 is associated with AS in many ethnic groups of patients, while there are also HLA-B27 subtypes which seem to protect against SpAs. Additionally, appropriate transgenic animals develop SpAs similar to human SpAs. Moreover, the HLA-B27 association with AS is one of the strongest ever reported in literature. In most studies 80–95% of patients with AS are positive for HLA-B27, which confers a high relative risk (N100) [8]. The concordance rate is 63% for HLA-B27 positive monozygotic twin siblings and 23% for dizygotic twin siblings [7]. As a result many theories have been proposed in order to explain the possible role of HLA-B27 subtypes in SpAs’ pathogenesis.
2. Theories suggesting the role of HLA-B27 in SpAs’ pathogenesis 2.1. Arthritogenic peptide hypothesis
Table 1 HLA-B27 frequencies in all over the world (data were obtained from www. allelefrequencies.net database). Country
HLA-B27 frequency
Country
HLA-B27 frequency
Albania Algeria Argentina Australia Austria Azores Bangladesh Dhaka Bangalee Bolivia Aymara Bosnia and Herzegovina Brazil Bulgaria Burkina China Colombia Costa Rica Croatia Cuba Czech England France Germany Greece India Israel Italy Japan FYROM Madeira Malaysia Martinique Mexico Mongolia Morocco
0.025 0.010 0.000–0.024 0.005–0.030 0.048 0.027–0.035 0.017 0.006 0.049 0.000–0.042 0.073 0.000–0.102 0.000–0.031 0.000–0.007 0.000 0.049 0.012–0.031 0.014–0.120 0.017–0.048 0.015–0.060 0.043–0.066 0.010–0.025 0.000–0.038 0.009–0.032 0.000–0.035 0.002–0.006 0.031–0.041 0.032–0.035 0.000–0.069 0.020 0.000–0.061 0.000–0.058 0.005–0.037
Norway Oman Pakistan Peru Philippines Portugal Romania Russia Rwanda Saudi Arabia Scotland Senegal Serbia Singapore South Africa South Korea Spain Sri Lanka Sudan Sweden Taiwan Tanzania Thailand Trinidad Tunisia Turkey United Arab Emirates United Kingdom USA Venezuela Vietnam Hanoi Wales
0.075–0.155 0.004 0.000–0.094 0.007 0.010 0.010–0.049 0.020–0.057 0.012–0.104 0.009 0.007–0.028 0.025 0.018 0.031 0.013 0.000 0.028–0.031 0.006–0.060 0.009 0.028–0.033 0.087 0.000–0.109 0.000 0.033–0.053 0.007–0.010 0.030 0.028 0.006 0.059 0.011–0.046 0.010–0.035 0.020 0.041
HLA-B27 presents peptides arising from degradation of endogenous proteins to CD8+ T-lymphocytes. Molecular mimicry between microbial and self-antigens may break self-tolerance leading to autoimmunity which is the basis of this hypothesis. HLA-B27 was revealed to present a self-antigen derived from its own molecule (aa 309–320) which shows a high homology to a peptide derived from Chlamydia trachomatis [26]. It is worth mentioning that this selfpeptide is a natural ligand of HLA-B2705, HLA-B2702, and HLA-B2704 subtypes related to AS, but not of HLA-B2706 and HLA-B2709 subtypes [26]. In support to this theory, many peptides derived from cartilage/bone-related proteins were revealed as possible ligands of HLA-B27 as well as a big number of HLA-B27 peptides were found to show high homology to pathogenic bacterial sequences [27]. Moreover in support to this hypothesis a self-ligand of HLA-B27 is sub-optimally presented by AS-associated HLA-B27 subtypes. In this case the molecular mimicry between a microbial and a self-peptide could trigger a cross-reaction in individuals carrying autoreactive T-cells which have not been eliminated during ontogenesis in the thymus. Specifically, a self-peptide (aa 400–408) of VIPR1 (vasoactive intestinal peptide receptor 1) shows highly homology to an Epstein–Barr virus derived peptide pLMP2 (latent membrane protein 2 of Epstein–Barr, aa 236–244). HLA-B2705 binds VIPR1 with a conventional and a non-conventional mode, while HLA-B2709 with the conventional one. The binding of pLMP2 shows highly molecular mimicry when it is bound with the non-conventional mode which could trigger subsequently T-cell cross-reaction in individuals carrying the HLA-B2705 subtype (related to AS) where autoreactive T-cell escaped negative selection in thymus [28,29]. Moreover, another self-peptide pGR (glucagon receptor), which shows homology with pVIPR1 and pLMP2 and binds HLA-B2705 in a dual conformation, further supports the arthritogenic peptide theory [30].
