Abstract
Background: Complement proteins constitute a proinflammatory system of the innate immunity which bridges with the adaptive immunity. It comprises of a group of serum zymogens, complement regulatory proteins (Cregs) and receptors. Most of the Cregs, namely CD59, CR1, DAF and MCP are membrane bound. Their soluble forms circulate in the body fluids. Activation of the zymogens through three distinct but interconnected pathways generate functionally important peptides. Most of the effects are produced by the interaction of the active peptides with their cell surface receptors. Uncontrolled activation of the system due to the overburdening triggers and deficient regulatory mechanisms leads to self-tissue injury in autoimmune and inflammatory disorders. Modulation of the Cregs has been evidenced in systemic rheumatoid disorders.
Objective: This review is an attempt to collate the literature culminated and insight gained regarding the association of CD59, a membrane Creg with the pathophysiology of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and its potential as a biomarker and therapeutic target for these two diseases.
Methodology: This review enfolds the information obtained from the original primary research papers, citations and review articles including our own laboratory findings and publications with key search from the PUBMED. Although CD59 has been implicated in several diseases, here our search remained focused only to SLE and RA.
Results: Evidences suggest disease related modulation and protective role of CD59 in SLE and RA. The bulk of information came from the animal studies.
Conclusions: An intimate relation of CD59 with the pathophysiology of SLE and RA is envisaged. CD59 appears to hold promise as a biomarker and therapeutic target for these two autoimmune disorders. More studies on human subjects along with supportive evidences from the animal models are needed. Modulation of CD59 expression by cytokines opens up a new avenue in the context.
Keywords
CD59, Complement, Creg, SLE, RA, Pathophysiology
Introduction
Complement system is a proinflammatory system that bridges between the innate and adaptive immunity. It comprises of about 50 humoral and cellular components consisting of a group of serum zymogens, complement regulatory proteins and complement receptors. Most of the Cregs are membrane bound. The effecter functions of the system are initiated by the activation of the zymogens through three distinct but interconnected pathways by defined molecular patterns [1].
The system is a double-edged sword. On one hand, it serves as the first line of defense against invading pathogens and clears the undesired body elements including the immune complexes and senescing proteins, debris and apoptotic cells [2], on the other hand, its effecter mechanisms, if massive and un-controlled, may cause severe inflammatory reactions and cellular injury serving as the key mediator of the immune inflammatory disorders [3].
Over the years, a large body of research has been carried out to gain insight into the molecular mechanisms underlying the pathophysiology of autoimmune diseases and association of the complement proteins with the same. In this context, the work on the complement regulatory proteins (Cregs), however, has gained momentum only in the recent years.
Following this quick introduction, the article commences with a brief account of the complement system, the complement regulatory proteins, the relevant details on CD59, ending with its relations with the pathophysiology of SLE, RA, its potential as a biomarker and, as a therapeutic target for these two diseases.
The complement system
The components of the system are the humoral complement cascade proteins, the membrane bound and soluble complement regulatory proteins and membrane complement receptors.
The complement cascade and its activation
The classical proteins of the complement cascade are C1 to C9. Further, Factor B, factor P, D, and later, mannose binding lectin (MBL) and MBL associated serum proteases 1(MASP1) and 2 (MASP2) were added to the system [4].
Complement is activated through the classical, MBL, or the alternative pathway. Whatever may the activation pathway be, the common strategy is the initiation of the cascade activation by distinct molecular triggers, formation of C3 and C5 convertases which lead to the proteolytic cleavage of these components to generate biologically active peptides, which further assemble to form the C5b, C6-C9(n) the membrane attack complex (MAC) also known as the terminal complement complex (TCC). The classical pathway begins with the activation of C1, alternative pathway with the activation of C3 and the lectin pathway starts with the activation of C2, C4.
The classical pathway is initiated by antibodies produced during the humoral response, by natural antibodies, either aggregated or in the form of immune complexes and, by other molecules like C-reactive protein or serum amyloid protein that are generated as a result of an inflammatory reaction. The activation of the pathway takes place in a step wise cascade manner flowing down from the 1st complement component C1 (qrs) to the terminal complement component C9 via the activation of C2, C4, C3, C5 ending in non- enzymatic assembly of C6-C9(n) with active fragment of C5, the C5b. On activation, the conversion of inactive zymogens to biologically active peptides occur by the cleavage of the parent protein, the primary fragments named as ‘a’ and ‘b’ like C3a, C3b, C4a, C4b, C5a, C5b.
The Mannose binding lectin pathway commences with binding of the complex MBL and mannose-binding lectin-associated proteases 1 and 2 (MASP1 and MASP2), respectively, to a bacterial cell wall. MASP2, a protein similar to C1s, leads to the formation of the C3 convertase C4b2a.
