Current Medicine Research and Practice 9 (2019) 182e188 Contents lists available at ScienceDirect Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp Review Article The membrane complement regulatory protein CD59 and its association with rheumatoid arthritis and systemic lupus erythematosus * Nibhriti Das a, Devyani Anand a, Bintili Biswas b, Deepa Kumari c, Monika Gandhi c, a Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India b Department of Zoology, Ramjas College, University of Delhi, India c University School of Biotechnology, Guru Gobind Singh Indraprastha University, India article info abstract Article history: The complement cascade consisting of about 50 soluble and cell surface proteins is activated in auto- Received 8 May 2019 immune inflammatory disorders. This contributes to the pathological manifestations in these diseases. In Accepted 30 July 2019 normal health, the soluble and membrane complement regulatory proteins protect the host against Available online 5 August 2019 complement-mediated self-tissue injury by controlling the extent of complement activation within the desired limits for the host's benefit. CD59 is a membrane complement regulatory protein that inhibits the Keywords: formation of the terminal complement complex or membrane attack complex (C5b6789n) which is CD59 generated on complement activation by any of the three pathways, namely, the classical, alternative, and RA SLE the mannose-binding lectin pathway. Animal experiments and human studies have suggested impor- Pathophysiology tance of membrane complement proteins including CD59 in the pathophysiology of rheumatoid arthritis Disease marker (RA) and systemic lupus erythematosus (SLE). Here is a brief review on CD59 and its distribution, structure, functions, and association with RA and SLE starting with a brief introduction on the com- plement system, its activation, the biological functions, and relations of membrane complement regu- latory proteins, especially CD59, with RA and SLE. © 2019 Sir Ganga Ram Hospital. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved. 1. Introduction (Fig. 1 a). To name a few, immune complexes, altered self-mole- cules, and microbial mannose surfaces trigger the classical, alter- The complement system represents about fifty cell surface and native, and lectin pathways, respectively. The activation takes place soluble proteins consisting of zymogens, receptors, and regulators. in a step-wise cascade manner flowing down from the 1st com- The zymogens get activated by three different pathways, namely, plement component C1 (qrs) to the terminal complement compo- the classical pathway, the alternative pathway, and the mannose- nent C9 via the activation of C2, C4, C3 and C5 ending in a binding lectin pathway triggered by different molecular patterns nonenzymatic assembly of C6eC9 with active fragment from C5. On activation, the conversion of inactive zymogens to biologically active peptides occurs by the cleavage of the parent protein, the primary fragments named as ‘a’ and ‘b’ such as C3a, C3b, C4a, C4b, Abbreviations: MAC, Membrane attack complex; CRPs, Complement regulatory proteins; TCC, Terminal complement complex; DAF, decay-accelerating factor; MCP, C5a, and C5b. The classical pathway commences with the activation Membrane cofactor protein; fH, Factor H; SLE, Systemic lupus erythematosus; RA, of C1, alternative pathway with the activation of C3, and the lectin Rheumatoid arthritis; OA, Osteoarthritis; HRF-2, Homologous Restriction factor-2; pathway with the activation of C2 and C4. GPI, glycosylphosphatidylinositol; LPS, Lipopolysaccharide; RTX, Rituximab; AA, Each of the active peptides has effecter functions expedited by Aplastic anemia; PNH, Paroxysmal nocturnal hemoglobinuria; AIMF, Autoimmune fi myelofibrosis; PBMC, Peripheral Blood Mononuclear Cells. their interactions with the speci c cell surface receptors. C3a and * Corresponding author. University School of Biotechnology, Guru Gobind Singh C5a are endowed with strong chemotactic and anaphylactic prop- Indraprastha University, Sector16c, Dwarka, New Delhi 110019, India. erties, whereas C3b and C4b are opsonins. In addition, C5b gets E-mail addresses: [email protected] (N. Das), [email protected] assembled with C6-9 to form a terminal complement complex C5b- (D. Anand), [email protected], [email protected] (B. Biswas), 6-7-8-9(n) also known as the membrane attack complex (MAC). [email protected] (D. Kumari), [email protected] (M. Gandhi). https://doi.org/10.1016/j.cmrp.2019.07.013 2352-0817/© 2019 Sir Ganga Ram Hospital. