ABSTRACT
Without adaptive immunity, invertebrates have evolved innate immune systems that react to antigens on the surfaces of pathogens. These defense mechanisms are included in horseshoe crab hemocytes' cellular responses to pathogens. Secretory granules, large (L) and small (S), are found on hemocytes. Once the invasion of pathogens is present, these granules release their contents through exocytosis. Recent data in biochemistry and immunology on the granular constituents of granule-specific proteins are stored in large and small granules which are involved in the cell-mediated immune response. L-granules contain most clotting proteins, which are necessary for hemolymph coagulation. They also include tachylectins;protease inhibitors, such as cystatin and serpins;and anti-lipopolysaccharide (LPS) factors, which bind to LPS and agglutinate bacteria. Big defensin, tachycitin, tachystatin, and tachyplesins are some of the essential cysteine-rich proteins in S-granules. These granules also contain tachycitin and tachystatins, which can agglutinate bacteria. These proteins in granules and hemolymph act synergistically to fight infections. These biomolecules are antimicrobial and antibacterial, enabling them to be drug resistant. This review is aimed at explaining the biomolecules identified in the horseshoe crab's hemolymph and their application scopes in the pharmaceutical and biotechnology sectors.Copyright © 2022 Md. Ashrafuzzaman et al.
ABSTRACT
Patients receiving renal replacement therapy (RRT) in the form of maintenance hemodialysis (MHD) belong to a group of particularly high risk of infection and the course of COVID-19. The new coronavirus infection also has a great impact on long-term outcomes. Material(s) and Method(s): A retrospective observational study included 510 patients on MHD, hospitalized from April 1, 2020 to April 01, 2021. The outcome of hospitalization was chosen as the primary endpoint of the study: discharge or 28-day mortality. Death within 6 months after discharge and the development of complications related to COVID-19 during this period were considered as secondary endpoints. Data collection was carried out by analyzing electronic and archival medical records. Quantitative variables: age, duration of hospitalization, days in the intensive care unit, laboratory blood parameters: the level of D-Dimer, Glucose, Interleukin-6, Procalcitonin, Lymphocytes and Platelets, CRP, CPK, CPK-MB, LDH, Fibrinogen, Ferritin. Qualitative indicators: gender, ventilator, ARDS, the presence of diabetes, the presence of obesity, the presence of complications: cardiovascular, gastrointestinal, septic, macrothrombotic, stage of pneumonia. To identify statistically significant predictors of the risk of an event, the odds ratio (OR) method was used. Result(s): average age 57.8+/-14 years, men - 59.5%, average bed day 17.6+/-10.6 days. In concomitant diseases, diabetes mellitus was indicated in 24% of patients, obesity was registered in 4.3% of patients. Hospital mortality (28-day) in the total cohort of follow-up was 16.05%, in total with out-of-hospital mortality of 22%. Mortality in intensive care reached 62.7%, on ventilator more than 86%, with ARDS 94.3%. No statistical significance was revealed by gender and the presence of diabetes mellitus (DM) in concomitant diseases. When comparing short-term outcomes, the age groups over 65 differed statistically. The following laboratory blood parameters showed a significant difference (P<0.001): D-Dimer, Glucose, IL-6 lymphocytes, Leukocytes, Neutrophils, Platelets, LDH, Ferritin. The following odds ratios (OR) were obtained: ARDS (OR 143.78;95% CI 33.4-616.2;p=0.0001), on ventilator (OR 57.96;95% CI 23.1-144.5;p=0.0001), the presence of septic complications (OR 26.4;95% CI 13.8-50;p=0.0001), the course of the disease is defined as severe (OR 25;95% CI 12.9-48.2;p=0.0001), the course of the disease is defined as complicated (OR 11.6;95% CI 6.8-19.7;p=0.0001), the presence of gastrointestinal complications (OR 6.5;95% CI 2.28-18.4;p=0.0007), the presence of obesity (OR 2.57;95% CI 1.0-6.5;p=0.039). Mortality of patients receiving two main treatment regimens T-1 and T-2 did not differ (15.8% vs 15.7%). Significant differences (p=0.0001) appeared when compared with the T-0 and T-4 schemes, in which mortality was recorded at 8.8% and 85.7%, respectively. When comparing long-term outcomes, the analysis did not reveal statistical significance by gender. The statistical difference was noted by age. Among laboratory indicators, the PCT level was higher in survivors with complications. A significant difference among all survivors and deceased (P<0.001) was shown by: D-Dimer, blood glucose level, IL-6, CRP. The highest OR was calculated for the following indicators: the presence of gastrointestinal complications (OR 7.7;95% CI 1.0-57.7;p=0.03), the initial LDH blood level of 622 units /l (OR 4.7;95% CI 1.63-13.63;p=0.0086), the course of the disease defined as complicated (OR 4.05;95% 1.97-8.33;p=0.003), the course of the disease is defined as severe (OR 2.4;95% CI 1.17-5.0;p=0.03). Conclusion(s): gastrointestinal complications had the greatest impact on unfavorable short-term and long-term outcomes in patients on programmed hemodialysis. In relation to such laboratory markers as Ferritin, CRH, LDH, threshold values of a significant increase in the chances characteristic of dialysis patients were obtained. During the first year of the epidemic, therapy remained largely supportive and aimed at prevent ng complications, the main isolated treatment regimens showed no significant differences in the impact on the outcomes of COVID-19.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.