The alternative pathway is initiated by the spontaneous hydrolysis of C3 with the formation of C3(H2O). This forms a complex with factor B, followed by the cleavage of factor B within this complex by factor D. Subsequently, the C3(H2O) Bb complex is formed which activates more of C3 to C3b forming C3bBb. The C3bBb complex cleaves C3 to C3b and C3a. C3b gets deposited on the surface of the pathogens or other adherent surfaces and binds more of factor B, Once deposited on the surface of cells or pathogens, and this binding gradually amplifies the activation cascade. The binding of properdin stabilizes the C3bBb complex, the C3 convertase of the alternative pathway. C3 convertases generated through various pathways cleave C3 to C3a and C3b. C3b leads to the formation of the C5 convertase which cleaves C5 to C5a and C5b.
After the formation of C5b, the steps are all identical. The effecter peptides and the membrane attack complex generated by these three different pathways are the same irrespective of the pathway involved C3b further gets proteolyzed to produce biologically active peptides C3c and C3d.
Effecter functions of the biologically active complement peptides
The effecter functions of the biologically active complement peptides include inflammation and anaphylaxis by C3a and C5a; immune adherence and opsonization followed by facilitation of phagocytosis and immune complex clearance by C3b, C4b, and ultimate lysis of the cell membrane of the microbes by the formation of C5-C9(n), the membrane attack complex (MAC). Complement C3d is important in the induction of the B-cell responses and C3b contributes to immune regulation and immune complex clearance. It is also suggested that these fragments contribute to immune tolerance and immunological memory. While the membrane attack complex directly gets inserted onto the cell membrane, rest of the functions of the effecter peptides are mediated by the complement receptors, namely, CR1, CR2, CR3, CR4 and C3a, C5a and C3d receptors distributed either ubiquitously or in a cell specific manner predominantly on the blood cells [4].
Complement regulatory proteins are listed (Table 1). They protect the host against complement mediated tissue damage. Membrane-bound complement regulatory proteins are expressed on the cells of the hematopoietic system and protect the host cells against the complement mediated lyses. The balance between acceleration and inhibition of complement activation is critical to determine whether complement activation leads to the host defense, or, to the tissue injury of the host organs [5].
|
Regulator
|
Location
|
Function
|
|
C1 INH |
Plasma |
Dissociates activated C1 |
|
C4 binding protein (C4BP) |
Plasma |
Dissociates classical C3 convertase Cofactor for Factor I |
|
Properdin |
Plasma |
Stabilizes C3bBb3b |
|
Factor H |
Plasma |
Dissociates alternative C3 convertase |
|
Factor I |
Plasma |
Degrades C4b and C3b |
|
Serum proteases |
Plasma |
Inactivate anaphylatoxins |
|
S protein (vitronectin) |
Plasma |
Block membrane binding of soluble C567 |
|
CR1 |
Membrane |
Dissociates C3 convertase |
|
Decay Accelerating Factor (DAF, CD55) |
Membrane |
Dissociates C3 and C5 convertases |
|
Membrane Cofactor Protein (MCP, CD46) |
Membrane |
Cofactor for Factor I |
|
Homologous restriction Factor (HRF, C8BP, MIP) |
Membrane |
Inhibits MAC formation |
|
MIRL (protectin, CD59) |
Membrane |
Inhibits MAC formation |
A large number of complement regulatory proteins are known of which, CR1, DAF, MCP, and CD59 are membrane bound. Soluble form of these membrane bound complement regulatory proteins are also known [6]. These Cregs control the complement activation at the specific steps of the complement cascade ( Figure1).
Figure 1. Regulation of the complement cascade. The figure depicts the Cregs and their sites of action in inhibiting the complement cascade. CD59 inhibits the assembling of C5-C9 as soon as they start assembling at the membrane surface, thereby preventing the formation of the membrane attack complex and controlling their injurious effects on cells and tissues.
CD59 (Protectin/ Membrane inhibitor of Reactive Lysis [MIRL]/ Homologous Restriction Factor-20 [HRF-20]/ Mac Inhibitory Factor [MACIF] CD59 glycoprotein, MAC-inhibitory protein [MAC-IP])
Cluster of differentiation 59 (CD59) is an 18-21 KD, GPI-anchored glycoprotein (GPIAP). It belongs to the leukocyte antigen 6 (Ly6) family of proteins. It has a high homology to the mouse protein, Ly6 [7]. CD59 attaches to the host cells via its glycophosphatidyl inositol (GPI) anchor. When complement activation leads to the deposition of C5b678 on the host cells, CD59 is the only complement regulator that can prevent C9 from polymerizing and forming the complement membrane attack complex and also the channel formation to dig through the membrane [8,9] (Figure 2).
Figure 2. Inhibition of MAC assembly by CD59. CD59 anchored on the cell membrane by its GPI portion, intervenes in the formation of the C5-9 assembly and polymerization of C9 and inhibits the formation of the membrane attack complex.
Thus, it is the most crucial regulator of the complement cascade that prevents direct tissue injury because of the complement activation in the normal health. CD59 also facilitates endocytosis of the CD59-CD9 complex and may signal the cell to perform active measures such as antigen presentation, immune tolerance, down regulation of the MAC and T-cell activation [10,11].
