This review describes my journey in Eli Sercarz's laboratory and my sincere indebtness of my academic career which was the result of his input and care.Autoimmunity results from the breakdown of immune tolerance to defined target self antigens. Like any foreign antigen, a self antigen is continuously processed by antigen-presenting cells (APCs) and its epitopes are displayed by the major histocompatibility complex on the cell surface (dominant epitopes). However, this self antigen fails to induce a T cell response as the T cells against its dominant epitopes have been purged in the thymus during negative selection. In contrast, the T cells against poorly processed (cryptic) self epitopes escape tolerance induction in the thymus and make it to the periphery. Such T cells are generally harmless as their cognate epitopes in the periphery are not presented efficiently. But, under conditions of inflammation and immune activation, previously cryptic epitopes can be revealed on the APC surface for activation of ambient T cells. This can initiate autoimmunity in individuals who are susceptible owing to their genetic and environmental constellation. Subsequent waves of enhanced processing of other epitopes on the same or different self antigens then cause "diversification" or "spreading" of the initial T cell response, resulting in propagation of autoimmunity. However, depending on the disease process and the self antigen involved, "epitope spreading" may instead contribute to natural regression of autoimmunity. This landmark conceptual framework developed by Eli Sercarz and his team ties together determinant hierarchy, selection of epitope-specific T cells, and the induction/progression of autoimmunity. I am extremely fortunate to have worked with Eli and to have been a part of this fascinating research endeavor.The physicochemical properties of an antigen (Ag) influence the type, specificity, as well as duration of emerging immune responses. Like immune responses arising to nominal protein Ags, reactivities to protozoan parasites, Plasmodium falciparum and P. berghei, the causative agents of human and mouse malaria, respectively, are shaped by the form of the parasite. While repeated natural exposures to infectious Plasmodium sporozoites (spzs) typically induce malaria, immunizations with radiation or genetically attenuated forms of Plasmodium spzs induce sterile and durable protective immunity. The immune mechanisms that are responsible for these diametrically opposite outcomes are still not well understood. It has been observed that infectious spzs engage in mechanisms that evade immune recognition and thus prevent protective immune responses from occurring. The responses that develop are characteristic of anti-disease immunity; acquisition of protective immunity against infection is a prolonged process, and it decays once exposure to the parasite ceases. In contrast, repeated exposures to attenuated Plasmodium spzs induce antibodies and CD4 T cells directed primarily to the spz surface Ags and effector and memory CD8 T cells that localize in the liver and are specific for Plasmodium liver-stage Ags. Understanding the precise mechanisms, including early interactions between the spzs and Ag-presenting cells that lead to the manner of Ag processing and presentation, are of key importance as such information would substantially contribute to the successful development of malaria vaccine.In humans and mice, susceptibility to infections and autoimmunity increases with age due to age-associated changes in innate and adaptive immune responses. Aged innate cells are also less active, leading to decreased naive T- and B-cell responses. Aging innate cells contribute to an overall heightened inflammatory environment. Naive T and B cells undergo cell-intrinsic age-related changes that result in reduced effector and memory responses. However, previously established B- and T-cell memory responses persist with age. One dramatic change is the appearance of a newly recognized population of age-associated B cells (ABCs) that has a unique cluster of differentiation (CD)21-CD23- phenotype. Here, we discuss the discovery and origins of the naive phenotype immunoglobulin (Ig)D+ versus activated CD11c+T-bet+ ABCs, with a focus on protective and pathogenic properties. In humans and mice, antigen-experienced CD11c+T-bet+ ABCs increase with autoimmunity and appear in response to bacterial and viral infections. However, our analyses indicate that CD21-CD23- ABCs include a resting, naive, progenitor ABC population that expresses IgD. Similar to generation of CD11c+T-bet+ ABCs, naive ABC response to pathogens depends on toll-like receptor stimulation, making this a key feature of ABC activation. Here, we put forward a potential developmental map of distinct subsets from putative naive ABCs. We suggest that defining signals that can harness the naive ABC response may contribute to protection against pathogens in the elderly. CD11c+T-bet+ ABCs may be useful targets for therapeutic strategies to counter autoimmunity.Posttranslational modifications (PTMs) such as protein arginine methylation are involved in the regulation of diverse cellular processes such as epigenetic modifications, DNA damage response (DDR), RNA processing, signal transduction, and immune responses. Protein methyltransferases (PRMTs), which mediate arginine methylation, have been studied because of their dysregulation in several diseases. PRMT5, a type II arginine methyltransferase is relevant to cancer progression. Inhibition/deletion of PRMT5 augments tumor immunity by modulating Tip60 histone acetyltransferase activity and FOXP3 levels and limits the inhibitory function of T regulatory (Treg) cells, providing an approach to treat human cancers in an effective and exclusive manner. The activity of PRMT5 is regulated at various levels involving interaction with regulatory proteins, PTM modifications and noncoding RNA. Several PRMT5 inhibitors have been developed and are undergoing clinical trials or are in the preclinical phases. The current review concerns the regulation, biological functions, and therapeutic approaches for targeting PRMT5 with a focus on its role in tumor immunity.  https://www.selleckchem.com/products/AZD2281(Olaparib).html  Critically, PRMT5 regulates the expression of Tip60 which we have shown is needed for FOXP3 regulatory interactions with DNA.