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However, despite the acceptance of this theory there are several points under consideration [31]. Up to date, the arthritogenic peptide has not been demonstrated. Both HLA-B2705 and HLA-B1403 have been associated with AS but do not show homology. Finally, transgenic rats developed inflammatory phenotype independently to CD8+ T-cells. All the aforementioned points led to the suggestion of additional hypotheses that could explain HLA-B27 association with the SpAs’ pathogenesis [32,33]. 2.2. Misfolding hypothesis The function of a protein is highly dependent of its proper folding, otherwise partially folded or misfolded proteins should be degraded by cellular quality control processes. However, gain-of-function processes [e.g. endoplasmic reticulum (ER) expansion, apoptosis, inclusion bodies, aggresomes, and amyloid fibrils] of misfolding proteins can cause autoimmune diseases through immune related cells. Class I molecules associate in ER with β2-microglobulin (β2m) and antigenic peptides for cell surface expression and presentation to T-cells. However, HLA-B27 can form covalent homodimers and polymers though their cysteine-67 residue in the α1 domain. The accumulation of HLA-B27 misfolded proteins in ER trigger ER stress which seems to lead to activation of unfolded protein response (UPR) resulting in activation of nuclear factor-κΒ (NF-κΒ). Subsequently, many pro-inflammatory cytokines are induced such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1), IL-6 (interleukin-6) favoring inflammatory conditions [31,34]. HLA-B27 molecules show slower folding rate in comparison to other HLA molecules and therefore the proper folding is disturbed much more easily leading subsequently to ER stress [35]. Furthermore, misfolded HLA-B27 molecules and UPR activation were observed in transgenic rats with inflammatory disease [36]. However, the hypothesis of misfolded HLA-B27 molecules was also challenged by the results of a recent study. Specifically, in a new HLA-B27 transgenic rat model the accumulation of HLA-B27 misfolded heavy chains was reversed by increasing the expression of β2m protein [37]. In this rat model, arthritis, spondylitis, and enthesitis were still developed even though the reduction of HLA-B27 misfolding. Additionally, while HLA-B2706 and HLA-B2709 molecules are folded more efficiently than the AS related subtypes HLA-B2705, HLA-B2704 and HLA-B2702, the HLA-B2707 subtype, which is associated with AS, is folded as efficiently as the non-disease related subtypes [38]. 2.3. Cell surface HLA-B27 homodimers hypothesis HLA-B27 heavy chains homodimers are thought to be produced in cell surface during endosomal recycling [39]. HLA-B27 homodimers bind to specific receptors expressed on NK cells, T-lymphocytes, and myelomonotic cells and therefore could play a role in the pathogenesis of autoimmune disorders [40–42]. In support to this theory are the results of a study in which HLA-B27 positive patients showed increased number of NK and CD4+ T-cells expressing a receptor which recognizes HLA-B27 homodimers but not heterodimers [41]. This theory may explain CD4+ T-cells related spontaneous inflammatory disease in transgenic mice models which do not express β2m protein [43]. Furthermore, CD4+ T-cells that interact with non-conventional forms of HLA-B27 have been isolated from HLA-B27 positive AS patients, but not from HLA-B27 positive healthy individuals breaking the theory of SpAs related to CD8+ T-cell-function [44]. However, residue Cys67, which is critical for the formation of homodimers, exists both in HLA-B27 subtypes related or not related to SpAs. No association was reported between free heavy chains of HLA-B27 molecules and predisposition to AS [45]. Furthermore, HLAB2706 subtype which is not related to AS also forms homodimers [8].
As a result additional alternative theories were suggested in a try to explain HLA-B27 association with SpAs. 2.4. β2m deposition hypothesis AS-associated HLA-B27 subtypes exhibit a higher rate of β2mdissociation from peptide-complexed surface-expressed HLA-B27. Subsequently, β2m molecules accumulate and become trapped in synovia, where they bind to collagen, form amyloid deposits or interact with synovial fibroblasts in which they induce the synthesis and secretion of proteins involved in tissue destruction [46]. 2.5. β2m-free/peptide free heavy chains of HLA-I hypothesis β2m-free, peptide free heavy chains support a helix-coil transition facilitating rotation of backbone angles around amino acid 167/168, and as a result the residues 169–181 (identical to a known HLA-B27 ligand) loop around and occupy the molecule's own peptide binding cleft. Such ‘auto-display’, occurring either within B27 molecules or between B27 molecules, could induce an autoimmune disease [47]. 2.6. Enhanced survival of some microbes in HLA-B27 cells hypothesis Enhanced survival has been reported of Salmonella enteritis in cells expressing HLA-B27 [48]. This impaired immune response may result in the subsequent SpAs, but without being able to explain the precise mechanism by which this pathological situation occurs. 2.7. ERAP1/ERAP2 aminopeptidase and Tapasin function hypothesis Peptide repertoire of HLA-B27 is highly determined by N-terminal trimming of ligand precursors by ERAP1and ERAP2 aminopeptidases. Tapasin is a chaperone which is mediated in peptide loading into class I molecules during quality control processes of ER [49,50]. However, HLA-B27 molecules are less dependent to tapasin compared to other class I molecules [51]. As a result, this fact leads HLA-B27 molecules to present suboptimal ligands which favor both overpresentation of exogenous antigens and dissociations between HLAB27 molecules and peptides enabling homodimerization of HLA-B27 heavy chains. Further studies are needed to support this hypothesis. 2.8. β2m over-expression hypothesis In a new HLA-B27/β2m transgenic rat model expressing more β2m molecules spondylitis was induced even in the absence of colitis [37]. Additional studies are needed to explain these primary results in the pathogenesis of axial inflammation. 3. From a puzzle of distinct hypotheses to a global theory The phenotypic diversity of SpAs reveals that it may be misleading to suggest only one hypothesis aiming to explain HLA-B27 mode of function in SpAs’ pathogenesis. As it is shown in Fig. 1 all the hypotheses seem to inter-play which may explain the diversity in the severity of a clinically diagnosed SpA. 4. Conclusions A strong association of HLA-B27 with SpAs and especially with AS is well established. Apart from HLA-B27's role on inflammatory arthritis manifestation, recently it was associated with diseases affected different human organs and systems (ocular, aural, pulmonary, cardiovascular, haematological, renal, endocrine, bone, and skin) and the virulence of HIV (human immunodeficiency virus), HCV (hepatitis C virus), EBV (Epstein–Barr virus), HSV2 (herpes simplex virus 2) and other viruses [52].
