CD55 and CD59 are glycosylphosphatidylinositol-anchored proteins with regulatory properties on the activating cascades of the complement system. This regulation occurs through inhibition of the C3-convertase formation by CD55, and prevention of the terminal polymerization of the membrane attack complex by CD Deficiency in the expression of these proteins can be associated with increased susceptibility to complement-mediated cell death.
Systemic lupus erythematosus patients with hemolytic anemia and lymphopenia seem to have an acquired deficiency of CD55 and CD59 proteins. However, the mechanisms involved in this deficiency and its impact on the clinical manifestation of SLE needs to be further investigated.
CS in mammals has more than 30 serum and cell membrane proteins produced mainly by the liver. However, many cell types, like monocytes, fibroblasts, epithelial and endothelial cells, may also synthesize most components of the complement system. Evidences in the literature suggest that CS can perform an important immunoregulatory function through its role in humoral immunity, 2 T cells immunity modulation, 3 and tolerance regulation for own nuclear antigens.
Activating cascades of the complement system may be initiated through the classic pathway antibody dependent , alternative pathway spontaneous or lectin pathway mediated by mannose-binding lectins pathway. After its activation, fragments generated from complement work modulating humoral and cell reactions, especially chemotaxis and anaphylaxis, through interaction of these activation fragments with cell receptors or through deposition of protein complexes in cell membrane. The classic pathway, a powerful mechanism of humoral immunity, is activated by C1 component interaction with the constant fraction CF of immunoglobulin Ig IgM or IgG complex to antigen antibody-antigen immune complex.
C1 consists of three proteins C1q, C1r, C1s , and for C1 complex activation at least two of its six globular sites should bind to Ig molecules linked to the pathogen. After this binding, C1q suffers a conformation change generating C1r activation and C1s cleavage that can cleave C4 and C2. C4b fragment is bound to the pathogen cell membrane and allows the binding of C2a; the formed C4b2a complex is the C3-convertase of the classic pathway. The alternative pathway is directly activated when there are no antibodies by particles rich in carbohydrates found in the invasive microorganism surface, involving C3b binding found soluble in plasma and other components in the alternative pathway: factor B, factor D and properdin factor P.
Properdin can stable C3bBb complex, which can cleave other C3 molecules.
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Lectin pathway is activated by MBL - mannose-binding lectin, a soluble component in our organism, with carbohydrates found in the target microorganism surface. MBL is a member of calcium-dependent lectins and has a C1q-similar structure. Therefore, the three activation pathways converge to generate proteolytic enzymes, called C3-convertases, that cleave protein C3 in C3a and C3b.
Fragments C3a and C5a are powerful anaphylatoxins. Fragment C5b aggregates with C6 and C7 to form the C5b-7 insertion complex; after this step, the recruitment of C8 and multiple units of C9 in the target cell membrane occurs, forming the MAC - membrane attack complex 13,14 Figure 1. MAC's functional unit is a pore inserted in the phospholipid bilayer that interferes in selective permeability of membrane, allowing water, ions and small molecules to enter to target cell cytosol, leading to its rupture.
Additionally to an effector action against pathogens, the complement has other biological activities in the organism, such as: opsonization and phagocytosis, solubilization and removal of immune complexes and apoptotic cells, interface between innate and adaptative immunity, and proinflammatory action. These effects occur through the binding of activation products to specific membrane receptors found in different types of cells.
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When complement is activated by external antigen-directed antibodies, but also eventually by its own antigens, explosive and uncertain activation of the final common pathway and excessive formation of inflammation may damage tissues and autological cells. In order to protect against or restrain these damages, CS is strongly regulated by soluble substances or cell membrane bound substances. Normal cells, which are resistant to autologous lysis mediated by complement, have a regulatory complement system in cell membrane made of proteins, and the main proteins are CD55, DAF - decay accelerating factor, and CD59, or MIRL - membrane inhibitor of reactive lysis Table 1.