Mechanisms underlying the CD59-mediated transduction of signals into the cells, remain unclear as CD59 does not span the membrane. However, the recent studies suggest that the lipid rafts act as platforms for the associations of signaling molecules [12]. Therefore, the function of CD59 in signal transduction is dependent on its localization to the lipid rafts.
It is hypothesized that the phosphatidyl inositol (PI) moiety of the GPI may participate in signal transduction via a palmitate group that is located at the second position of the PI (PI- 2nd). Linker for activation of T-cells (LAT) was first observed in 1990. In the year 1998; it was purified from activated Jurkat cells and named LAT based on its properties [13].
CD59 is widely expressed in the majority of tissues, including the heart, liver, kidneys, and the circulating cells, such as leukocytes and red blood cells [14].
The Soluble CD59 is present in cell-free seminal plasma at a concentration of at least 20µg/ml. It is also found in saliva, tears, sweat, concentrated cerebro-spinal fluid, amniotic fluid, seminal fluid and breast milk. CD59 from amniotic fluid, seminal plasma and cerebrospinal fluid retains its GPI anchor, can incorporate into cell membranes and, is an efficient MAC inhibitor whereas that found in urine is devoid of its GPI anchor [15].
CD59 and disease association
Altered expression of CD59 in the immune- inflammatory diseases and cancers facilitated the understanding on the pathophysiology of these diseases and formed the basis of envisaging and exploring the diagnostic and therapeutic potential of this protein. Reduced expression of CD59 or the GPI anchor had been found associated with the severity of poor prognosis of the diseases like PNH, Alzheimer’s, advanced macular degeneration and few other diseases [16]. Over expression of CD59 had been observed in a variety of cancers. This might make cancer cells protected against complement mediated lyses [17]. Following is an update on the association of CD59 with SLE and RA.
Association of CD59 with SLE and RA
Recent studies with gene knockout mice have suggested that membrane-bound complement regulatory proteins may critically determine the sensitivity of host tissues to complement mediated injury in autoimmune and inflammatory disorders [18]. A good number of studies suggest close association of CD59 with cancer and, that it can serve as a biomarker and therapeutic target. This review however is focused entirely to the importance of CD59 in SLE and RA.
CD59 and SLE
SLE is a multi-systemic disorder and may have cutaneous, musculoskeletal, renal, cardiopulmonary, neurological, hematological or gastrointestinal manifestations. Clinically, SLE is difficult to diagnose and manage because of its heterogeneous presentation and unpredictable course that consists of periods of remission and exacerbation (flares).
Although most flares are caused by reversible inflammatory processes, over the time, they can lead to irreversible organ damage that greatly affects the morbidity and mortality of the patients with SLE. The disease has multi-factorial etiology. It predominantly affects women in their childbearing age (female: male ratio is 9:1)[19] .
Like any other autoimmune disorder, SLE is an outcome of the multifaceted immune dysregulation. These may include; loss of immune tolerance, increased antigenic load, excess T cell help, defective B cell suppression and aberrant cytokine profiles. All these lead to B cell hyperactivity and the production of pathogenic auto antibodies. The presence of anti-double-stranded DNA antibody (anti-dsDNA Ab) remains the hallmark of lupus erythematosus. Defective immune regulatory mechanisms, clearance of apoptotic cells and immune complexes are important contributors to the disease manifestations in SLE. The pathophysiology of SLE however, is not completely understood. Complement proteins especially the reduced levels of C3, genetic or acquired, had been found associated with the pathophysiology of SLE [20].
The exact etiology of SLE remains elusive. Predisposing factors include; genetic factors (certain types of human leukocyte antigens, null complement alleles and a host of other susceptibility genes), environmental factors (e.g., sun exposure, some drugs such as sulfa antibiotics, viral infection, etc.) and hormonal factors. The disease shows a strong familial aggregation, with a much higher frequency among first-degree relatives of patients indicating a genetic basis. However, most cases of SLE are sporadic without identifiable genetic predisposing factors [21].