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ERAP1/ERAP2 play a role in the generation of specific HLA-B27 ligands and tapasin in the optimization of the class I peptide repertoire. Therefore, these enzymes could affect the stability of HLA-B27/peptide complex.
Some HLA-B27 subtypes may modify microbial handling leading to an impaired immune response which gives rise to SpAs pathogenesis (enhanced survival of some microbes in HLA-B27 cells hypothesis).
A peptide showing molecular mimicry with a self-antigen is the basis of arthritogen hypythesis, while its binding stability to HLAB27 gives rise to the other hypotheses.
Where does begin and where does stop each hypothesis if we take into account the complexity of genetic and environmental background of each individual?
Disturbance in the folding rate of HLA-B27 heavy chains is the basis of HLA-B27 misfolding hypothesis, while β2m expression levels up to normal can also be related to SpAs pathogenesis (β 2m over-expression hypothesis).
If the complex HLA-B27/peptide is not stable, it favors the formation of HLA-B27 homodimers at cell surface (cell surface HLA-B27 homodimers hypothesis). Taking into account that some HLA-B27 subtypes exhibit higher rate of β2m dissociation, this fact favors the β 2m deposition hypothesis. Both the above have as a result the presence of free HLA-B27 heavy chains on cell surface which is the basis of β 2m-free/peptide free heavy chains of HLA-I hypothesis.
Fig. 1. From a puzzle of distinct hypotheses to a global theory.
HLA-B27 is still one of the most fascinating molecules in medical researches. HLA-B27 typing seems to be of some value in the diagnosis of specific disorders since its association with diseases varies between different racial and ethnic groups of patients affecting its sensitivity and specificity in clinical practice [53]. Its clinical usefulness could only refer to a young man or woman with inflammatory back pain without classical radiographic features or unexplained oligoarthritis or enthesitis but always with the appropriate crisis of the clinician [54]. SpAs are complex diseases with different genetic and environmental factors to contribute to their susceptibility. Even though HLAB27 is almost essential for example in AS inheritance, its penetrance and phenotypic expression are highly modified by other gene or gene complexes [55]. Therefore, SpAs should be encountered as polygenic disorders keeping in mind for genetic association studies that they reduce in frequency by the square root with each increase in distance of the probands’ relationship. In addition, sample size, sample ethnicity, disease heterogeneity and proper statistical analysis should be kept in mind as to diminish the false-positive results and to detect the true-positive associations.
Take-home messages • HLA-B27 contributes to SpAs pathogenesis. • Up to 70 HLA-B27 subtypes have been described all over the world. • HLA-B27*04, *05, *02, *07, *06 and *09 show decreasing association with ankylosing spondylitis. • The number of hypotheses which try to explain the role of HLA-B27 in SpAs pathogenesis is increasing. • The complexity of the genetic and environmental background of each individual suggests passing from a puzzle of distinct hypotheses to a global theory as more rational.
• Sample size, sample ethnicity, disease genetic and phenotypic heterogeneity, and proper statistical analysis should be kept in mind as to diminish the false-positive results and to detect the truepositive HLA-B27 subtypes’ associations with SpAs.
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[36] Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al. HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 2005;175:2438–48. [37] Tran TM, Dorris ML, Satumtira N, Richardson JA, Hammer RE, Shang J, et al. Additional human beta2m curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27 transgenic rats. Arthritis Rheum 2006;54:1317–27. [38] Galocha B, de Castro JA. Folding of HLA-B27 subtypes is determined by the global effect of polymorphic residues and shows incomplete correspondence to ankylosing spondylitis. Arthritis Rheum 2008;58:401–12. [39] Bird LA, Peh CA, Kollnberger S, Elliott T, McMicheal AJ, Bowness P. Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol 2003;33:748–59. [40] Kollnberger S, Bird L, Sun MY, Retiere C, Braud VM, McMichael A, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum 2002;46:2972–82. [41] Chan AT, Kollnberger SD, Wedderburn LR, Bowness P. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. Arthritis Rheum 2005;52:3586–95. [42] Allen RL, Trowsdale J. Recognition of classical and heavy chain forms of HLA-B27 by leukocyte receptors. Curr Mol Med 2004;4:59–65. [43] Roddis M, Carter RW, Sun MY, Weissensteiner T, McMichael AJ, Bowness P, et al. Fully functional HLA-B27 restricted CD4+ as well as CD8+ T cell responses in TCR transgenic mice. J Immunol 2004;172:155–61. [44] Boyle LH, Goodall JC, Gaston JS. Major histocompatibility complex class I-restricted alloreactive CD4+ T cells. Immunology 2004;112:54–63. [45] Vazquez MN, Lopez de Castro JA. Similar cell surface expression of β2microglobulin-free heavy chains by HLA-B27 subtypes differentially associated with ankylosing spondylitis. Arthritis Rheum 2005;52:3290–9. [46] Uchanska-Ziegler B, Ziegler A. Ankylosing spondylitis: a b2m-deposition disease? Trends Immunol 2003;24:73–6. [47] Luthra-Guptasarma M, Singh B. HLA-B27 lacking associated b2-microglobulin rearranges to auto-display or cross-display residues 169–181: a novel molecular mechanism for spondyloarthropathies. FEBS Lett 2004;575:1–8. [48] Penttinen MA, Heiskanen KM, Mohapatra R, DeLay ML, Colbert RA, Sistonen L, et al. Enhanced intracellular replication of Salmonella enteretidis in HLA-B27expressing human monocytic cells: dependency on glutamic acid at position 45 in the B pocket of HLA-B27. Arthritis Rheum 2004;50:2255–63. [49] Momburg F, Tan P. Tapasin—the keystone of the loading complex optimizing peptide binding by MHC class I molecules in the endoplasmic reticulum. Mol Immunol 2002;39:217–33. [50] Williams AP, Peh CA, Purcell AW, McCluskey J, Elliott T. Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity 2002;16:509–20. [51] Peh CA, Burrows SR, Barnden M, Khanna R, Cresswell P, Moss DJ, et al. HLA-B27restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity 1998;8:531–42. [52] Sheehan NJ. HLA-B27: what's new? Rheumatology 2010;49:621–31. [53] Khan MA. Genetic aspects of ankylosing spondylitis. Best Pract Res Clin Rheumatol 2002;16:675–90. [54] Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63:535–43. [55] Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000;59:883–6.
Complement system and T helper type 1 cells: a winding road If the role of complement system is quite well understood, its multiple implications in the development of autoimmunity are yet far to be clarified. What seems to be clear is that an imbalance in complement activation can lead to a cascade of events finally bringing to autoimmune reactions and tissue destruction. That is the reason why not only the complement system effectors, but also the receptors and the antagonists are of great weight in the scale pans of autoimmunity. Membrane cofactor protein (MCP; CD46) is a type I transmembrane protein functioning as a receptor for complement. It was identified as a protector against uncontrolled activation of the complement system. Nonetheless, it works as receptor for several microorganisms including viruses (measles, herpesvirus 6) and bacteria (Neisseria spp. and Streptococcus pyogenes). Cardone et al. (Nat Immunol. 2010;11:862-71) recently demonstrated that CD4+ T effector cells when engaged by the complement regulator CD46 are driven through the promotion of T helper type 1 (Th1) cells with the production of IFN-γ. However, in response to T cell antigen receptor-mediated activation and in the presence of IL-2, there is a switch towards a regulatory phenotype with an up-regulation of IL-10 (Th1 IFN-γ-IL-10+). The authors discussed the underlying mechanisms of downstream signaling pathway of activation of CD46, identifying Ste20 (SPS1)-related proline alanine-rich kinase (SPAK), that, acting as a partner for CYT-1, can lead to the phosphorylation of extracellular signal-related kinase (Erk) and then to the production of IL-10. This broad spectrum of evidences adds another knot to the rope linking the complement system and adaptive immunity. Of great interest appears the possibility that the complement system, through CD46, may act as a switcher between the “effector mode” and the “immunoregulatory mode” of Th1. The failure of this switch could be a factor in the development of autoimmune diseases: in the presence of CD46, CD4+ T cells of patients with rheumatoid arthritis may not be driven to differentiate into “immunoregulatory”, rather producing excessive IFN-γ. How this may affect the in vivo mechanisms leading to autoimmunity is an intriguing question to be addressed in further studies. Carlo Perricone, M.D.
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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
What is the role of HLA-B27 in spondyloarthropathies? Anthoula Chatzikyriakidou, Paraskevi V. Voulgari, Alexandros A. Drosos ⁎ Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, 45110 Ioannina, Greece
a r t i c l e
i n f o
Article history: Received 13 January 2011 Accepted 28 January 2011 Available online 4 February 2011
a b s t r a c t HLA-B27 (Human Leukocyte Antigen-B27) accounts approximately for the one third of the overall genetic susceptibility to spondylorthropathies (SpAs). Up to 70 HLA-B27 subtypes have been reported all over the world with a decreasing north–south gradient of its frequency, which is reverse to that of endemic malaria. In an attempt to explain the possible role of HLA-B27 in SpAs pathogenesis, several theories have been suggested [1. Arthritogenic peptide, 2. Misfolding, 3. Cell surface HLA-B27 homodimers, 4. β2m (β2-microglobulin) deposition, 5. β2m-free/peptide free heavy chains of HLA-I, 6. Enhanced survival of some microbes in HLA-B27 cells, 7. ERAP1/ERAP2 (endoplasmic reticulum aminopeptidases 1 and 2) and Tapasin function, 8. β2m overexpression] each of which contributes up to a point to our understanding of HLA-B27 subtypes’ role in SpAs manifestation. However, reviewing all the suggested hypotheses it seems logical to pass from a puzzle of distinct hypotheses to a global theory. This review summarizes the current knowledge of HLA-B27 aiming to understand its potential use in clinical practice of SpAs diagnosis and to direct its future studies. © 2011 Elsevier B.V. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theories suggesting the role of HLA-B27 in SpAs’ pathogenesis . . . . . 2.1. Arthritogenic peptide hypothesis . . . . . . . . . . . . . . . . 2.2. Misfolding hypothesis . . . . . . . . . . . . . . . . . . . . . 2.3. Cell surface HLA-B27 homodimers hypothesis . . . . . . . . . . 2.4. β2m deposition hypothesis . . . . . . . . . . . . . . . . . . 