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Gangliosides are structurally and functionally polymorphic sialic acid containing glycosphingolipids that are widely distributed in the human body. They play important roles in protecting us against immune attacks, yet they can become targets for autoimmunity and act as receptors for microbes, like the influenza viruses, and toxins, such as the cholera toxin. The expression patterns of gangliosides vary in different tissues, during different life periods, as well as in different animals. Antibodies against gangliosides (AGA) can target immune attack e.g., against neuronal cells and neutralize their complement inhibitory activity. AGAs are important especially in acquired demyelinating immune-mediated neuropathies, like Guillain–Barré syndrome (GBS) and its variant, the Miller–Fisher syndrome (MFS). They can emerge in response to different microbial agents and immunological insults. Thereby, they can be involved in a variety of diseases. In addition, antibodies against GM3 were found in the sera of patients vaccinated with Pandemrix® , who developed secondary narcolepsy, strongly supporting the autoimmune etiology of the disease.

The functions of pentraxins, like C-reactive protein (CRP), serum amyloid protein P (SAP) and pentraxin-3 (PTX3), are to coordinate spatially and temporally targeted clearance of injured tissue components, to protect against infections and to regulate related inflammation together with the complement system. For this, pentraxins have a dual relationship with the complement system. Initially, after a focused binding to their targets, e.g., exposed phospholipids or cholesterol in the injured tissue area, or microbial components, the pentraxins activate complement by binding its first component C1q. However, the emerging inflammation needs to be limited to the target area. Therefore, pentraxins inhibit complement at the C3b stage to prevent excessive damage. The complement inhibitory functions of pentraxins are based on their ability to interact with complement inhibitors C4bp or factor H (FH). C4bp binds to SAP, while FH binds to both CRP and PTX3. FH promotes opsonophagocytosis through inactivation of C3b to iC3b, and inhibits AP activity thus preventing formation of the C5a anaphylatoxin and the complement membrane attack complex (MAC). Monitoring CRP levels gives important clinical information about the extent of tissue damage and severity of infections. CRP is a valuable marker for distinguishing bacterial infections from viral infections. Disturbances in the functions and interactions of pentraxins and complement are also involved in a number of human diseases. This review will summarize what is currently known about the FH family proteins and pentraxins that interact with FH. Furthermore, we will discuss diseases, where interactions between these molecules may play a role.

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.

With that, Peter said that we can do whatever we want. [...]it was sent to J. Exp. Med., where it was published. On the other the hand, he seemingly enjoyed the aristocratic traditions of the United Kingdom, life at the Christ’s College, where he occasionally invited his guests for a High Table Dinner and a glass of sherry afterwards. Conflicts of Interest The author declares no conflict of interest.

Complement-mediated inflammation or dysregulation in lipid metabolism are associated with the pathogenesis of several diseases. These include age-related macular degeneration (AMD), C3 glomerulonephritis (C3GN), dense deposit disease (DDD), atherosclerosis, and Alzheimer’s disease (AD). In all these diseases, formation of characteristic lipid-rich deposits is evident. Here, we will discuss molecular mechanisms whereby dysfunction of complement, and especially of its key regulator factor H, could be involved in lipid accumulation and related inflammation. The genetic associations to factor H polymorphisms, the role of factor H in the resolution of inflammation in lipid-rich deposits, modification of macrophage functions, and complement-mediated clearance of apoptotic and damaged cells indicate that the function of factor H is crucial in limiting inflammation in these diseases.

Treatment-related toxicity remains a challenge in pediatric hematopoietic stem cell transplantation (HSCT). In this prospective, single-center study we studied activation of the complement system peri- and post-transplant through plasma C3a and SC5b-9. We also studied acute adverse events and key vascular complications and analyzed their possible relationship to complement activation. Out of 42 patients, 39 (92.9%) had at least one adverse event (grade 2–4) during the first 100 days post-transplant, and 23 (54.8%) at least one severe (grade 3 or 4) event. We identified a total of 4/42 (9.5%) patients with capillary leak syndrome (CLS), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). 50% of the patients with endotheliopathy died of toxicity. Complement activation was assessed in 26 patients. HSCT was accompanied with increases in blood C3a, peri-transplant C3a peaked at 30 min and 24 h. During the first 6 months post-transplant ten patients showed at least a 50% elevation in SC5b-9, but this did not clearly correlate with clinical adverse events. One patient with severe TMA had a significant increase in SC5b-9 peaking at 1-month post-transplant at nearly 40 times the pre-transplant level. Terminal complement activation thus appears to be linked only to clinically significant HSCT-TMA.

Epithelial ovarian cancer is the sixth most common malignant neoplasm in women and the leading cause of death from gynecological malignancies in the Western World. The five-year survival rate is 45–48% because of the high frequency of late-stage diagnoses and the development of chemo-resistant disease. To assess the potential of antibodies and complement to kill platinum (Pt)-resistant and Pt-sensitive cell lines, antibodies S2 and Yth53.1 were tested at varying concentrations using high-grade serous ovarian cancer (HGSOC) cells. Cell lysis was quantified after 60 minutes using the impermeant dyes 7-Aminoactinomycin D and Annexin V. The cytotoxic effect of S2 was demonstrated through the activation of the complement and Yth53.1 monoclonal antibody neutralized the membrane attack complex (MAC) inhibitor CD59 and allowed assembly of the MAC. In contrast to Pt-based therapy, we found no evidence that chemo-resistance plays an important role when considering the antibody based therapy for Pt-resistant HGSOC cell lines. Significant killing efficiencies were achieved using antibodies against breast cancer cells (S2) and antibody against CD59 (Yht53.1) regardless whether the cell lines HGSOC (OVCAR-3, OVCAR-8) or CRISPR-Cas9 BRCA2 deleted OVCAR-4 were homologous recombination (HR) deficient or proficient, Pt sensitive or resistant. This work shows a potential towards antibody-based therapy development for Pt-resistant HGSOC.

Treatment-related mortality and morbidity remain a challenge in hematopoietic stem cell transplantation (HSCT). In this retrospective, single-center study, we analyzed endothelial damage as a potential, common denominator and mechanism for the adverse effects. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 pediatric patients with an allogeneic HSCT between 2001 and 2013. The spectrum and frequency of acute adverse events emerging ≤100 days post transplant were graded according to the CTCAE 4.03 and analyzed. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome, veno-occlusive disease/sinusoidal obstruction syndrome or thrombotic microangiopathy. The patients had a poorer overall survival (77% versus 26%, p < 0.001). Nearly one half (56/122, 45.9%) had at least one, severe (grade 3 or 4) adverse event. Patients with vascular complications had more often edema/effusions (p = 0.023), thrombocytopenia (p = 0.001), gastrointestinal bleeding (p < 0.001), acute kidney injury (p < 0.001), ascites (p < 0.001) or bilirubin increase (p = 0.027). These endotheliopathy-related adverse events appeared early post HSCT, varied in their clinical phenotype and predicted a poor outcome. An unrelated donor but not previous exposure to leukemia or irradiation-based conditioning was identified as a risk factor for vascular complications and endotheliopathy.