CD 59
Several studies have demonstrated increased serum levels of MAC in active SLE patients [22] indicating the potential role of complement mediated tissue injury in the disease process. Since CD59 is a very important surface molecule protecting the autologous cells from the MAC mediated lysis and self-tissue injury, it is likely that it plays an important role in the modulation of the complement mediated injury in SLE. Up regulation of CD59, when suppressed by different doses of monoclonal antibody, a dose dependent increase in MAC deposition and exacerbated tubulointerstitial injury in rats had been observed [23,24]. This, further elucidated the role of CD59 in the maintenance of normal integrity of kidney. Cultured glomerular epithelial, endothelial and mesangial cells have been shown to exhibit increased susceptibility to complement mediated lysis in the presence of neutralizing antibodies in vitro [25,26]. In a study on CD59a gene knockout mice, Turnberg and coworkers [27] demonstrated that mice lacking the mCD59a gene were more susceptible to accelerated nephrotoxic nephritis than matched controls. These mice developed higher glomerular cellularity, severe glomerular thrombosis and proteinuria at different time points. Higher levels of C9 deposition indicated a larger quantity of MAC. This apparently related to the absence of CD59 which caused greater tissue damage. Most of the studies on CD59 in autoimmunity relate to the expression of CD59 in the kidney of patients with renal diseases. Arora et al. [28] reported that in SLE patients with diffuse proliferative glomerulonephritis, expression of CD59 on the RBCs increased significantly. Another report stated that the levels of CD59 on the red cells of SLE patients with autoimmune hemolytic anemia were decreased [29]. Thus, the expression of CD59 on erythrocytes may vary with the varied manifestations of SLE.
Tamai et al. [29] were the first to report an up-regulation of CD59 in the glomerular cells of lupus nephritis patients. Few other reports also showed increased CD59 in the glomeruli of SLE patients [28]. Studies carried out by Biswas [30] found significant down regulation of CD59 in lymphocytes from the patients with SLE but not in the neutrophils and monocytes.
A serial study on 12 patients with alternating flare-remission pattern of the SLE showed a significant reduction in the expression of CD59 transcript in the patients during remission when compared to the CD59 levels during the first flare. Levels of CD59 transcripts increased significantly in the patients who suffered a second flare when compared to the remission state and that during the first flare [30]. Recently, in a case study, CD59 deficiency syndrome was found associated with serial clinical features of repeated acute inflammatory polyradiculoneuropathy, angioedema, paresthesia, myelitis, and finally malar rash and autoantibodies with final diagnosis of SLE [31].
Apart from its role as a regulator of MAC formation, CD59 enhances T cell proliferation and IL-2 secretion [32]. This function of CD59 in the alteration of cytokine profile and induction of T cell proliferation may have some significance in the pathogenesis of SLE.
CD59 and RA
RA is a complex immune-mediated disease affecting 0.5%-1.0% of the adult population world-wide with two to three times more female than male patients [33,34]. It is the most common systemic autoimmune disease characterized by the presence of various autoantibodies in serum and synovial fluid [35]. The disease can start at any age, although the mean age at the onset is 40 to 60 years [36,37]. The etiology of RA has been elusive. However, a growing body of evidence suggests that it results from a combination of genetic, environmental and immunological factors [38,39]. Studies had reported correlation of complement split products (C3d, C4d, C3b, C3bi, C3c, C4b/c) and circulating immune complex (CIC) levels with the RA disease activity [40-42]. However, plasma levels of complement activation products are rarely used as an inflammation marker in RA since analysis of complement activation in patients is hampered by in vitro artifacts. RA can be serologically characterized by the presence of auto antibodies such as Rheumatoid Factor (RF) or anti-citrullinated protein antibodies (ACPA), which are present in about two third of individuals with the disease. C1q-C4 complexes had been described that hold promise as potential biomarker for disease activity in RA [43].
CD59: There are studies to suggest that CD59 has an important role in the pathogenesis of RA.
However, most of the data indicating a possible role of CD59 in the pathogenesis of RA came from the animal studies. In a study on CD59a gene knockout mice, Williams et al. [44] demonstrated that mice lacking the CD59a gene had exacerbated joint pathology. These mice developed significantly greater joint swelling, as well as increased scores in multiple histological parameters of damage. Synovial deposits of MAC were present in the arthritic joints of CD59a deficient mice.
Prevention of MAC assembly is, therefore, considered important for protection from tissue injury and here CD59 is envisaged to play a very significant role.
When rat knee joints were injected with a monoclonal antibody that specifically blocked the activity of CD59, joint swelling, thickening of the synovial tissues, infiltration of inflammatory cells into the synovium and deposition of membrane attack complex (MAC on the synovial surface occurred [45].
Lack of CD59 in the synovial lining cells and relatively weak expression of CD59 in the stromal and endothelial cells in RA had earlier been observed [46]. A single study documented decreased expression of CD59 on T-cells in RA [47]. Studies on CR1, CR2 and CD59 deficient mice models further emphasized that these two complement regulatory proteins protect hosts from developing pathological manifestations of RA [48]. Mizuno et al. [49] demonstrated that when CD59 and Crry, a rodent functional homologue of human MCP and DAF were functionally blocked at 2 weeks after the induction of CIA in rats, swelling of the knee joints was markedly increased. Deposits of membrane attack complex were found in the synovium. Membrane-targeted recombinant rat CD59 (sCD59-APT542) administration at the time of disease induction markedly reduced pathology in CD59a knockout mice. The crucial role played by CR1 and CD59 in preventing tissue injury in RA further came from studies on animal models. Systemic inhibition of early complement activation and MAC by administration of recombinant soluble CR1 (sCR1) and membrane-targeted soluble recombinant form of rat CD59 (sCD59-APT542) respectively inhibited development and progression of joint disease in RA animal models.