2.5. β2m-free/peptide free heavy chains of HLA-I hypothesis . . . . 2.6. Enhanced survival of some microbes in HLA-B27 cells hypothesis . 2.7. ERAP1/ERAP2 aminopeptidase and Tapasin function hypothesis. . 2.8. β2m over-expression hypothesis . . . . . . . . . . . . . . . . 3. From a puzzle of distinct hypotheses to a global theory . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Spondyloarthropathies (SpAs) occur in 0.5–1% of the population and comprise several immune-mediated inflammatory disorders such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, and undifferentiated spondylorthropathy [1–3]. SpAs predominate on the axial skeleton (spinal, thoratic, and pelvic joints) ⁎ Corresponding author. Tel.: + 30 26510 07503; fax: + 30 26510 07054. E-mail address: [email protected] (A.A. Drosos). URL: http://www.rheumatology.gr (A.A. Drosos). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.01.011
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while peripheral arthritis and peripheral enthesitis also exist in a large subgroup of patients. Axial inflammation is fibrocartilaginous enthesitis in the attachment of tendons, ligaments and joint capsules to bone while inflammation may also cause extraarticular symptoms (psoriasis, anterior uveitis, urerthritis, and inflammatory bowel disease). The recurrence rate of SpAs among first degree relatives of patients is 12% [2]. Family studies have shown that SpAs are phenotypic variants of the same disease that can be distinguished in two major subtypes: a predominantly axial disease and a more diffuse pattern of articular and extraarticular manifestations [4]. Ankylosing spondylitis (AS), which is the prototype of SpAs, is largely known to be highly
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familial, with the sibling of a patient with AS may have 50 times higher risk developing the disease compared to the general population [5]. Today, it is well established that SpAs are complex disorders involving both environmental and genetic factors to their susceptibility. Major histocompatibility complex (MHC) genes confer the 40–50% of the genetic susceptibility to SpAs, with HLA-B27 accounting approximately for the 30% of the overall genetic susceptibility to SpAs [6,7]. Additionally, recently many non-MHC genes have also been implicated in SpAs susceptibility such as IL23R (interleukin 23 receptor), ERAP1 (endoplasmic reticulum aminopeptidase 1), IL1R2 (interleukin 1 receptor 2), ANTXR2 (anthrax toxin receptor 2), CARD9 (caspase recruitment domain family, member 9), TNFSF15 [tumor necrosis factor (ligand) superfamily, member 15], and KIR (killer immunoglobulin receptor) [8]. However, HLA-B27 still remains the cornerstone of the genetic factors related to SpAs (Table 1). Up to 70 HLA-B27 subtypes have been reported all over the world (http://hla.alleles.org/class1.html), with a decreasing north–south gradient of its frequency [9]. Specifically, HLA-B27 subtypes differ in one or more amino acid substitutions of the alpha 1 and alpha 2 domains (exons 2 and 3), which constitute the peptide binding cleft [10–12]. The binding cleft has six side pockets (A–F) that accommodate the side chains of the amino acids of the bound peptide. From the six side pockets side-pockets B (binds the P2 peptide residue) and F (binds the C-terminal P9 peptide residue) are the critical sites for the usual nine-residue HLA-B27 peptide [13–15]. The most widespread HLA-B2705 subtype is thought to be the ancestral subtype and it is common in Caucasians and American Indians. The HLA-B2704 is most frequent in Asians, while the HLA-B2702 in Mediterranean populations [16]. Interestingly, the geographic distribution of HLA-B27 seems to be the result of a negative selection induced by malaria endemic [17–20].
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The majority of HLA-B27 subtypes have been associated with AS. However, some of them are rare or for other the results are not univocal and therefore their association with AS is under consideration [21,22]. Up to date, there appears to be a hierarchy of HLA-B27 subtypes’ association with AS. HLA-B2704 shows the strongest association, followed by HLA-B2705, HLA-B2702, and HLA-B2707, while HLA-B2706 and HLA-B2709 show the weakest association with the disease [8]. Many reasons reveal difficulties to understand the potential HLAB27 association with SpAs. The extend linkage disequilibrium within the HLA region reveals the difficulty to discern the real disease related gene. In addition to this, the manifestation may be the result of the synergic role of many HLA or non-HLA genes. Furthermore, the autoimmune diseases are complex disorders with both genetic and environmental factors contributing to their manifestation which is also extremely heterogenic [23]. On the other hand, many points support the association of HLA-B27 with SpAs [24,25]. First of all, HLA-B27 is associated with AS in many ethnic groups of patients, while there are also HLA-B27 subtypes which seem to protect against SpAs. Additionally, appropriate transgenic animals develop SpAs similar to human SpAs. Moreover, the HLA-B27 association with AS is one of the strongest ever reported in literature. In most studies 80–95% of patients with AS are positive for HLA-B27, which confers a high relative risk (N100) [8]. The concordance rate is 63% for HLA-B27 positive monozygotic twin siblings and 23% for dizygotic twin siblings [7]. As a result many theories have been proposed in order to explain the possible role of HLA-B27 subtypes in SpAs’ pathogenesis.
