Semaphorins belong to a family of membrane-bound and secreted molecules that regulate the functional activity of axons in the nervous system. Sema4A and Sema4D were the first semaphorins also found to be expressed in immune cells and were, therefore, termed “immune semaphorins”. It is known that Sema4A has three functional receptors, namely Plexin D1, Plexin B1, and Tim-2, ...

The discovery of the Th17 lineage in 2005 triggered a major change in how immunity to infectious diseases is viewed. Fungal infections, in particular, have long been a relatively understudied area of investigation in terms of the host immune response. Candida albicans is a commensal yeast that colonizes mucosal sites and skin. In healthy individuals, it is non-pathogenic, but ...

T cell recognition of antigen is a crucial aspect of the adaptive immune response. One of the most common means of pathogen immune evasion is mutation of T cell epitopes. T cell recognition of such ligands can result in a variety of outcomes including activation, apoptosis and anergy. The ability of a given T cell to respond to a specific ...

Recent research on hematological malignancies has shown that malignant cells often co-opt physiological pathways to promote their growth and development. Bone marrow homeostasis requires a fine balance between cellular differentiation and self-renewal; cell survival and apoptosis; and cellular proliferation and senescence. The Ras/Raf/MEK/ERK pathway has been shown to be important in regulating these biological functions. ...

Toxins secreted by bacteria can impact the host in a number of different ways. In some infections, toxins play a crucial and central role in pathogenesis (i.e., anthrax), while in other bacterial infections, the role of toxins is less understood. The cholesterol-dependent cytolysins (CDCs), of which streptolysin O is a prototype, are a class of pore-forming toxins ...

Tumor antigen (TA)-targeted monoclonal antibodies (mAb), trastuzumab, cetuximab, panitumumab, and rituximab, have been among the most successful new therapies in the present generation. Clinical activity is observed as a single agent, or in combination with radiotherapy or chemotherapy, against metastatic colorectal cancer, head and neck cancer, breast cancer, and follicular lymphoma. However, the activity is seen only in a ...

The E-protein transcription factors E2A and HEB function in a lineage- and stage-specific manner to orchestrate many critical events throughout lymphocyte development. The function of E-proteins in both B- and T-lymphocyte development has been extensively studied through the use of single-gene knockout animals. Unlike B cells, which rely primarily on E2A alone, T cells are ...

Osteopontin (OPN) is a protein involved in various pathophysiological events. OPN has been studied as a secreted protein, but recent reports showed that OPN can be found in the cytoplasm and the nucleus. Therefore, some OPN molecules are not secreted and stay in cells. Such intracellular OPN (iOPN) has biological functions distinct from secreted OPN (sOPN). iOPN is involved in ...

Naturally occurring regulatory T cells (TReg) suppress multiple cell types of the immune system to maintain dominant tolerance to protect from autoimmunity, down-modulate anti-tumor immunity and restrain allergic diseases. In addition to these functions, TReg can alter effector responses to invading pathogens, leading to a variety of outcomes affecting both the host and infecting microorganisms. Here, we review ...

There is no approved therapy for food allergies, which affect 12 million people in the United States and millions more worldwide. In the last few years, our research team at Duke has begun to develop protocols to treat peanut and other food allergies. Two distinct therapies are being developed. Oral immunotherapy (OIT), which relies on ingestion of increasing amounts of the ...

Myeloid-derived suppressor cells (MDSCs) have been investigated largely in the context of tumor progression. In contrast to the negative connotation of MDSCs in cancer immunity, our laboratory has recently reported on the development and role of pulmonary MDSC-like cells (CD11b+Gr1intF4/80+) in the regulation of allergic airway inflammation. These regulatory cells were expanded in a TLR4/MyD88-dependent ...

Expression of activation-induced cytidine deaminase (AID) by germinal center (GC) B cells drives the processes of immunoglobulin (Ig) somatic hypermutation (SHM) and class switch recombination (CSR) necessary for the generation of high affinity IgG serum antibody and the memory B-cell compartment. Increasing evidence indicates that AID is also expressed at low levels in developing B cells but to ...

B-lymphocytes have traditionally been thought to contribute to immunity and autoimmune disease through terminal differentiation into plasma cells that secrete antibody. However, studies in mice and recent clinical studies have demonstrated that genetically altered B-cell function and B-cell-targeted therapies can significantly affect autoimmune diseases that were predominantly thought to be T-cell-mediated. B-cell depletion ...

Microparticles are small membrane-bound vesicles that display pro-inflammatory and pro-thrombotic activities important in the pathogenesis of a wide variety of diseases. These particles are released from activated and dying cells and incorporate nuclear and cytoplasmic molecules for extracellular export. Of these molecules, DNA is a central autoantigen in systemic lupus erythematosus (SLE). As studies in our laboratory ...

Systemic sclerosis (SSc) is a progressive and highly debilitating autoimmune disorder characterized by inflammation, fibrosis, and vascular damage of the connective tissue. T cell-derived cytokines have been implicated in the induction of fibrosis. We found that high levels of the profibrotic type-2 cytokine IL-13 are produced by peripheral blood effector CD8+ T cells from SSc patients compared ...