While there is ample evidence from animal studies that implicates CD59 in RA, there are only few reports on the status of CD59 expression in humans. Several studies had reported increased levels of plasma and synovial fluid TCC in RA patients [49-52]. High levels of MAC deposits in the synovium had also been reported [53-55]. In vitro studies had shown that non-lethal amounts of MAC stimulate human synoviocytes to secrete prostaglandins, reactive oxygen metabolites and pro-inflammatory cytokines [56,57].
Previous studies had shown decreased expression of CD59 on erythrocytes [58-60]. Jones et al. [61] observed no difference in CD59 surface expression on synovial fluid neutrophils compared with the PBMC s of the RA patients. These results provide a link between the in vivo observations of MAC localization and inflammatory mediator production in rheumatoid synovium and firmly implicate the MAC in disease pathogenesis. In their retrospective study involving 114 controls and 110 patients with active RA, Anand D [62] found that the CD59 transcript in the isolated peripheral blood mononuclear cells (PBMCs) was significantly decreased in patients as compared to controls which correlated significantly and negatively with DAS28. Levels of CD59 transcript correlated significantly and negatively with the levels of C4 in patients. These observations suggested relationship of PBMC-CD59 with the RA pathology.
In a serial study involving 17 patients with active RA from the day 1 of their diagnosis, (the week 0) Anand D [62] also found that the levels of DAS28 declined significantly on the week 24 as compared to the week 0 and, week 12. No significant change in the levels of CD59 transcript on the week 24 as compared to the week 0 was observed. However, levels of CD59 transcript increased significantly on the week 24 as compared to the week 12. An analysis of the individual patients revealed that all the patients who improved at either on the week 12 or the week 24, showed an increase in the levels of CD59 transcript excepting three patients whose levels of CD59 transcript remained unchanged. Patients who did not improve showed decline in the levels of CD59 excepting three patients whose levels of CD59 transcript remained unchanged [62].
Thus, this follow-up study revealed a relationship between the up-regulation of CD59 transcript with better prognosis and, vice versa.
Modulation of CD59 expression by cytokines in relation to SLE and rheumatoid arthritis
Expression of CD59 on human vascular endothelial cells had been shown to be upregulated by interleukin-4 (IL-4) and tumor necrosis factor (TNF-α) and downregulated by IL-1b [63]. Gasque and Morgan [64] reported upregulation of CD59 expression after interferon-gamma (IFN-ϒ) treatment of human oligo dendrocytes. IFN-ϒ was shown to increase CD59 expression in human PBMCs ex vivo and in patients with SLE.
In another study, it has been reported that the host CD59 expression is highly unregulated by the Varicella zoster virus (VZV) infection in human T cells and dorsal root ganglia (DRG). The same however had not been observed in human skin xenografts in SCID- hu mice in vivo. The modulation of host CD59 might help VZV in evading the complement-mediated pathogenesis [65]. Studies are in progress to elucidate the molecules that might be modulating the levels of CD59 in SLE.
Das et al. [66] found IFN-ϒ to cause marked signi?cant increase in CD59 transcripts in the neutrophils of patients with SLE. The same had been true for the TNF-α. The studies carried out by Anand et al. [62] showed that IL-18 downregulated the expression of CD59 in PBMCs in patients with RA.
The modulation of CD59 by cytokines is being explored as a strategy to develop CD59 based therapeutics in several diseases especially cancer (Not discussed here).
Conclusions
In brief, the studies suggest an association of CD59 with the pathophysiology of SLE Expression of CD59 is related to the disease progression or remission. Up regulation of CD59 is related to good prognosis and vice versa. A protective role of CD59,is therefore envisaged. Studies also suggest that CD59 plays an important role in determining the course of both the diseases. This molecule, therefore, holds promise as a biomarker and therapeutic target for SLE and RA. A detailed study on the human subjects, therefore, is desired. There are studies to suggest modulation of CD59 by cytokines (Details not discussed) in different cell types in the normal health as well as in SLE.
The modulation of CD59 in the desirable dimension may emerge as a therapeutic strategy for both the diseases. A large-scale correlative study on the healthy human subjects and, in the patients with SLE and RA during the course of disease, would help evaluating the two way interlinks between CD59 and cytokines and, the significance of CD59 as a biomarker. Human studies however need to be supported and confirmed by the ex vivo and animal experimentations.
It is warranted that any cytokine therapy in these two diseases or otherwise, should take care of their synergistic or antagonist effect on the complement regulatory proteins. This review thus opens up a new horizon in the future management of RA and SLE.
Acknowledgements
The authors remain grateful to the All India Institute of the Medical Sciences where they carried out their research work on the disease association of complement regulatory proteins.
References
2. Das N. Complement and membrane-bound complement regulatory proteins as biomarkers and therapeutic targets for autoimmune inflammatory disorders, RA and SLE.
