The recognition of pathogen-associated molecular patterns stimulates the production of proinflammatory cytokines such as tumor necrosis factor , and activates components of the complement cascade (1). inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients’ IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies SCDGF-B might play a role in recovery from a disease. The initial host response to infection relies on cellular and molecular effectors of the innate immune system. The recognition of pathogen-associated molecular patterns stimulates the production of proinflammatory cytokines such as tumor necrosis factor , and activates components of the complement cascade (1). Natural antibodies, which represent the spontaneous repertoire of circulating immunoglobulins in healthy unimmunized individuals, are part of the innate immune system; they promote the clearance of pathogenic substances from the circulation and para-iodoHoechst 33258 prevent pathogen dissemination (2, 3). The inability to regulate para-iodoHoechst 33258 the inflammatory response initiated upon infection leads to severe sepsis that is characterized by widespread microvascular injury and thrombosis, organ ischemia, and dysfunction (4). Catalytic antibodies are immunoglobulins endowed with a capacity to hydrolyze an antigenic substrate. Catalytic antibodies have mostly been reported in diverse pathological states, including autoimmunity, alloimmune and inflammatory disorders, and viral infections (5C9). Although there is evidence supporting a pathogenic role for factor VIII-hydrolyzing antibodies in para-iodoHoechst 33258 inhibitor-positive patients with hemophilia A and for a subset of platelet-fragmenting antibodies in HIV infection (8, 10), the deleterious role of catalytic antibodies in the other disorders remains debated. Catalytic antibodies of the IgG and IgM isotypes are also part of naturally occurring antibodies (11, 12) and are suggested to participate in the removal of metabolic wastes and protect from bacterial infections (13C15). We hypothesized that catalytic antibodies may limit infection and para-iodoHoechst 33258 inflammation in patients with sepsis, and, conversely, that the lack of a catalytic antibody response may hasten pathogenesis. Materials and Methods Patients. Plasma from 34 consecutive patients diagnosed with severe sepsis (9 of 34) or septic shock (25 of 34) for <24 h, was obtained from the Department of Medical Intensive Care, H?pital Cochin, Paris, under approval by the local ethic board on human subject research. Patients were 17C81 years old (median, 53.5 years) with a 16:18 male/female ratio. Seventeen patients had no underlying disease. Twenty-two patients presented with pneumonia, three presented with urosepsis, two presented with osteoarthritis, two presented with intraabdominal infection, two presented with liver abscess, two presented with bloodborn infection, and one presented with meningitis. The simplified acute physiology score II (SAPS II) and the sequential organ failure assessment (SOFA) score were recorded on the day of diagnosis. The median SAPS II was 40.5, and the median SOFA was 7. Twenty-three patients had at least two dysfunctional organs or systems, and 18 required mechanical ventilation. Patients had equal incidence of Gram-positive and -negative infections. All patients received standard medical care and daily clinical and laboratory data were recorded. Ten patients (29.4%) died within the 28 days after admission. The activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined as described (16). aPTT is expressed as the ratio of the scored value to a reference value. PT is expressed as the percentage of the clotting time measured with reference to a standard plasma. Plasma from 10 healthy blood donors and a healing planning of i.v. immunoglobulins (IVIg, ZLB Behring, Bern, Switzerland) had been used as resources of control IgG. Purification of IgG. IgG was isolated from plasma by chromatography on proteins G-Sepharose, accompanied by instant size-exclusion chromatography on the superose-12 column equilibrated with 50 mM Tris, 8 M urea, and 0.02% NaN3, pH 7.7. IgG-containing fractions were dialyzed and pooled against 50 mM Tris/100 mM glycine/0.02% NaN3, pH 7.7, in 4C. The purity of IgG preparations was assessed by immunoblot and SDS/PAGE. IgG was.
The recognition of pathogen-associated molecular patterns stimulates the production of proinflammatory cytokines such as tumor necrosis factor , and activates components of the complement cascade (1)
