The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias
Introduction
Discovered over a century ago, the complement system has been traditionally envisioned as a cascade of soluble serum proteins whose sequential activation eventually results in cell lysis. Additionally, several by-products of the activation of such proteins are capable to recruit inflammatory cells [1]. The highly efficient defensive role of complement in infectious diseases has never been questioned, but its capability to mediate damage to self in several instances is also recognized [2], [3]. Whether activated by antibodies directed to self or non-self antigens, or by means of other triggering substances, the explosive and unspecific activation of the common final pathway of the complement system might be harmful to healthy neighboring cells and tissues in a process that has been known as the damage to the “innocent bystander”. To counteract or contain self-damage, the complement system has many regulators, both soluble and membrane-bound, which appear to be more or less efficient in distinct conditions. Normal cells resist complement-mediated lysis, by several mechanisms comprising a self-recognition system [4]. This system is composed primarily of specific membrane-bound proteins such as decay accelerating factor (DAF, CD55) [5], membrane cofactor protein (CD46) [6], and homologous restriction factor (membrane inhibitor of reactive lysis [MIRL], protectin, CD59) [7]. Complement receptor type 1 (CD35) is also involved in the regulation of C3 fragment deposition [8]. This review focuses on CD55 and CD59, and their possible pathogenic role in autoimmune hemocytopenias.
Section snippets
CD55
Also named DAF, CD55 is a single chain, glycosylphosphatidylinositol (GPI)-anchored, type I cell surface protein. It inhibits formation of the C3 convertases through binding to C3b and C4b. It also binds the alternate pathway convertase C3bBb, the classical pathway convertase and C4b2a to accelerate their decay. Inasmuch as it works optimally with human complement, while not with complement of other species, it is commonly said to show homologous restriction [9]. The function of CD55 is to
CD59
Also called MIRL or protectin, CD59 is a single chain, GPI-anchored cell surface protein structurally homologous to snake venom neurotoxins [17], which is broadly expressed on cells from all tissues. Its expression on erythrocytes is important for their survival upon homologous complement activation [18]. CD59 protects cells from complement mediated lysis through binding C9, inhibiting its incorporation into the C5b-9 complex and preventing the terminal polymerization of the membrane attack
Paroxysmal nocturnal hemoglobinuria, the original link between complement regulators and human disease
Paroxysmal nocturnal hemoglobinuria (PNH) is an ancient but accurate term to describe the clinical manifestation of red cell lysis and release of hemoglobin into the urine that is manifested most prominently by dark-colored urine in the morning. The term “nocturnal” refers to the belief that the hemolytic episode was triggered by acidosis during sleep and activates complement to hemolyse an abnormally susceptible red cell membrane. However, this last observation has been disproved with time,
Autoimmune hemolytic anemia
Three years ago we published what seems to be the first description of the acquired deficiency of complement regulators in humans [24]. In this study, we evaluated the membrane density of CD55 and CD59 in erythrocytes from patients with autoimmune hemolytic anemia (AIHA) and its possible relation with the presence of anti-phospholipid antibodies. We studied 19 patients with AIHA, eleven of which fulfilled at least four of the American College of Rheumatology diagnostic criteria for systemic
Concluding remarks
When we initiated this series of studies, we hypothesized that autoantibodies, most likely those bearing reactivity towards phospholipids, could be responsible for the decreased expression of complement regulatory proteins CD55 and CD59. Antibodies with phospholipid reactivity might hinder the binding of the proteins to the GPI anchorage, or shed the GPI-protein complexes from the cell surface of erythrocytes, platelets and lymphocytes. In the case of lymphocytes, internalization of
Take-home messages
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CD55 and CD59 are glycosylphosphatidylinositol (GPI)-anchored proteins with complement inhibitory properties. Congenital deficiency of the expression of these proteins, as in paroxysmal nocturnal hemoglobinuria, lead to augmented sensitivity to complement mediated lysis, which results in hemolytic anemia.
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Patients with autoimmune hemolytic anemia, autoimmune thrombocytopenia, and with systemic lupus erythematosus with lymphopenia, have an acquired deficiency of CD55 and CD59 on the involved
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