3. Eddie Ip WK, Takahashi K, Alan Ezekowitz R, Stuart LM. Mannose‐binding lectin and innate immunity. Immunological Reviews. 2009 Jul;230(1):9-21.
4. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. The American Journal of Pathology. 2007 Sep 1;171(3):715-27.
5. Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement—their role in inflammation. In Seminars in Immunopathology. 2012 Jan; 34(1):151-165.
6. Kim DD, Song WC. Membrane complement regulatory proteins. Clinical Immunology. 2006 Feb 1;118(2-3):127-36.
7. Davies AL, Simmons DL, Hale G, Harrison RA, Tighe H, Lachmann PJ, et al. CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. The Journal of Experimental Medicine. 1989 Sep 1;170(3):637-54.
8. Meri S, Morgan BP, Davies A, Daniels RH, Olavesen MG, Waldmann H, et al. Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology. 1990 Sep;71(1):1.
9. Farkas I, Baranyi L, Ishikawa Y, Okada N, Bohata C, Budai D, et al. CD59 blocks not only the insertion of C9 into MAC but inhibits ion channel formation by homologous C5b‐8 as well as C5b‐9. The Journal of Physiology. 2002 Mar;539(2):537-45.
10. Maio M, Brasoveanu LI, Coral SA, Sigalotti L, Lamaj E, Gasparollo A, et al. Structure, distribution, and functional role of protectin (CD59) in complement-susceptibility and in immunotherapy of human malignancies. International Journal of Oncology. 1998 Aug 1;13(2):305-23.
11. Venneker GT, Asghar SS. CD59: A molecule involved in antigen presentation as well as downregulation of membrane attack complex. Experimental and Clinical Immunogenetics. 1992 Jan 1;9(1):33-47.
12. Wang LN, Gao MH, Wang B, Cong BB, Zhang SC. A role for GPI-CD59 in promoting T-cell signal transduction via LAT. Oncology Letters. 2018 Apr 1;15(4):4873-81.
13. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998 Jan 9;92(1):83-92.
14. Meri S, Waldmann H, Lachmann PJ. Distribution of protectin (CD59), a complement membrane attack inhibitor, in normal human tissues. Laboratory Investigation; A Journal of Technical Methods and Pathology. 1991 Nov 1;65(5):532-7.
15. Rushmere NK, Van Den Berg CW, Morgan BP. Production and functional characterization of a soluble recombinant form ofmouse CD59. Immunology. 2000 Feb;99(2):326-32.
16. Donev RM, Kolev MV. CD59 (CD59 molecule, complement regulatory protein). Atlas of Genetics and Cytogenetics in Oncology and Haematology. 2013.
17. Chen S, Caragine T, Cheung NK, Tomlinson S. CD59 expressed on a tumor cell surface modulates decay-accelerating factor expression and enhances tumor growth in a rat model of human neuroblastoma. Cancer Research. 2000 Jun 1;60(11):3013-8.
18. Das N, Biswas B, Khera R. Membrane-bound complement regulatory proteins as biomarkers and potential therapeutic targets for SLE. Complement Therapeutics. 2013:55-81.
19. Das N, Anand D, Biswas B, Kumari D, Gandhi M. The membrane complement regulatory protein CD59 and its association with rheumatoid arthritis and systemic lupus erythematosus. Current Medicine Research and Practice. 2019 Sep 1;9(5):182-8.
20. Lam NC, Ghetu MV, Bieniek ML. Systemic lupus erythematosus: primary care approach to diagnosis and management. American Family Physician. 2016 Aug 15;94(4):284-94.
21. Choi J, Kim ST, Craft J. The pathogenesis of systemic lupus erythematosus—an update. Current Opinion in Immunology. 2012 Dec 1;24(6):651-7.
22. Gawryl MS, Chudwin DS, Langlois PF, Lint TF. The terminal complement complex, C5b–9, a marker of disease activity in patients with systemic lupus erythematosus. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1988 Feb;31(2):188-95.
23. Nangaku M, Alpers CE, Pippin J, Shankland SJ, Kurokawa K, Adler S, et al. CD59 protects glomerular endothelial cells from immune-mediated thrombotic microangiopathy in rats. Journal of the American Society of Nephrology. 1998 Apr 1;9(4):590-7.
24. Watanabe M, Morita Y, Mizuno M, Nishikawa K, Yuzawa Y, Hotta N, et al. CD59 protects rat kidney from complement mediated injury in collaboration with crry. Kidney International. 2000 Oct 1;58(4):1569-79.
25. Quigg RJ, Morgan BP, Holers VM, Adler S, Sneed III AE, Lo CF. Complement regulation in the rat glomerulus: Crry and CD59 regulate complement in glomerular mesangial and endothelial cells. Kidney International. 1995 Aug 1;48(2):412-21.
26. Rooney IA, Davies A, Griffiths D, Williams JD, Davies M, Meri S, et al. The complement‐inhibiting protein, Protectin (CD59 antigen), is present and functionally active on glomerular epithelial cells. Clinical & Experimental Immunology. 1991 Feb;83(2):251-6.