2. Theories suggesting the role of HLA-B27 in SpAs’ pathogenesis 2.1. Arthritogenic peptide hypothesis
Table 1 HLA-B27 frequencies in all over the world (data were obtained from www. allelefrequencies.net database). Country
HLA-B27 frequency
Country
HLA-B27 frequency
Albania Algeria Argentina Australia Austria Azores Bangladesh Dhaka Bangalee Bolivia Aymara Bosnia and Herzegovina Brazil Bulgaria Burkina China Colombia Costa Rica Croatia Cuba Czech England France Germany Greece India Israel Italy Japan FYROM Madeira Malaysia Martinique Mexico Mongolia Morocco
0.025 0.010 0.000–0.024 0.005–0.030 0.048 0.027–0.035 0.017 0.006 0.049 0.000–0.042 0.073 0.000–0.102 0.000–0.031 0.000–0.007 0.000 0.049 0.012–0.031 0.014–0.120 0.017–0.048 0.015–0.060 0.043–0.066 0.010–0.025 0.000–0.038 0.009–0.032 0.000–0.035 0.002–0.006 0.031–0.041 0.032–0.035 0.000–0.069 0.020 0.000–0.061 0.000–0.058 0.005–0.037
Norway Oman Pakistan Peru Philippines Portugal Romania Russia Rwanda Saudi Arabia Scotland Senegal Serbia Singapore South Africa South Korea Spain Sri Lanka Sudan Sweden Taiwan Tanzania Thailand Trinidad Tunisia Turkey United Arab Emirates United Kingdom USA Venezuela Vietnam Hanoi Wales
0.075–0.155 0.004 0.000–0.094 0.007 0.010 0.010–0.049 0.020–0.057 0.012–0.104 0.009 0.007–0.028 0.025 0.018 0.031 0.013 0.000 0.028–0.031 0.006–0.060 0.009 0.028–0.033 0.087 0.000–0.109 0.000 0.033–0.053 0.007–0.010 0.030 0.028 0.006 0.059 0.011–0.046 0.010–0.035 0.020 0.041
HLA-B27 presents peptides arising from degradation of endogenous proteins to CD8+ T-lymphocytes. Molecular mimicry between microbial and self-antigens may break self-tolerance leading to autoimmunity which is the basis of this hypothesis. HLA-B27 was revealed to present a self-antigen derived from its own molecule (aa 309–320) which shows a high homology to a peptide derived from Chlamydia trachomatis [26]. It is worth mentioning that this selfpeptide is a natural ligand of HLA-B2705, HLA-B2702, and HLA-B2704 subtypes related to AS, but not of HLA-B2706 and HLA-B2709 subtypes [26]. In support to this theory, many peptides derived from cartilage/bone-related proteins were revealed as possible ligands of HLA-B27 as well as a big number of HLA-B27 peptides were found to show high homology to pathogenic bacterial sequences [27]. Moreover in support to this hypothesis a self-ligand of HLA-B27 is sub-optimally presented by AS-associated HLA-B27 subtypes. In this case the molecular mimicry between a microbial and a self-peptide could trigger a cross-reaction in individuals carrying autoreactive T-cells which have not been eliminated during ontogenesis in the thymus. Specifically, a self-peptide (aa 400–408) of VIPR1 (vasoactive intestinal peptide receptor 1) shows highly homology to an Epstein–Barr virus derived peptide pLMP2 (latent membrane protein 2 of Epstein–Barr, aa 236–244). HLA-B2705 binds VIPR1 with a conventional and a non-conventional mode, while HLA-B2709 with the conventional one. The binding of pLMP2 shows highly molecular mimicry when it is bound with the non-conventional mode which could trigger subsequently T-cell cross-reaction in individuals carrying the HLA-B2705 subtype (related to AS) where autoreactive T-cell escaped negative selection in thymus [28,29]. Moreover, another self-peptide pGR (glucagon receptor), which shows homology with pVIPR1 and pLMP2 and binds HLA-B2705 in a dual conformation, further supports the arthritogenic peptide theory [30].
