Klitgaardmacdonald5194

ious disease, cancer, autoimmunity, and allergies.Acute rheumatic fever (ARF) is caused by an autoimmune response to throat infection with Streptococcus pyogenes in individuals who present some susceptibility genes. Rheumatic heart disease (RHD) is the major sequela and can cause heart failure and premature mortality. The disease is mediated by humoral and cellular immune responses. In this review, we present the major events that can trigger heart lesions.Immunity in infants and young children must tolerate a myriad of new antigens that the newborn encounters after birth. CA-074 methyl ester We dedicated many years to defying the innate and adaptive mononuclear cell repertoire in pediatric subjects to conclude that immune regulation differs in children and adults and dominates immune functions in babies.This brief review is written in memory of Eli Sercarz, a colleague who among many achievements, pioneered and revitalized early-life immunity, a field that is of high relevance to child health. For a long time, the neonatal stage was viewed as a window during which exposure to antigen (Ag) induces immune tolerance. In early 1990, however, it was discovered that the newborn mouse given Ag on the day of birth develops immunity when challenged later with the same Ag. But, these secondary responses displayed a deficit in T-helper (Th)1 cells and excess Th2 lymphocytes. Such discoveries explain the perceived tolerance of Ags given at the neonatal stage and correlate the paucity of effective neonatal vaccines and vulnerability to allergic reactions. Analyzing the mechanisms underlying neonatal Th1 cell deficits revealed a complex developmental interaction between Ag-presenting cells and the cytokines that they produced. This culminated into limited interleukin (IL)-12 in the environment and up-regulation of IL-13Rα1 expression and its association with IL-4Rα on the surface of Th1 cells. After Ag re-exposure, Th2 cells produce IL-4 and -13. Both bind to the heteroreceptor on Th1 cell surfaces and trigger their death. Usually, cytokines promote growth of T cells, but in this case IL-4 and -13 stimulate production of interferon regulatory factor 1 (IRF-1). IRF-1 translocates from nucleus to cytoplasm and stimulates apoptotic machinery that terminates Th1 cells. This suggests that vaccine formulations that could elevate IL-12 production are likely to counter IL-13Rα1 expression, preserve Th1 cells, and potentiate vaccine efficacy in neonates.Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation in which the body does not reject the organ after discontinuing immunosuppression for at least a year. We revisited the data generated by The Brazilian Multicenter Study on Operational Tolerance involving different conceptual fields - antigen-specific cytokine response, immune cell numbers and repertoire, signaling pathways, and epigenetics. We integrated our data to pave the way to systems biology thinking and harness debate on potential mechanisms in OT. We present original data on systems biology in OT, connecting potential mechanistic players. Using bioinformatics, we identified three dominant features that discriminate OT from its opposing clinical outcome, chronic rejection (CR). The OT-CR discriminative molecules were FOXP3, GATA3 and STAT6, each corresponding to a differential profile (1) In FOXP3, OT presents preserved regulatory T cell (Treg) numbers but decreased numbers in CR; (2) in GATA3, increased expression is seen in OT; and (3) in STAT6, decreased monocyte activation is seen in OT. With these variables, we built molecular networks to identify interactions related to OT versus CR. Our first systems biology endeavor gave rise to novel potentially relevant interconnected players in OT mechanisms FOXP3 connecting to interleukin-9 (IL-9) and IL-35 signaling, suggesting their immunoregulatory involvement in OT. Likewise, GATA3/FOXP3 interactions incrementing/stabilizing FOXP3 transcription suggest participation in keeping healthy FOXP3+ Tregs in OT. We envision that systems biology thinking will greatly contribute to advancing knowledge in human transplantation tolerance in an interactive perspective.Ample evidence exists for activation of invariant natural killer T (iNKT) cells in a sterile manner by endogenous ligands or microbial antigens from the commensal flora, indicating that iNKT cells are not truly self-tolerant. Their controlled autoreactivity state is disturbed in many types of sterile inflammatory disease, resulting in their central role in modulating autoimmune responses. This review focuses on sterile iNKT-cell responses that are initiated by metabolic triggers, such as obesity-associated inflammation and fatty liver disease, as a manifestation of metabolic disease and dyslipidemia, as well as ischemia reperfusion injuries and sickle cell disease, characterized by acute lack of oxygen and oxidative stress response on reperfusion. In the intestine, inflammation and iNKT-cell response type are shaped by the microbiome as an extended "self". Disease- and organ-specific differences in iNKT-cell response type are summarized and help to define common pathways that shape iNKT-cell responses in the absence of exogenous antigen.Like all of us, cells proceed through stages of life. In this whimsical review, aspects of several such stages, including birth, growth, aging, death, and "afterlife," are considered, with a special emphasis on cells of the immune system. Discussed along the way are asymmetric division of activated, naive cluster of differentiation 8+ T cells, c-Myc and polyamines in lymphocyte function and aging, cell survival after induction of cell death pathways, cell death consequences, and clearance of dead cells from surrounding tissues. This is offered in memory of the unique and wonderful Dr. Eli Sercarz.Rituximab (a chimeric anti-CD20 monoclonal antibody [mAb]) was the first U.S. Food and Drug Administration- approved therapeutic antibody for non-Hodgkin's lymphomas (NHLs). Although initially monotherapy treatments with anti-CD20 mAb were partially effective clinically, its combination with a cocktail of chemotherapeutic drugs (R-CHOP) resulted in significant improvement of clinical responses and progression free survivals. Several mechanisms have been reported on the underlying mechanisms of the activities of anti-CD20 mAbs; those consisted of ADCC, CDC, PCD, and inhibition of intracellular survival signaling pathways (leading to sensitization to both chemo and immunotherapeutic drugs). Such mechanisms share in common the pleiotropic effects of nitric oxide (NO) donors' treatment of B-NHL cells, including the inhibition of intracellular survival/anti-apoptotic pathways and the reversal of resistance of chemo-immunotherapeutic drugs. This review describes briefly both the mechanisms of activity of anti-CD20 antibodies and NO donors and establishes the presence of cell signaling cross-talks.