27. Turnberg D, Botto M, Lewis M, Zhou W, Sacks SH, Morgan BP, et al. CD59a deficiency exacerbates ischemia-reperfusion injury in mice. The American Journal of Pathology. 2004 Sep 1;165(3):825-32.
28. Arora M, Arora R, Tiwari SC, Das N, Srivastava LM. Expression of complement regulatory proteins in diffuse proliferative glomerulonephritis. Lupus. 2000 Feb;9(2):127-31.
29. Tamai H, Matsuo S, Fukatsu A, Nishikawa K, Sakamoto N, Yoshioka K, et al. Localization of 20‐kD homologous restriction factor (HRF20) in diseased human glomeruli. An immunofluorescence study. Clinical & Experimental Immunology. 1991 May;84(2):256-62.
30. Al-Faris L, Al-Humood S, Behbehani F, Sallam H. Altered expression pattern of CD55 and CD59 on red blood cells in anemia of chronic kidney disease. Medical Principles and Practice. 2017;26(6):516-22.
31. Biswas B. Elucidation of the expression of Complement Reguatory Proteins in the pathophysiology and severity of Systemic Lupus Erythematosus. PhD thesis, All India Institute of Medical Sciences, New Delhi, India. Submitted on August 2010, qualified on 2011 .
32. Parvaneh VJ, Ghasemi L, Rahmani K, Shiari R, Mesdaghi M, Chavoshzadeh Z, et al. Recurrent angioedema, Guillain-Barré, and myelitis in a girl with systemic lupus erythematosus and CD59 deficiency syndrome. Autoimmunity Highlights. 2020 Dec;11(1):1-7.
33. Noris M, Remuzzi G. Overview of complement activation and regulation. In Seminars in Nephrology 2013 Nov 1; 33(6):479-492.
34. Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: what have we learned?. Immunogenetics. 2011 Aug;63(8):459-66.
35. Martínez OE, Hernandez Ramírez DF, Nunez-Alvarez CA. Citrullinated proteins in rheumatoid arthritis. Cabiedes J. Reumatol Clin 2011;7:68-71
36. Fattahi MJ, Mirshafiey A. Prostaglandins and rheumatoid arthritis. Arthritis.2012. 2012: 239310.
37. O’Dell JR, Smolen JS, Aletaha D, Robinson DR, Saint Clair EW. Rheumatoid arthritis. A clinicians pearls and myths in rheumatology In: Stone JH, Ed. Springer 2010;1-13.
38. Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology. 2006 Jun 1;45(6):669-75.
39. Lossius A, Johansen JN, Torkildsen Ø, Vartdal F, Holmøy T. Epstein-Barr virus in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis—association and causation. Viruses. 2012 Dec;4(12):3701-30.
40. Morrow WJ, Williams DJ, Ferec C, Casburn-Budd R, Isenberg DA, Paice E, et al. The use of C3d as a means of monitoring clinical activity in systemic lupus erythematosus and rheumatoid arthritis. Annals of the Rheumatic Diseases. 1983 Dec 1;42(6):668-71.
41. Takemura S, Ueda M, Tagami H, Kato H, Yoshikawa T, Kawakami N, et al. Relation of clinical activity of rheumatoid arthritis to immune complexes, complement components and anti-immunoglobulins. Rheumatology International. 1984 Dec 1;4(4):159-63.
42. Molenaar ET, Voskuyl AE, Familian A, van Mierlo GJ, Dijkmans BA, Hack CE. Complement activation in patients with rheumatoid arthritis mediated in part by C‐reactive protein. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2001 May;44(5):997-1002.
43. Wouters D, Voskuyl AE, Molenaar ET, Dijkmans BA, Hack CE. Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q–C4 complexes as novel activation products. Arthritis & Rheumatism. 2006 Apr;54(4):1143-50.
44. Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proceedings of the National Academy of Sciences. 1992 Oct 15;89(20):9784-8.
45. Fraser DA, Harris CL, Williams AS, Mizuno M, Gallagher S, Smith RA, et al. Generation of a recombinant, membrane-targeted form of the complement regulator CD59: activity in vitro and in vivo. Journal of Biological Chemistry. 2003 Dec 5;278(49):48921-7.
46. Mizuno M, Nishikawa K, Goodfellow RM, Piddlesden SJ, Morgan BP, Matsuo S, et al. The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1997 Mar;40(3):527-33.
47. Christmas SE, De La Mata Espinosa CT, Halliday D, Buxton CA, Cummerson JA, Johnson PM. Levels of expression of complement regulatory proteins CD46, CD55 and CD59 on resting and activated human peripheral blood leucocytes. Immunology. 2006 Dec;119(4):522-8.