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However, despite the acceptance of this theory there are several points under consideration [31]. Up to date, the arthritogenic peptide has not been demonstrated. Both HLA-B2705 and HLA-B1403 have been associated with AS but do not show homology. Finally, transgenic rats developed inflammatory phenotype independently to CD8+ T-cells. All the aforementioned points led to the suggestion of additional hypotheses that could explain HLA-B27 association with the SpAs’ pathogenesis [32,33]. 2.2. Misfolding hypothesis The function of a protein is highly dependent of its proper folding, otherwise partially folded or misfolded proteins should be degraded by cellular quality control processes. However, gain-of-function processes [e.g. endoplasmic reticulum (ER) expansion, apoptosis, inclusion bodies, aggresomes, and amyloid fibrils] of misfolding proteins can cause autoimmune diseases through immune related cells. Class I molecules associate in ER with β2-microglobulin (β2m) and antigenic peptides for cell surface expression and presentation to T-cells. However, HLA-B27 can form covalent homodimers and polymers though their cysteine-67 residue in the α1 domain. The accumulation of HLA-B27 misfolded proteins in ER trigger ER stress which seems to lead to activation of unfolded protein response (UPR) resulting in activation of nuclear factor-κΒ (NF-κΒ). Subsequently, many pro-inflammatory cytokines are induced such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1), IL-6 (interleukin-6) favoring inflammatory conditions [31,34]. HLA-B27 molecules show slower folding rate in comparison to other HLA molecules and therefore the proper folding is disturbed much more easily leading subsequently to ER stress [35]. Furthermore, misfolded HLA-B27 molecules and UPR activation were observed in transgenic rats with inflammatory disease [36]. However, the hypothesis of misfolded HLA-B27 molecules was also challenged by the results of a recent study. Specifically, in a new HLA-B27 transgenic rat model the accumulation of HLA-B27 misfolded heavy chains was reversed by increasing the expression of β2m protein [37]. In this rat model, arthritis, spondylitis, and enthesitis were still developed even though the reduction of HLA-B27 misfolding. Additionally, while HLA-B2706 and HLA-B2709 molecules are folded more efficiently than the AS related subtypes HLA-B2705, HLA-B2704 and HLA-B2702, the HLA-B2707 subtype, which is associated with AS, is folded as efficiently as the non-disease related subtypes [38]. 2.3. Cell surface HLA-B27 homodimers hypothesis HLA-B27 heavy chains homodimers are thought to be produced in cell surface during endosomal recycling [39]. HLA-B27 homodimers bind to specific receptors expressed on NK cells, T-lymphocytes, and myelomonotic cells and therefore could play a role in the pathogenesis of autoimmune disorders [40–42]. In support to this theory are the results of a study in which HLA-B27 positive patients showed increased number of NK and CD4+ T-cells expressing a receptor which recognizes HLA-B27 homodimers but not heterodimers [41]. This theory may explain CD4+ T-cells related spontaneous inflammatory disease in transgenic mice models which do not express β2m protein [43]. Furthermore, CD4+ T-cells that interact with non-conventional forms of HLA-B27 have been isolated from HLA-B27 positive AS patients, but not from HLA-B27 positive healthy individuals breaking the theory of SpAs related to CD8+ T-cell-function [44]. However, residue Cys67, which is critical for the formation of homodimers, exists both in HLA-B27 subtypes related or not related to SpAs. No association was reported between free heavy chains of HLA-B27 molecules and predisposition to AS [45]. Furthermore, HLAB2706 subtype which is not related to AS also forms homodimers [8].
As a result additional alternative theories were suggested in a try to explain HLA-B27 association with SpAs. 2.4. β2m deposition hypothesis AS-associated HLA-B27 subtypes exhibit a higher rate of β2mdissociation from peptide-complexed surface-expressed HLA-B27. Subsequently, β2m molecules accumulate and become trapped in synovia, where they bind to collagen, form amyloid deposits or interact with synovial fibroblasts in which they induce the synthesis and secretion of proteins involved in tissue destruction [46]. 2.5. β2m-free/peptide free heavy chains of HLA-I hypothesis β2m-free, peptide free heavy chains support a helix-coil transition facilitating rotation of backbone angles around amino acid 167/168, and as a result the residues 169–181 (identical to a known HLA-B27 ligand) loop around and occupy the molecule's own peptide binding cleft. Such ‘auto-display’, occurring either within B27 molecules or between B27 molecules, could induce an autoimmune disease [47]. 2.6. Enhanced survival of some microbes in HLA-B27 cells hypothesis Enhanced survival has been reported of Salmonella enteritis in cells expressing HLA-B27 [48]. This impaired immune response may result in the subsequent SpAs, but without being able to explain the precise mechanism by which this pathological situation occurs. 2.7. ERAP1/ERAP2 aminopeptidase and Tapasin function hypothesis Peptide repertoire of HLA-B27 is highly determined by N-terminal trimming of ligand precursors by ERAP1and ERAP2 aminopeptidases. Tapasin is a chaperone which is mediated in peptide loading into class I molecules during quality control processes of ER [49,50]. However, HLA-B27 molecules are less dependent to tapasin compared to other class I molecules [51]. As a result, this fact leads HLA-B27 molecules to present suboptimal ligands which favor both overpresentation of exogenous antigens and dissociations between HLAB27 molecules and peptides enabling homodimerization of HLA-B27 heavy chains. Further studies are needed to support this hypothesis. 2.8. β2m over-expression hypothesis In a new HLA-B27/β2m transgenic rat model expressing more β2m molecules spondylitis was induced even in the absence of colitis [37]. Additional studies are needed to explain these primary results in the pathogenesis of axial inflammation. 3. From a puzzle of distinct hypotheses to a global theory The phenotypic diversity of SpAs reveals that it may be misleading to suggest only one hypothesis aiming to explain HLA-B27 mode of function in SpAs’ pathogenesis. As it is shown in Fig. 1 all the hypotheses seem to inter-play which may explain the diversity in the severity of a clinically diagnosed SpA. 4. Conclusions A strong association of HLA-B27 with SpAs and especially with AS is well established. Apart from HLA-B27's role on inflammatory arthritis manifestation, recently it was associated with diseases affected different human organs and systems (ocular, aural, pulmonary, cardiovascular, haematological, renal, endocrine, bone, and skin) and the virulence of HIV (human immunodeficiency virus), HCV (hepatitis C virus), EBV (Epstein–Barr virus), HSV2 (herpes simplex virus 2) and other viruses [52].