CD55 inhibits formation of new C3- and C5-convertases, preventing C3 and C5 cleavage, additionally to accelerating the preformed enzyme decay. CD55, reviewed in Mikesch et al. It is found in soluble form in plasma, tear fluid, saliva, urine, synovial liquid and liquor. CD55 may also work as an intercellular adhesion binder, interacting with CD97 in leucocytes, and as a receptor for certain virus and microorganisms. CD59, reviewed by Kimberley et al.
Due to its crucial role in preventing damages to the organism itself through inadequate deposition of MAC lithium complex, this protein is widely expressed in most tissues and in all circulating cells.
The pathologic consequence of complement regulatory deficiency found in the membrane was initially observed in paroxysmal nocturnal hemoglobinuria PNH. This acquired hematologic disease was first described in by William Gull, and in by Paul Strubing, as a different form of rare hemolytic anemia, associated with hemoglobinuria during the night. Among GPI-anchored proteins, we find complement regulatory proteins, like CD55, CD59, and CD46 membrane cofactor protein ; and other proteins involved in immune function, 24,25 like receptor FC CD16 in granulocytes and NK cells, lipopolysaccharide CD14 in monocytes, cell adhesion molecule CD58 in all hematopoietic cells, and CD24 in lymphocytes, with still unknown activity.
There are few reports in the literature about the normal expression pattern of these proteins in blood cells. Araten et al. Oelschlaegel et al. Isolated CD55 deficiency in human beings was not associated with intravascular hemolysis or with other evidence of failure in complement regulation. However, isolated CD59 deficiency was associated with signs and symptoms similar to HPN 28 due to the fact that CD59 is a more effective inhibitor in complement, as it blocks the formation of membrane attack complex.
CD55 and CD59 deficiency has been studied in other diseases and correlated with its severity.
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Wang et al. This deficiency causes hemolytic processes mediated by complement similar to those found in HPN. In Isoda et al. Cutoff value obtained for the negative cells ratio in healthy subjects was lower than 0. Resistance of carcinogenic cells to lysis mediated by complement is one of the strategies acquired by these cells, characterizing an obstruction in developing immunotherapies based on antitumor antibodies that fix complement.
We believe that one of the action mechanisms is the signaling and induction of complement-mediated B cell apoptosis. This drug has been more and more used as an efficient and specific treatment, especially in lymphoproliferation B particularly lymphomas and autoimmune diseases.
Recent studies in animal models with autoimmune diseases concurrent with removal of complement regulatory proteins, through addition of monoclonal antibodies or gene deletion, have evaluated the role of CD55 and CD59 in organism cells. Multiple sclerosis MS is among the pathologies studied in this context; this disease attack the central nervous system CNS and is more common in young adults. Its etiology is still unknown, but there is evidence of formation of autoantibodies against antigens in the myelin layer.
In MS, loss of myelin demyelination interferes in pulse transmission, causing varied symptoms of the disease. Mead et al. Antineutrophil cytoplasmic autoantibodies ANCA are cytoplasmatic antiproteins specific for neutrophils and monocytes, and myeloperoxidase and proteinase 3 are the main target antigens in patients with vasculitis and glomerulonephritis. Xiao et al. Matsuo et al. In myasthenia gravis mg , the immune system produces antibodies against nicotinic acetylcholine receptors located in the neuromuscular junction, preventing muscular activation.
It is suggested that the complement system participates in the mg pathology based on the identification of complement activation products in plasma and deposit in the motor plate of patients. Systemic lupus erythematosus SLE is a chronic inflammatory disease that affects especially young women, characterized by attacking multiple organs and presenting changes in the immune response, with the presence of antibodies against proteins in the organism itself.
Autoantibodies against blood cells may cause cell lysis for antibody-dependent cytotoxicity mechanisms, opsonization, apoptosis and receptors blocks, and others. Antibodies produced in autoimmune diseases may connect to cell surface antigens or form immune complexes after binding to circulating antigens.
