This article is about my amazing immunological journey for over a decade with Eli as an “achaarya” - which in Sanskrit means an enlightened mentor. My training and routine interactions with not only colleagues in Eli’s laboratory, but also other colleagues at UCLA, LIAI, TPIMS and UCSD were instrumental in my continued quest to understand how activation of autoimmune inflammatory cells results in pathology

In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei province, China. The pathogen identified was a novel enveloped RNA beta-coronavirus named SARS-CoV-2. This outbreak has been declared a pandemic by the World Health Organization (WHO), as the continual spread of this deadly and highly infectious virus is a health emergency for all nations in the world

Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation, when 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

The COVID-19 pandemic has imposed urgency to answer numerous questions about the control of viral infections and the dual immune response of protection of and damage to the host, with the purpose of finding specific and efficient treatments and strategies for prevention of infection. The association between severe cases of the disease and overactivation of the immune response has raised the hypotheses

This article is a tribute to Eli Sercarz and draws on his proposal of a hierarchical order of T cell determinants in antigen presentation and T cell activation. Here I revisit the concept of dominance and crypticity in the context of lymphocyte cooperation in the generation of the adaptive immune response with emphasis on Th-Th cooperation. The remarks made in this article serve as a basis for a reassessment

The physicochemical properties of an antigen influence the type, specificity, as well as duration of emerging immune responses. Like immune responses arising to nominal protein antigens, reactivities to protozoan parasite, 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

Acute rheumatic fever (ARF) is caused by an autoimmune response to throat infection with Streptococcus pyogenes, in individuals that 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 response. In this review, we present the major events that trigger the heart

COVID-19 consists in a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. But there exist other infectious respiratory syndromes that have the same initial respiratory symptoms, show similar pattern in the size of the antigenic proteins and release comparable cytokines pathways, but with an unlike response magnitude. Here we propose that COVID-19 disease wrong

Coronavirus disease (COVID-19) caused by SARS-COV2 has had a huge impact on global human health, and declared a worldwide distributed pandemic by the World Health Organization. SARS-CoV-2 has strong transmission and pathogenicity, so far, there are more than 16,000,000 cases has been infected around the world and caused more than 656,000 deaths. Current data indicate risk factors of patients infected

A silent revolution has occurred in our understanding of how T cell mediated immunity protects the host from recrudescent pathogens and how it fits into occurrences of autoimmunity and allergies. Under the new paradigm, the hitherto unknown, non-circulatory, tissue resident memory T cells (TRM) constitute the host defense sentinels posted in diverse anatomic compartments and are the key actors in protection

The immunity of infants and young children has to tolerate the myriad of new antigens that the baby encounters after birth. We dedicated many years defying the innate and adaptive mononuclear cell repertoire in pediatric subjects, coming to the conclusion that the immune regulation differs from the adults and dominates immune functions in babies.

Ample evidence exists for the activation of iNKT cells in a sterile manner by endogenous ligands or by microbial antigens from the commensal flora, indicating that iNKT cells are not truly self-tolerant. Their state of controlled autoreactivity is disturbed in many types of sterile inflammatory disease, resulting in a central role of iNKT cells in modulating auto-immune responses. This review focuses

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 also have reduced activity which decreases functions that impact naïve T cell and B cell responses. Aging innate cells also contribute to an overall heightened inflammatory environment. Naïve T cell and B cells undergo cell intrinsic

The neonatal stage was, for a long time 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. These secondary responses though displayed a deficit in Th1 cells but an excess of Th2 lymphocytes. These discoveries explain

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, naïve CD8+ T cells, c-Myc and polyamines in lymphocyte function and aging, cell survival after the induction

Post-translational 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

Autoimmunity results from the breakdown of immune tolerance to defined target self antigens. As with any foreign antigen, a self antigen is continuously processed by the 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

Macrophages are cells of the myeloid lineage with important roles not only in immune regulation and tissue repair, but also in pathological states such as autoimmune disease and cancer. A plethora of macrophage subtypes exist with distinct phenotypes and functions, not least within the tumor microenvironment (TME) of solid tumors. The abundant macrophages located within the TME are often referred to

The autoimmune disease multiple sclerosis (MS) is driven by T cells that are reactive to self-antigens of the brain and spinal cord. Many drugs have been developed to treat MS, but we believe that immune-specific targeting of pathogenic T cells may be a better approach for treatment. This type of therapy identifies specific components of the self-reactive T-cell repertoire that would undergo similar

