Natural antibodies of the IgM and IgG isotypes have serine protease activity and are capable of hydrolyzing peptide bonds. The first catalytic antibodies were reported in 1986.Ĭatalytic antibodies are also produced spontaneously (or, naturally) by the immune system in the absence of deliberate immunization. It was not until the development of hybridoma technology, by Kohler and Milstein in 1975, which allows one to produce antigen-specific monoclonal antibodies, that the hypothesis raised by Pauling was confirmed. According to Pauling, if the structure of the antigen-binding site of antibodies were to be produced in a random manner, the antigen-binding site of some of the antibodies might resemble the active site of enzymes and these antibodies might express enzymatic activity. The concept that some antibodies may be endowed with catalytic activity was first proposed by Linus Pauling in the early 1940s. At present, the therapeutic options tend to modulate the response of the host organism to infection by using molecules, such as activated protein C, which have anti-coagulant and anti-inflammatory properties (Bernard et al., 2001). Trials using antibodies to molecules of the inflammation and complement cascades, or anti- endotoxin antibodies, although encouraging in animal models of sepsis, were revealed to be ineffective in human individuals. This is probably the reason why large spectrum anti-inflammatory drugs are inefficient in treating sepsis. The response to infection varies from patient to patient. Immunodepression favors nosocomial infections and delayed mortality, characteristic of severe infections. The first inflammatory phase is followed by a phase of immunodepression, which is secondary to the release of anti-inflammatory cytokines and excessive apoptosis of the cells from the adaptive immune system. The insufficiency in tissue perfusion strengthens the inflammatory reaction, leading ultimately to multi-visceral failure and patient death. The most serious forms of sepsis correlate with an improper innate immune response which induces alterations in vascular tonicity, perturbations in capillary permeability, abnormal activation of coagulation, disseminated microthrombosis, and altered regional circulation. The interaction between PAMPs and TLR activates the nuclear factor kappa B (NF-κB) signaling pathway that leads to the expression of a series of inflammatory molecule-encoding genes, among which tumor necrosis factor alpha ( TNFα) has been shown to play a major role. PAMPs include molecules such as lipopolysaccharide, lipoarabinomanan and peptidoglycan, which are specific to microorganisms and cannot be found in any multicellular organism. This is initiated by the binding of evolutionarily distant and conserved bacterial molecules referred to as pathogen-associated molecular patterns (PAMPs) to specific receptors, among which Toll-like receptors (TLR) are of critical importance. Sepsis occurs as a result of the activation of innate immunity in response to the invasion of the host by pathogenic agents. Septic shock is the most frequent cause of death in intensive care units and is responsible for 20,000 patient deaths per year in France, or, one person every thirty minutes. Serious forms of sepsis (i.e., severe sepsis or septic shock) include organ failure and/or shock that negatively impact the prognosis for patient survival. Sepsis is defined as a systemic inflammatory response syndrome (SIRS), which is secondary to an infection. We propose that the catalytic potential of natural IgG may be the basis for an alternative complementary treatment of sepsis in the future. It remains, however, unclear whether catalytic antibodies play a direct bactericidal role, participate in the control of disseminated microvascular thrombosis, and/or regulate inflammation. We have recently documented that the presence of immunoglobulin G (IgG) in plasma, which has a serine protease-like hydrolytic activity, strongly correlates with survival from sepsis, thus providing the first evidence that hydrolytic antibodies might play a role in recovery from a disease. Although initially perceived as potentially harmful, catalytic antibodies have been proposed as participants in the removal of metabolic wastes and protection against infection. It results from the host’s systemic response to infection, which at times can be deleterious. Sepsis is the leading cause of death in intensive care units. Catalytic antibodies can bind to and destroy factors released during sepsis and may alleviate the pathology. Severe sepsis leads to the powerful activation of innate immune responses, resulting in vascular and circulation crisis. Abstract: Pope John Paul II was reported to have died of multiple organ failure caused by sepsis shock as a consequence of an infection.
0 Comments
Leave a Reply. |