These immune complexes tend to be deposited in organs, like kidney glomerulus, with subsequent activation of complement system by the classic pathway, damaging tissues. A work published by Miwa et al. These animals presented stressed lymphadenopathy and esplenomegalia, higher levels of anti-chromatin antibodies and more severe dermatitis than controls.
Until today few studies have been carried out about CD55 and CD59 expression profile in lymphocytes and erythrocytes of patients with LES, 67 and no study evaluated expression in granulocytes and monocytes. Richaud-Patin et al. In this study, authors evaluated the presence of IgG and IgM antiphospholipid antibodies and no correlation between these immunoglobulins and the CD55 and CD59 expression was found.
Later, the same authors 42 researched the intensity of CD55 and CD59 expression in T and B lymphocytes in LES patients with and without lymphopenia and showed that cells in patients with lymphopenia presented reduction of CD55 and CD59 expression when compared with controls. Interestingly, they found that, in patients with SLE who did not present lymphopenia, lymphocytes presented a higher intensity of these proteins than controls.
Another finding of this study was that titer of tested autoantibodies anti-SSA, anti-dsDNA and ribosomal anti-P was higher in lymphopenic patients. However, the prevalence of antibody positivity was equal, excepting anti-SSA, which was significantly higher in the group of patients with lymphopenia - findings that corroborate those previously reported in the literature.
In order to evaluate apoptosis in vitro in autoimmune diseases, Tsunoda et al. Arosa et al. Authors suggest that this CD55 and CD59 increase happens to compensate reduced CR1 expression complement regulator in C3- and C5-convertase level and as an attempt of the cell to protect against complement action.
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Acquired deficiency of these proteins in SLE does not seem to be dependent on genetic mutations, as in HPN, and was not correlated with autoantibody production either. On the other hand, it seems that there is an association with the disease activity. Additionally, the role of these proteins in the induction of SLE cytopenias is not very well defined.
However, studies suggest that levels of CD55 and CD59 cell expression below normal provide low protection to exacerbated lysis mediated by complement. Interestingly, cells expressing high levels of these proteins appear to be involved with a mechanism to protect cytolic actions of complement. Walport MJ. First of two parts. N Engl J Med ; 14 MarkedLy impaired humoral immune response in mice deficient in complement receptors 1 and 2. Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat Immunol ;2 8 Carroll MC. The role of complement in B cell activation and tolerance.
Adv Immunol ; Welch TR. Complement in glomerulonephritis. Nat Genet ;31 4 Second of two parts. N Engl J Med ; 15 Activation of the first component of complement.
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Annu Rev Immunol ; Nonimmune activation of the classical complement pathway. Behring Inst Mitt ; 93 Analysis of the interactions between properdin, the third component of complement C3 , and its physiological activation products. Biochem J ; 1 Disorders of the complement system: an overview. Saudi J Kidney Dis Transpl ;13 2 The role of mannose-binding lectin in systemic lupus erythematosus. Clin Rheumatol ;27 4 MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway.
Immunity ;15 1 Complement and innate immunity. Immunopharmacology ;49 Complement in inflammatory tissue damage and disease. Trends in immunology ;23 2 The importance of complement regulation for good health is highlighted by recent work that seems to imply that individuals carrying point mutations or single nucleotide polymorphisms in their genes for factor H may be more susceptible to diseases including atypical hemolytic uremic syndrome ,  dense deposit diseases or membranoproliferative glomrulonephritis type 2 and - most notably because of its prevalence in the elderly - age-related macular degeneration.
Complement control proteins also play a role in malignancy. Complement proteins protect against malignant cells- both by direct complement attack and through initiation of Complement-dependent cytotoxicity , which synergises with specific monoclonal antibody therapies. However, some malignant cells have been shown to have increased expression of membrane-bound complement control proteins, especially CD46, DAF and CD From Wikipedia, the free encyclopedia.
Complement regulatory proteins and autoimmunity.
Three-dimensional structure of a complement control protein module in solution. J Mol Biol 4 : Solution structure of a functionally active fragment of decay-accelerating factor. Structure of complement receptor 2 in complex with its C3d ligand. Science : Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.
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