Eli Sercarz pioneered epitope recognition by T cells. Studying mice, he made the seminal observation decades ago that epitope dominance is so unpredictable with mixed MHC haplotypes that he coined it aleatory, for dice-like. Accordingly, for every individual there is a unique potential epitope space that is defined by the polymorphic and polygenic MHC molecules (restriction elements) expressed. Of

The contribution of Eli E. Sercarz to immunology and immunopathology has been remarkable and achieved many milestones in the understanding of the processes of the mechanisms fine-tuning immune responses. A part of his work was dedicated to the study of the deep complexity of the lymphocyte T cell repertoire and its importance during the physiologic development and disease, such as clonal heterogeneity

We identified a druggable defect in IL-2 receptor (IL-2R) signaling by comparing the response of regulatory T cells (Tregs) of autoimmune disease patients to that of healthy controls. This defect was in the inhibition of Treg desensitization and was shared across various autoimmune diseases. Low-dose IL-2 stimulation results in maintained pSTAT5 expression for > 4 h, allowing the Treg transcriptome

COVID-19 infection tends to be more lethal in older persons than in the young; death results from an overactive inflammatory response, leading to cytokine storm and organ failure. Here we describe immune regulation of the inflammatory response phenotype as emerging from a process that is analogous to machine-learning algorithms used in computers. We briefly describe some strategic similarities between

We have previously demonstrated that natural killer (NK) cells are the main immune effectors that can mediate selection and differentiation of different cancer stem cells and undifferentiated tumors via lysis and secreted or membrane-bound interferon-γ and tumor necrosis factor-α, respectively. This leads to growth inhibition and tumor metastasis curtailment. In this review, we present an overview

T lymphocytes undergo carefully orchestrated programming during development in the thymus and subsequently during differentiation in the periphery. This intricate specification allows for cell-type and context-specific transcriptional programs that regulate immune responses to infection and malignancy. Epigenetic changes, including histone modifications and covalent modification of DNA itself through

The immune system is a potent defense mechanism regulating tumor development and progression. However, immune cells are often functionally compromised in cancer patients, and tumor rejection does not follow successful induction of a CTL response. This is, in part, due to the existing conflict between the tumor system and an unfavorable tumor microenvironment (TME) that is able to neutralize or paralyze

Coronavirus disease 2019 (COVID-19) poses a great public health challenge worldwide. While studies on the effects of SARS-CoV-2 on immune cell function continue to progress, we know very little about the significance of depletion of key immune effectors by the virus in the mortality and morbidity of the disease. This commentary reviews what is known thus far about the effects of the virus on natural

Mucosa-associated invariant T cells (MAIT cells) are unconventional, innate-like T lymphocytes with remarkable effector and immunoregulatory functions. They are abundant in the human peripheral blood and also enriched in mucosal layers and in the lungs, SARS-CoV-2's main ports of entry. Once activated, MAIT cells produce inflammatory cytokines and cytolytic effector molecules quickly and copiously

Pancreatic cancer is one of the most lethal kinds of cancer; numerous patients die from it every year all over the word. Fewer than 5% of people with pancreatic cancer survive death and recover. Recent evidence suggests that inflammation parameters, such as Th17 cells and Tregs, affect the progression and even the diagnosis and treatment of pancreatic cancer. In the inflammation process, T lymphocytes

Therapeutic antibodies and nanotherapeutic drugs are of great concern due to their widespread use against numerous diseases worldwide. They are frequently used for targeted therapy under the assumption that they cause fewer side effects than nontargeted drugs. Despite their specificity and particular design for therapeutic actions, they might still exhibit unintended adverse effects in the immune system

Human immunodeficiency virus (HIV) infection is associated with greatly increased risk for development of non-Hodgkin lymphoma (NHL). Nearly all acquired immunodeficiency syndrome (AIDS)-associated NHL (AIDS-NHL) is of B-cell origin. Two major mechanisms are believed to contribute to the genesis of AIDS-NHL: (1) loss of immunoregulation of Epstein-Barr virus (EBV)+ B cells, resulting from impaired

Most chronic diseases, caused by lifestyle factors, appear to be linked to inflammation. Inflammation is activated mechanistically, and nuclear factor-κB (NF-κB) is a significant mediator. NF-κB, one of the most studied transcription factors, was first identified in the nucleus of B lymphocytes almost three decades ago. This protein has a key function in regulating the human immune system, and its

