Abstract: HIV-1 infection is characterized by a continuous viral replication throughout the illness that can be controlled to some extent by effective treatment. Early during primary infection, latent reservoirs where the virus remains hidden in metabolically inert cells are established. These reservoirs are responsible for a low-rate viral replication that can be observed even during effective treatment and are a major obstacle for the complete eradication of the infection. This low-rate viral replication also comes from anatomical sites where drug penetration is limited and only a suboptimal drug concentration can be achieved. Further understanding of the mechanisms underlying HIV-1 latency is of primary importance to develop new strategies that ensure the complete destruction of reservoirs and, therefore, the eradication of the infection. ... Read more

Abstract: Systemic lupus erythematosus (SLE) is a common autoimmune disease with unclear etiology. Treatments for it often provide inadequate control of disease activity or are limited by side effects. Recent studies have shown that rapamycin can be an effective treatment in both murine lupus models and human SLE. We demonstrated that rapamycin could directly alter molecular abnormalities in SLE T cells related to calcium signaling but not mitochondrial function. However, in light of increased knowledge of the role of mammalian target of rapamycin (mTOR) signaling throughout the immune system, several other potential sites of rapamycin action have been revealed. Specifically, mTOR regulates the production of interferon-α and the maintenance of immune tolerance at the level of the regulatory T cell and the dendritic cell, and can promote Th1 versus Th2 immune responses. Thus mTOR offers a window into diverse facets of SLE pathogenesis as well as a potentially unifying narrative in our understanding of diverse facets of the disease. ... Read more

Abstract: Mast cells (MC) are specialized exocytic cells that lie beneath the external surfaces of the body. For many decades, MCs were thought to primarily function as effector cells for IgE mediated allergic diseases. However, recent evidence indicates that MCs also function as important cells in immune surveillance. When activated by pathogens, MCs initiate innate and adaptive immune responses thereby resulting in protection against pathogens. The question remains if MC activation may also function in establishing immune responses against allergens and hence allergic disease. New studies suggest that MCs are not only the effector cell of allergy but may also be the initiator of allergy. ... Read more

Abstract: Ovarian cancer is the leading cause of cancer death among gynecological malignances. Despite the initial successful multimodality therapy with cytoreductive surgery and subsequent combination chemotherapy, most patients with advanced disease will ultimately relapse and become incurable. For this reason novel therapeutic approaches for the treatment of this malignancy are urgently needed. Adoptive transfer of genetically modified autologous tumor-reactive T cells is a promising novel antitumor therapy for many cancers. T cells may be genetically modified ex vivo to express chimeric antigen receptors (CARs), which are artificial T cell receptors targeted to specific tumor antigens. The resulting T cells are thus programmed to recognize tumor cells. Ovarian carcinomas in particular appear to be suited to this therapeutic approach based on the fact that these tumors are relatively immunogenic, inducing an endogenous T cell response. Furthermore, the degree to which this endogenous T cell mediated immune response is evident correlates to long-term patient prognosis following surgery and chemotherapy. To this end, adoptive T cell immunotherapy strategies for the treatment of ovarian carcinomas appear to be particularly promising and are currently being investigated at several centers in both pre-clinical and clinical settings. ... Read more

Abstract: One-third of humans carry Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) where microbe/host immune response interactions result in persistence or active TB. However, immune mediators associated with human TB remain poorly defined. Through a series of comparative studies of lung immune response of TB cases at the time of diagnosis and patients with other infectious lung diseases and volunteers, we found that TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity critical for containment of M. tuberculosis. Despite the concomitant heightened levels of Th1-type mediators, they are likely rendered ineffectual by high levels of intracellular (e.g., SOCS) and extracellular (e.g., IL-10) immune suppressors. These modulators are a direct response to M. tuberculosis as many suppressive factors declined to the levels of controls by 30 days of anti-TB treatment while most Th1-type and innate immune mediators rose above the pre-treatment levels. Parallel laboratory studies and monitored lung alveolar macrophage effector, nitric oxide synthase-2 (being shown critical for killing M. tuberculosis), support that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type/innate immunity as an immunopathological strategy. Our studies highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response. ... Read more

Abstract: In this review, I outline a current view of how T lymphocytes use extracellular signals to decide between activation and tolerance, and how the tolerant state is established and maintained at the molecular level. This decision is made by a series of intracellular proteins that actively oppose the induction of effector genes, and are inactivated by signals from costimulatory and/or growth factor receptors. ... Read more

Abstract: Rasmussen encephalitis (RE) is characterized by chronic inflammation of one cerebral hemisphere which causes intractable epileptic seizures and progressive neurological deficits. Since antiepileptic pharmacotherapy is often ineffective the traditional therapy for Rasmussen encephalitis is hemispherectomy in one of its modern variants which renders the patient seizure free but leads to a severe deficit. To escape this dilemma, immunomodulatory therapeutic approaches such as rituximab, a monoclonal anti-CD20 antibody, offer an alternative and bear promising therapeutic potentials in Rasmussen encephalitis. ... Read more

Abstract: Interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints. This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells. Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies. ... Read more

Abstract: The activation and clonal expansion of naive T cells by antigen-loaded dendritic cells (DCs) in the lymph nodes is a key event during immune response. This activation involves the formation of a specialized cell-cell contact region, formed between a mature DC and a CD4 T cell, which is called immunological synapse (IS). The IS includes a DC and a T cell side that we call IS(DC) and IS(T cell), respectively. Most studies on the IS have focused on the IS(T cell) and the information gathered on the IS(DC) is sparse. However, lines of emerging evidence indicate that the IS(DC), likewise the IS(T cell), is a signaling and functional region that makes important contribution to T cell activation and the immune response. ... Read more

Abstract: Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it. ... Read more