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ERAP1/ERAP2 play a role in the generation of specific HLA-B27 ligands and tapasin in the optimization of the class I peptide repertoire. Therefore, these enzymes could affect the stability of HLA-B27/peptide complex.
Some HLA-B27 subtypes may modify microbial handling leading to an impaired immune response which gives rise to SpAs pathogenesis (enhanced survival of some microbes in HLA-B27 cells hypothesis).
A peptide showing molecular mimicry with a self-antigen is the basis of arthritogen hypythesis, while its binding stability to HLAB27 gives rise to the other hypotheses.
Where does begin and where does stop each hypothesis if we take into account the complexity of genetic and environmental background of each individual?
Disturbance in the folding rate of HLA-B27 heavy chains is the basis of HLA-B27 misfolding hypothesis, while β2m expression levels up to normal can also be related to SpAs pathogenesis (β 2m over-expression hypothesis).
If the complex HLA-B27/peptide is not stable, it favors the formation of HLA-B27 homodimers at cell surface (cell surface HLA-B27 homodimers hypothesis). Taking into account that some HLA-B27 subtypes exhibit higher rate of β2m dissociation, this fact favors the β 2m deposition hypothesis. Both the above have as a result the presence of free HLA-B27 heavy chains on cell surface which is the basis of β 2m-free/peptide free heavy chains of HLA-I hypothesis.
Fig. 1. From a puzzle of distinct hypotheses to a global theory.
HLA-B27 is still one of the most fascinating molecules in medical researches. HLA-B27 typing seems to be of some value in the diagnosis of specific disorders since its association with diseases varies between different racial and ethnic groups of patients affecting its sensitivity and specificity in clinical practice [53]. Its clinical usefulness could only refer to a young man or woman with inflammatory back pain without classical radiographic features or unexplained oligoarthritis or enthesitis but always with the appropriate crisis of the clinician [54]. SpAs are complex diseases with different genetic and environmental factors to contribute to their susceptibility. Even though HLAB27 is almost essential for example in AS inheritance, its penetrance and phenotypic expression are highly modified by other gene or gene complexes [55]. Therefore, SpAs should be encountered as polygenic disorders keeping in mind for genetic association studies that they reduce in frequency by the square root with each increase in distance of the probands’ relationship. In addition, sample size, sample ethnicity, disease heterogeneity and proper statistical analysis should be kept in mind as to diminish the false-positive results and to detect the true-positive associations.
Take-home messages • HLA-B27 contributes to SpAs pathogenesis. • Up to 70 HLA-B27 subtypes have been described all over the world. • HLA-B27*04, *05, *02, *07, *06 and *09 show decreasing association with ankylosing spondylitis. • The number of hypotheses which try to explain the role of HLA-B27 in SpAs pathogenesis is increasing. • The complexity of the genetic and environmental background of each individual suggests passing from a puzzle of distinct hypotheses to a global theory as more rational.
• Sample size, sample ethnicity, disease genetic and phenotypic heterogeneity, and proper statistical analysis should be kept in mind as to diminish the false-positive results and to detect the truepositive HLA-B27 subtypes’ associations with SpAs.
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Complement system and T helper type 1 cells: a winding road If the role of complement system is quite well understood, its multiple implications in the development of autoimmunity are yet far to be clarified. What seems to be clear is that an imbalance in complement activation can lead to a cascade of events finally bringing to autoimmune reactions and tissue destruction. That is the reason why not only the complement system effectors, but also the receptors and the antagonists are of great weight in the scale pans of autoimmunity. Membrane cofactor protein (MCP; CD46) is a type I transmembrane protein functioning as a receptor for complement. It was identified as a protector against uncontrolled activation of the complement system. Nonetheless, it works as receptor for several microorganisms including viruses (measles, herpesvirus 6) and bacteria (Neisseria spp. and Streptococcus pyogenes). Cardone et al. (Nat Immunol. 2010;11:862-71) recently demonstrated that CD4+ T effector cells when engaged by the complement regulator CD46 are driven through the promotion of T helper type 1 (Th1) cells with the production of IFN-γ. However, in response to T cell antigen receptor-mediated activation and in the presence of IL-2, there is a switch towards a regulatory phenotype with an up-regulation of IL-10 (Th1 IFN-γ-IL-10+). The authors discussed the underlying mechanisms of downstream signaling pathway of activation of CD46, identifying Ste20 (SPS1)-related proline alanine-rich kinase (SPAK), that, acting as a partner for CYT-1, can lead to the phosphorylation of extracellular signal-related kinase (Erk) and then to the production of IL-10. This broad spectrum of evidences adds another knot to the rope linking the complement system and adaptive immunity. Of great interest appears the possibility that the complement system, through CD46, may act as a switcher between the “effector mode” and the “immunoregulatory mode” of Th1. The failure of this switch could be a factor in the development of autoimmune diseases: in the presence of CD46, CD4+ T cells of patients with rheumatoid arthritis may not be driven to differentiate into “immunoregulatory”, rather producing excessive IFN-γ. How this may affect the in vivo mechanisms leading to autoimmunity is an intriguing question to be addressed in further studies. Carlo Perricone, M.D.