Cardiovascular disease (CVD) is the number one cause of death in the United States and worldwide. The most common cause of cardiovascular disease is atherosclerosis, or formation of fatty plaques in the arteries. Low-density lipoprotein (LDL), termed "bad cholesterol", is a large molecule comprised of many proteins as well as lipids including cholesterol, phospholipids, and triglycerides. Circulating

Dendritic cells (DCs) and macrophages (MΦs) are antigen-presenting phagocytic cells found in many peripheral tissues of the human body, including the blood, lymph nodes, skin, and lung. They are vital to maintaining steady-state respiration in the human lung based on their ability to clear airways while also directing tolerogenic or inflammatory responses based on specific stimuli. Over the past three

The innate immune system serves as the first line of defense to protect the host from pathogen infection. As a first step, the pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs), such as non-self DNA derived from pathogens, and damage-associated molecular patterns (DAMPs), such as self DNA released from damaged or injured cells. Sensing of such DNAs elicits

Among the inflammatory myopathies, anti-tRNA-synthetase syndrome (ASyS) is a severe autoimmune condition characterized by extramuscular involvement, affecting especially the lungs. ASyS specific serological markers are anti-tRNA-synthetase autoantibodies, among which anti-histidyl-tRNA-synthetase is the most common. In the past decades, ASyS has been distinguished by unique histological features attributed

Chronic inflammation is one of the most evident and common pathological conditions leading to deregulated osteoclastogenesis and bone remodeling. Tumor necrosis factor (TNF) as a pleiotropic cytokine plays a key role, not only in inflammation, but also in bone erosion in diseases associated with bone loss. TNF can stimulate the proliferation of osteoclast precursors and, in most conditions, act together

Inflammatory bowel disease (IBD) is caused by the interplay of various factors. It occurs in genetically susceptible people due to dysregulated immune responses to several unknown antigens, including those derived from the commensal microbiota. Effector T-helper cells, especially TH17 cells, are considered a major driver of disease progression. The endogenous resident counterparts of effector T-helper

Lamtor1 is a lysosome-anchored protein that was first reported in 2009. In this review, we describe the discovery and intracellular functions of Lamtor1, as well as physiological roles of Lamtor1 in immune cells, namely, macrophages, CD4+ helper T-cells, and regulatory T-cells. To date, the following three strains of immune cell-specific conditional Lamtor1-knockout mice have been generated: myeloid-specific

Fibroblasts are a major structural cell in the human lung, being responsible for the production of extracellular matrix components that provide the intricate structure necessary for correct lung function. Generally located in the submucosa, fibroblasts do not usually directly interact with the commensal microbes that we now know are resident in the airways. However, during situations in which alveolar

By acquiring, processing, and presenting both foreign and self-antigens, dendritic cells (DCs) initiate T cell activation that is shaped through the immunomodulatory functions of a variety of cell-membrane-bound molecules including BTLA-HVEM, CD40-CD40L, CTLA-4-CD80/CD86, CD70-CD27, ICOS-ICOS-L, OX40-OX40L, and PD-L1-PD-1, as well as several key cytokines and enzymes such as interleukin-6 (IL-6), IL-12

Eosinophils (Eos) are prominent inflammatory cells found in the sputum, airways, and airway walls during and after exacerbations of allergic asthma. These cells are potent secretors of a wide array of cytotoxic granule proteins, cytokines, and lipid mediators involved in the initiation and maintenance of the Th2-type inflammatory reaction. Even though respiratory viral and bacterial infections are

Exosomes, nanovesicles shown to regulate physiological processes in vivo, have been implicated in pathological conditions including cancer, autoimmune disease, infectious disease, neurodegenerative disease, and allograft rejection. Studies of lung transplant recipients with primary graft dysfunction, respiratory viral infection, and (acute) rejection have demonstrated circulating exosomes containing

The past decade has seen enormous progress in cancer immunotherapy. Checkpoint inhibitors are a class of immunotherapy that act to recruit endogenous T cells of a patient's immune system against cancer-associated peptide- MHC antigens. In this process, mutated antigenic peptides referred to as neoantigens often serve as the target on cancer cells that are recognized by the T cell receptor (TCR) on

Communication between the nervous and immune systems is required for the body to regulate physiological homeostasis. Beta-adrenergic receptors expressed on immune cells mediate the modulation of immune response by neural activity. Activation of beta-adrenergic signaling results in suppression of antitumor immune response and limits the efficacy of cancer immunotherapy. Beta-adrenergic signaling is