48. Konttinen YT, Ceponis A, Meri S, Vuorikoski A, Kortekangas P, Sorsa T, et al. Complement in acute and chronic arthritides: assessment of C3c, C9, and protectin (CD59) in synovial membrane. Annals of the Rheumatic Diseases. 1996 Dec 1;55(12):888-94.
49. Mizuno M, Nishikawa K, Spiller OB, Morgan BP, Okada N, Okada H, et al. Membrane complement regulators protect against the development of type II collagen–induced arthritis in rats. Arthritis & Rheumatism. 2001 Oct;44(10):2425-34.
50. Piccoli AK, Alegretti AP, Schneider L, Lora PS, Xavier RM. Expression of complement regulatory proteins CD55, CD59, CD35, and CD46 in rheumatoid arthritis. Revista Brasileira de Reumatologia. 2011;51:503-10.
51. Mizuno M, Nishikawa K, Morgan BP, Matsuo S. Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59. Clinical and Experimental Immunology. 2000 Feb;119(2):368.
52. Morgan BP, Daniels RH, Williams BD. Measurement of terminal complement complexes in rheumatoid arthritis. Clinical and Experimental Immunology. 1988 Sep;73(3):473.
53. Brodeur JP, Ruddy S, Schwartz LB, Moxley G. Synovial fluid levels of complement SC5b‐9 and fragment Bb are elevated in patients with rheumatoid arthritis. Arthritis & Rheumatism. 1991 Dec;34(12):1531-7.
54. Corvetta A, Pomponio G, Rinaldi N, Luchetti MM, Di Loreto C, Stramazzotti D. Terminal complement complex in synovial tissue from patients affected by rheumatoid arthritis, osteoarthritis and acute joint trauma. Clinical and Experimental Rheumatology. 1992 Sep 1;10(5):433-8.
55. Sanders ME, Kopicky JA, Wigley FM, Shin ML, Frank MM, Joiner KA. Membrane attack complex of complement in rheumatoid synovial tissue demonstrated by immunofluorescent microscopy. The Journal of Rheumatology. 1986 Dec 1;13(6):1028-34.
56. Kemp PA, Spragg JH, Brown JC, Morgan BP, Gunn CA, Taylor PW. Immunohistochemical determination of complement activation in joint tissues of patients with rheumatoid arthritis and osteoarthritis using neoantigen-specific monoclonal antibodies. Journal of Clinical & Laboratory Immunology. 1992 Jan 1;37(4):147-62.
57. Daniels RH, Houston WA, Petersen MM, Williams JD, Williams BD, Morgan BP. Stimulation of human rheumatoid synovial cells by non-lethal complement membrane attack. Immunology. 1990 Feb;69(2):237.
58. Arora M, Kumar A, Das SN, Srivastava LM. Complement-regulatory protein expression and activation of complement cascade on erythrocytes from patients with rheumatoid arthritis (RA). Clinical and Experimental Immunology. 1998 Jan;111(1):102.
59. Pourazar AA, Andalib AR, Oreizy F, Pournasr KB, Ghavami NA, Karimzadeh H. A flowcytometry study of CD55 and CD59 expression on erythrocytes in rheumatoid arthritis patients. Iranian Journal of Immunology. 2005; 2:91-96.
60. Fattouh M, Mohamed T, Al Fadl EM, Hafez AR. A flowcytometry study of complement regulatory proteins expression on peripheral blood cells in rheumatoid arthritis patients. Journal of American Science. 2013;9(11).
61. Jones J, Laffafian I, Cooper AM, Williams BD, Morgan BP. Expression of complement regulatory molecules and other surface markers on neutrophils from synovial fluid and blood of patients with rheumatoid arthritis. Rheumatology. 1994 Aug 1;33(8):707-12.
62. Anand D. Expression and modulation of leukocyte Complement Receptor 1 and CD59 (Protectin) in relation to rheumatoid arthritis. PhD Thesis submitted, 2011, qualified, 2012 by the All India Institute of Medical Sciences, New Delhi 2011.
63. Moutabarrik AB, Nakanishi I, Namiki M, Hara T, Matsumoto M, Ishibashi M, Okuyama A, Zaid DR, Seya T. Cytokine-mediated regulation of the surface expression of complement regulatory proteins, CD46 (MCP), CD55 (DAF), and CD59 on human vascular endothelial cells. Lymphokine and Cytokine Research. 1993 Jun 1;12(3):167-72.
64. Gasque P, Morgan BP. Complement regulatory protein expression by a human oligodendrocyte cell line: cytokine regulation and comparison with astrocytes. Immunology. 1996 Nov;89(3):338-47.
65. Wang W, Wang X, Yang L, Fu W, Pan D, et al. Modulation of host CD59 expression by varicella-zoster virus in human xenografts in vivo. Virology. 2016 Apr 1;491:96-105.
66. Das N, Biswas B, Arora V, Kumar U, Kumar A. Effect of immune complexes and cytokines on expression and modulation of neutrophil complement regulatory proteins in SLE. Frontiers Immunol. 2013. 208