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved. N. Das et al. / Current Medicine Research and Practice 9 (2019) 182e188 183 Fig. 1. (a) The complement cascade and activation pathways.1 (b) Inhibition of MAC assembly by CD59.20 MAC, membrane attack complex. MAC forms a pore in the microbial membranes on which it got Here is a brief review on the membrane complement regulatory assembled after the cascade activation. protein CD59 and its association with the systemic autoimmune The system is the first line of defense against invading disorders RA and SLE. pathogens, but activation, if goes unabated, leads to severe in- flammatory reactions and self-tissue injury because of the 2. CD59 (protectin/membrane inhibitor of reactive lysis/HRF- bystander or targeted effects of the MAC and the inflammatory 20/MACIF) peptides. In normal health, the self-injury by complement activation re- CD59 is a membrane-bound regulator of the C cascade.2 In mains insignificant because of the very stringent control effected by humans, CD59 is broadly expressed in the cell surface of different soluble and cell surface membrane complement regulatory proteins. tissues except erythrocytes. A soluble truncated form of CD59 is In autoimmune inflammatory disorders, exaggerated activation present in plasma and other body fluids.3 of the complement cascade had been evidenced. Studies are in progress to determine the role of complement 2.1. Structure of CD59 regulatory proteins in these diseases and also to explore their po- tential as disease markers and therapeutic targets. CD59 is an 18- to 20-kDa molecular-weight glyco- A set of complement regulatory proteins such as complement sylphosphatidylinositol (GPI)eanchored glycoprotein. The protein receptor 1 (CR1 or CD35), factor H (fH), decay-accelerating factor consists of 103 amino acid residues, with the first 25 amino acids (DAF or CD55), membrane cofactor protein (MCP or CD46), and constituting the signal sequence and the final 26 amino acids protectin (CD59) have been shown to be associated with the forming the GPI anchor. It has a single N-glycosylation site (N18 in pathogenesis of rheumatoid arthritis (RA) and systemic lupus ery- human CD59) and several potential O-glycosylation sites. This 1 thematosus (SLE). structure is characterized as a single cysteine-rich domain, having a 184 N. Das et al. / Current Medicine Research and Practice 9 (2019) 182e188 þ hydrophobic core with three loops and a small fourth loop, which is upregulation of CD59 on activated CD4 T cells which served to helical.4 The helical loop is made of two antiparallel beta sheets, downmodulate their activity in response to polyclonal and Ag- and the other three loops are three antiparallel beta sheets, which specific stimulation.21 Thus, CD59 is suggested to have a regulato- form the core. Connecting each of these loops are five disulphide- ry effect on T cells. In addition, CD59 is endowed with several bonded cysteine pairs. pleotropic functions. The soluble CD59 derived from urine does not possess an intact GPI anchor, is unable to insert into cells, and is consequently a poor 3.3. Functions of CD59 MAC inhibitor. In contrast, soluble CD59 from amniotic fluid, seminal plasma, and cerebrospinal fluid retains its GPI anchor, can Alternative roles of CD59 interacting with different proposed incorporate into cell membranes, and is an efficient MAC inhibitor.5 ligands are depicted in Fig. 2.22 Human CD59 is closely related to mouse Ly6 antigen.6 The hu- man gene gives rise to more than 4 different mRNA molecules, 1. The complement regulator CD59 has a major protective role which are generated by alternative polyadenylation.7 against autolysis of cells and tissues by the complement system. The gene for CD59 is localized on region p14-p13 of the short 2. CD59 localized in lipid raft as glycosylphosphatidylinositol arm of chromosome 11.8 The CD59 gene consists of 4 exons. The (GPI)-anchored protein helps in maintaining the stability of lipid first exon is untranslated, the second encodes the hydrophobic raft in various cell types. leader sequence of the protein, the third exon encodes the N-ter- 3. CD59 as another ligand for CD2 induces signal transduction minal portion of the mature protein, and the fourth exon encodes pathway in T-cell activation. the remainder of the mature protein including the GPI anchor 4. It is also involved in endocytosis of CD59-C9 complex by attachment in the plasma membrane. signaling the cells. 5. CD59 mediates the attenuation of angiogenesis by preventing 2.2. Expression of CD59 the lysis of newly grown blood vessels by complement cascade. 6. CD59 through complement-independent role transduces the CD59 is widely expressed in human cells and tissues. It is pre- lipopolysaccharide (LPS) signal into the nucleus via Nuclear sent on all circulating cells9, endothelial cells10,