Mouse cathelin-related antimicrobial peptide (CRAMP) and its homologue human cathelicidin (LL-37) play active roles in innate immune responses, angiogenesis, and wound healing. In addition, LL-37/CRAMP fends off microbes and protects against infections in the colon, where the epithelium is exposed to myriad of enteric pathogens. It is increasingly recognized that LL-37/CRAMP maintains colon mucosal

Signaling from the T cell receptor for antigen turns on the physiological response of a T cell. The canonical TCR signaling pathway relies on early activation of the Src kinase LCK. This step initiates a cascade of events that lead not only to the phenotypic changes that characterize effector T cells but also to the activation of negative regulatory mechanisms that stop early TCR signaling. These mechanisms

Interleukin 4 (IL4)-induced gene 1 (IL4I1) is an oxidase that degrades l-phenylalanine into phenylpyruvate, hydrogen peroxide, and ammonia. In contrast to other amino acid catabolic enzymes (i.e., indoleamine 2,3-dioxygenase and inducible nitric oxide synthase), IL4I1 is expressed not only in an intracellular form but also an active secreted form. Although about 20 yr ago IL4I1 was identified in murine

T cells are activated in response to the recognition of antigenic peptides on major histocompatibility complex molecules (pMHC) by the T cell receptors (TCR) and induction of downstream signaling. The strength of interaction between specific TCR with pMHC is a key defining factor for optimal T cell activation. But a number of studies have also suggested a crucial involvement of mechanical cues within

During the last decade, a wide variety of cellular RNA sensors and structural characteristics of their agonists have been identified. On the basis of this knowledge, RNA formulations were developed as innovative adjuvant candidates. In contrast to DNA, RNA does not have genotoxic potential and is rapidly degraded. In many aspects, RNA mimics viral infections and induces considerably strong immune responses

Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors such as the estrogen receptor and the androgen receptor and several other transcription factors to enhance their effects on target gene expression. SRC-3 plays important roles in many developmental, physiological, and pathologic events, including body growth, mammary gland development, energy

Regulatory effects of γδ T-cells on immune responses have been studied for years. We have investigated the regulatory effect of γδ T-cells on Th1 and Th17 autoimmune responses, and have studied molecular and cellular mechanisms by which γδ T-cells enhance or inhibit immune responses, exploiting a well-characterized murine model of experimental autoimmune uveitis (EAU). Our results show that (1) aberrant

Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Multiple mechanisms of tolerance are induced by oral-fed antigens, but induction of regulatory CD4 T-cells expressing the transcription factor Foxp3 and the membrane-bound TGF-β stands out as

Long-term treatment in the setting of metastatic Merkel cell carcinoma (MCC) and urothelial carcinoma (UC) has shown that current first-line chemotherapeutic agents are losing effectiveness and that there are limited treatment options available outside of radiation therapy and surgical interventions. The use of immunotherapeutic agents such as monoclonal antibodies has been considered a promising alternative

Tissue-resident memory T (TRM) cells have emerged as a major component of T cell biology. Recent investigations have greatly advanced our understanding of TRMs. Common features have been discovered to distinguish memory T cells residing in various mucosal and non-mucosal tissues from their circulating counterparts. Given that most organs and tissues contain a unique microenvironment, local signal-induced

T cells produce a wide variety of effector molecules in response to infections, such as cytokines, chemokines, granzymes, and perforins. Because different stimuli promote the production of specific effector molecules, T cell responses come in different flavors. In addition, single-cell analysis of protein production revealed that T cells respond heterogeneously to activation. To unravel the regulatory

Natural killer (NK) cells are innate immune cells equipped with the ability to rapidly kill stressed cells that are neoplastic or virally infected. These cells are especially important in settings where these stressed cells downregulate MHC class I molecules and evade recognition by cytotoxic T cells. However, the activity of NK cells alone is often suboptimal to fully control tumor growth or to clear

The marginal zone (MZ) is largely composed of a unique subpopulation of B cells, the so-called MZ-B cells. At a molecular level, memory B cells are characterized by the presence of somatically mutated IGV genes. The earliest studies in the rat have documented the presence of hapten-specific MZ-B cells after immunization in the MZ. This work later received experimental support demonstrating that the

The transcription factor RUNX3 is a prominent regulator of multiple hematopoietic cell lineages. Gene loss of function studies demonstrated the unique and essential roles of this master regulator in differentiated lymphoid and myeloid cells. As a complementary approach, RUNX3 was upregulated in various leukocyte subsets to probe the instructive role of this 'multilineage'-specific transcription factor

Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other