Redefining innate natural antibodies as important contributors to anti-tumor immunity

Myeloid, T and NK cells are key players in the elimination phase of cancer immunoediting, also referred to as cancer immunosurveillance. However, the role of B cells and NAbs, which are present prior to the encounter with cognate antigens, has been overlooked. One reason is due to the popular use of a single B cell-deficient mouse model, muMT mice. Cancer models using muMT mice display a similar tumor burden as their WT counterparts. Empirically, we observe what others have previously reported with muMT mice. However, using two other B cell-deficient mouse models (IgHELMD4 and CD19creDTA), we show a 3 to 5-fold increase in tumor burden relative to WT mice. In addition, using an unconventional, non-cancer-related, immune neoantigen model where hypoxic conditions and cell clustering are absent, we provide evidence that B cells and their innate, natural antibodies (NAbs) are critical for the detection and elimination of neoantigen-expressing cells. Finally, we find that muMT mice display anti-tumor immunity because of an unexpected compensatory mechanism consisting of significantly enhanced Type 1 interferon (IFN)-producing plasmacytoid dendritic cells (pDCs), which recruit a substantial number of NK cells to the tumor microenvironment compared to WT mice. Diminishing this compensatory pDC-IFN-NK cell mechanism revealed that muMT mice develop a 3 to 5-fold increase in tumor burden compared to WT mice. In summary, our findings suggest that NAbs are part of an early defense against not only microorganisms and dying cells, but precancerous cells as well.

Natural Antibodies and Alloreactive T Cells Long after Kidney Transplantation

Background. The relationship between circulating effector memory T and B cells long after transplantation and their susceptibility to immunosuppression are unknown. To investigate the impact of antirejection therapy on T cell-B cell coordinated immune responses, we assessed IFN-γ-producing memory cells and natural antibodies (nAbs) that potentially bind to autoantigens on the graft. Methods. Plasma levels of IgG nAbs to malondialdehyde (MDA) were measured in 145 kidney transplant recipients at 5–7 years after transplantation. In 54 of these patients, the number of donor-reactive IFN-γ-producing cells was determined. 35/145 patients experienced rejection, 18 of which occurred within 1 year after transplantation. Results. The number of donor-reactive IFN-γ-producing cells and the levels of nAbs were comparable between rejectors and nonrejectors. The nAbs levels were positively correlated with the number of donor-reactive IFN-γ-producing cells (rs = 0.39, p = 0.004 ). The positive correlation was only observed in rejectors (rs = 0.53, p = 0.003 ; nonrejectors: rs = 0.24, p = 0.23 ). Moreover, we observed that intravenous immune globulin treatment affected the level of nAbs and this effect was found in patients who experienced a late ca-ABMR compared to nonrejectors ( p = 0.008 ). Conclusion. The positive correlation found between alloreactive T cells and nAbs in rejectors suggests an intricate role for both components of the immune response in the rejection process. Treatment with intravenous immune globulin impacted nAbs.

Stress in paradise: effects of elevated corticosterone on immunity and avian malaria resilience in a Hawaiian passerine

Vertebrates confronted with challenging environments often experience an increase in circulating glucocorticoids, which result in morphological, physiological, and behavioral changes that promote survival. However, chronically elevated glucocorticoids can suppress immunity, which may increase susceptibility to disease. Since the introduction of avian malaria to Hawaii a century ago, low elevation populations of Hawaii Amakihi (Chlorodrepanis virens) have undergone strong selection by avian malaria and evolved increased resilience (the ability to recover from infection), while populations at high elevation with few vectors have not undergone selection and remain susceptible. We investigated how experimentally elevated corticosterone affects the ability of high and low elevation male Amakihi to cope with avian malaria by measuring innate immunity, hematocrit, and malaria parasitemia. Corticosterone implants resulted in a decrease in hematocrit in high and low elevation birds but no changes to circulating natural antibodies or leukocytes. Overall, leukocyte count was higher in low than high elevation birds. Malaria infections were detected in a subset of low elevation birds. Infected individuals with corticosterone implants experienced a significant increase in circulating malaria parasites while untreated infected birds did not. Our results suggest that Amakihi innate immunity measured by natural antibodies and leukocytes is not sensitive to changes in corticosterone, and that high circulating corticosterone may reduce the ability of Amakihi to cope with infection via its effects on hematocrit and malaria parasite load. Understanding how glucocorticoids influence a host's ability to cope with introduced diseases provides new insight into the conservation of animals threatened by novel pathogens.

Determination of natural antibodies, beta-hydroxybutyric acid, and non-esterified fatty acid levels in the serum of peripartum Tuj and Hemşin sheep

Background and Aim: Many metabolic and immunological changes occur during the transition period. Innate immunity plays an important role against to infections and natural antibodies (NAb) are important in immunity. This study aims to determine a connection between serum NAb titers, beta-hydroxybutyric acid (BHBA), and non-esterified fatty acid (NEFA) concentrations in Tuj and Hemsin sheep during the peripartum period. Materials and Methods: Serum NAb, BHBA, and NEFA levels were determined from the blood samples collected from Tuj and Hemsin sheep on days 30 and 15 before birth, on the day of birth (day 0), and on days 15 and 30 after birth. Results: NAb titers were found to be higher in Tuj than in Hemsin sheep (p<0.001). No statistically significant difference was found in serum BHBA concentrations of both breeds on all sampling days (p>0.05). The serum NEFA level was lower in Tuj sheep in the last 15 days of pregnancy compared to Hemsin sheep (p<0.05), while no difference was found in samples collected at the other time points. Conclusion: This study indicated that serum NAb titers significantly changed in Tuj and Hemsin sheep during the transition period. Serum BHBA and NEFA concentrations increased during the last stages of pregnancy and decreased after birth. Based on these findings, it is suggested that the immunological status could vary by the breed of sheep or various factors that affect the sheep's metabolic state.

The effect of influenza vaccine immunization on natural antibodies

Natural, polyreactive, low-affinity antibodies are known to play an important role not only in the immediate defense against pathogens, but also in shaping the acquired immune response. On the other hand, antigen specific, high-affinity antibodies can affect the balance of natural antibodies and lead to autoimmune diseases. In this study, we have analyzed the changes that occur in the IgM and IgG pool of natural antibodies after immunization with split or whole virion influenza vaccine. For this purpose, "in-house" developed ELISAs were used. The subjects were divided, according to the vaccination status, into those who had been immunized with the influenza vaccine in previous years and those who had been immunized for the first time. The analysis indicated that the pool of natural antibodies was not impaired by the immunization, evidenced by the lack of changes in any of the groups, and that certain fluctuations were induced in order to maintain the homeostasis of the immune system.