ABSTRACT
The proceedings contain 17 papers. The topics discussed include: a helix-swapped C3d dimer mediated by immune evasion protein Sbi hints at a novel s. aureus complement modulation strategy;the role of factor H in macrophages;an antibody targeting complement factor H causes anti-tumor immunity through B-cell activation;C5aR2 deficiency ameliorates inflammation in antibody transfer experimental epidermolysis Bullosa Acquisita and suggests regulating action on the decisive C5a receptor 1;clinical and biomarker characteristics of patients with C3G enrolled in two phase 2 studies investigating the factor D inhibitor Danicopan;perceiver-based machine learning diagnosis of TMA in renal biopsies;and recurrence of atypical hemolytic uremic syndrome After COVID-19 vaccination.
ABSTRACT
SARS-CoV-2 infection and vaccination have raised concerns in paroxysmal nocturnal hemoglobinuria (PNH). In fact, PNH patients carry an increased infectious risk secondary to complement inhibition treatment or associated bone marrow failure (BMF), and may therefore benefit from preventive strategies such as vaccinations. On the contrary, vaccines can be numbered among inflammatory complement amplifiers (e.g., infections, traumas, surgery), potentially triggering a disease exacerbation. In PNH patients on complement inhibitors, this phenomenon has been defined pharmacodynamic breakthrough hemolysis (BTH). Based on isolated reports of BTH following SARS-CoV-2 vaccines, we conducted a survey among 5 Italian reference centers to evaluate complications and BTH occurrence in PNH patients who completed the SARS-CoV-2 vaccination schedule from January, 2 2021 until the time of writing. Adverse events, hematologic and hemolytic parameters were recorded within 7-10 days before and after each dose of vaccine. A total of 67 patients (females/males 43/24, median age 47.6 years, range 21-90.5) were eligible for the analysis. According to the International PNH Interest Group classification, 45 patients suffered from hemolytic PNH, 20 from PNH in the context of BMF syndromes (aplastic anemia or myelodysplastic syndrome), and 2 from subclinical PNH. Fifty-five subjects (82%) were on regular complement inhibition therapy, i.e., eculizumab (N=35), ravulizumab (N=13), subcutaneous anti-C5 (N=3), anti-factor B (N=2) and ravulizumab + anti-factor D combination (N=2). Vaccines (Comirnaty/Pfizer-BioNTech N=53, mRNA-1273/Moderna N=12, and ChAdOx1 nCov-19/AstraZeneca N=2) were complessively well-tolerated, with 3 non-hematologic adverse events after the first dose (2 fever and 1 exercise-induced tachycardia, grade 1 according to CTCAE v5.0) and 2 after the second one (fever, accompanied by vomit in one patient, grade 1). During the observation period, 3 BTH and 1 hemolytic exacerbation were recorded (5.9% of patients), as detailed in Table 1. The most severe episode occurred in a young woman (Patient 3) on subcutaneous ravulizumab who experienced a hemoglobin (Hb) drop >2 g/dL, marked clinical signs of intravascular hemolysis and lactate dehydrogenase (LDH) increase >1.5 x upper limit of normal (ULN) from baseline, which is considered a clinical BTH according to the criteria proposed by the Severe Aplastic Anemia Working Party of the European group for Bone Marrow Transplantation. The patient required hospitalization for additional treatment with recombinant erythropoietin and anti-thombotic/bacterial prophylaxis. The second more severe BTH was registered in a male patient (Patient 1) on oral anti-factor B who experienced a Hb drop >2 g/dL without an overt hemolytic flare, and required hospitalization for intravenous antibiotic therapy (concomitant urinary tract infection). The remaining two patients experienced a subclinical BTH (Patient 2) and a hemolytic flare (Patient 4, not on complement inhibition). On the whole, a median delta variation from usual values of Hb and LDH of -25% (range -26+3%) and +80% (+18+105%) were observed, respectively. Of note, 3 episodes occurred after the second dose of vaccine, generally within 24-48 hours. Anti-complement drugs were not modified/discontinued in any of the 3 patients on regular treatment. Patients not experiencing BTH (94.1%) showed stable hematologic parameters after the first dose (Hb/LDH median delta variations from baseline -1%/+1%, range -14+12%/-32+40%) and the second dose of vaccine (Hb/LDH median delta variations from baseline +1%/0%, range -18+47%/-76+41%). Of note, 4 patients with a previous SARS-CoV-2 infection completed the vaccination without any complication/PNH exacerbation. In conclusion, this survey shows that BTH/hemolytic flares following SARS-CoV-2 vaccines are observed in about 6% of PNH patients, may be clinically relevant but manageable, and should not discourage vaccination. BTH has been registered mostly few days after the second dose of vaccine, suggesting a “boosterâ effect favoring a higher inflammatory response. Watchful clinical and laboratory monitoring is advised, in order to promptly recognize severe hemolytic flares in both treated and naïve patients. [Formula presented] Disclosures: Fattizzo: Novartis: Speakers Bureau;Kira: Speakers Bureau;Alexion: Speakers Bureau;Annexon: Consultancy;Momenta: Honoraria, Speakers Bureau;Apellis: Speakers Bureau;Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sica: Jazz Pharma: Consultancy;Alexion: Consultancy. Barcellini: Novartis: Other: Invited speaker, Research Funding;Agios: Membership on an entity's Board of Directors or advisory committees;Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Other: Invited speaker, Research Funding;Bioverativ: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.