Signal transducer and activator of transcription (STAT) proteins are critical mediators of cytokine signaling. Among the seven STAT proteins, STAT6 is activated by IL-4 and IL-13 and plays a predominant role in the immune system. However, there is increasing evidence that STAT6 may function in other tissues and organ systems. IL-4, IL-13, and STAT6 promote humoral ...

Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection ...

Photodynamic therapy (PDT) is an FDA-approved modality that rapidly eliminates local tumors, resulting in cure of early disease and palliation of advanced disease. PDT was originally considered to be a local treatment; however, both pre-clinical and clinical studies have shown that local PDT treatment of tumors can enhance systemic anti-tumor immunity. The current state of investigations into ...

Human leukocyte antigen (HLA) sensitization and ABO incompatibility continue to pose significant barriers to further expansion of live donor renal transplantation. However, the recent development of effective desensitization protocols and creative paired donation strategies demonstrates that the presence of circulating donor HLA-specific antibodies and the use of ABO incompatible organs should no longer be considered contraindications for renal transplantation. ...

Immune cells infiltrate tumors and make up a significant component of the multicellular cancer micro-environment, yet the immune system often fails to prevent tumor formation and progression. One explanation for this paradox is the presence of tolerance-promoting regulatory T cells (Tregs) that counteract antitumor immune cells. Tregs were known to be essential for maintaining self-tolerance. Recently, Tregs ...

IgE antibody concentration, affinity, clonality and specific activity (also known as the allergen-specific IgE to total IgE ratio) influence the translation of IgE responses into clinically evident allergic symptoms following allergen exposure. Reported IgE-specific activity levels >3–4% place allergic individuals undergoing anti-IgE (Omalizumab®) therapy at a disadvantage for poor resolution of their allergy symptoms following ...

Rituximab is a chimeric monoclonal anti-CD20 antibody and was the first monoclonal antibody (mAb) therapy approved by FDA (Food and Drug Administration) for the treatment of B-cell lymphoma. It has revolutionized the treatment of patients with CD20-positive non-Hodgkin’s lymphoma and CLL. Rituximab is currently being used in virtually all patients with B-cell lymphomas either alone ...

There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing the ability of heat shock temperatures (usually above 42°C) to result in radio- or chemosensitization. However, these high ...

High-dose cyclophosphamide (high-CY) is a potent immunosuppressive regimen that is increasingly used to mitigate both autoimmune and alloimmune conditions. Differential expression of aldehyde dehydrogenase between hematopoietic stem cells and lymphocytes accounts for the differential sensitivity of these cells to high-CY and explains why this regimen is immunosuppressive but not myeloablative. This article describes the clinical translation of ...

IL-10 plays an essential part in controlling inflammation and instructing adaptive immune responses. Consequently, dysregulation of IL-10 is linked with susceptibility to numerous infectious and autoimmune diseases in mouse models and in humans. It has become increasingly clear that appropriate temporal/spatial expression of IL-10 may be the key to how IL-10 contributes to the delicate ...

Viral encephalomyelitis is caused by virus infections of neurons in the brain and spinal cord. Recovery is dependent on immune-mediated control and clearance of virus from these terminally differentiated essential cells. Preservation of neuronal function is essential for prevention of neurologic sequelae such as paralysis, seizures and cognitive deficits. Using the model system of Sindbis virus-induced encephalomyelitis in ...

The attributes of specificity and memory enable CD8+ T cells to provide long-lasting protection against a variety of challenges. Although, the importance of CD8+ T cells for protection against intracellular infections and transformation is well-established, the functional type; effector phenotypes (Tc1, Tc2, Tc17 and/or Tcreg) and/or memory (effector or central), of CD8+ T cells most desirable ...

One of the defining characteristics of HIV is its ability to manipulate the human immune response to promote its own replication. Since the beginning of the epidemic, there has been controversy whether a robust immune response to the virus is beneficial or detrimental for the host. Therefore, the effects of HIV on signaling pathways and cytokine production need to be ...

Considerable progress has been made in understanding the Fas pathway at the molecular and cellular levels, but fundamental questions about the overall biological role of the Fas pathway remain unresolved. A major question is why lymphoproliferation caused by the lpr mutation of Fas and gld mutation of FasL ligand (FasL) is dominated by CD4− and CD8− double-negative αβ T ...

Advances in immunogenetics and histocompatibility have facilitated the clinical transplantation of solid organs and tissues. Improved definition of HLA antigens, alleles, and haplotypes has clarified the diversity of the HLA system among different racial/ethnic populations. Knowledge of allele and haplotypes frequencies derived from these studies can be applied to the estimates of transplant compatibility and the likelihood finding suitable ...

The two-signal model of T cell activation states that antigen recognition by TCR provides a tolerogenic signal (termed Signal 1) unless the T cell receives simultaneous costimulation (Signal 2) that permits antigen recognition to prime activation. Our efforts to characterize genetic and biochemical factors resulting from Signal 1 alone have identified signaling molecules, transcription factors, and an epigenetic regulator ...

Human immunodeficiency virus (HIV) is a major global health concern with more than 30 million individuals currently infected worldwide. To date, attempts to stimulate protective immunity to viral components of HIV have been unsuccessful in preventing or clearing infection. Lymphocytic choriomeningitis virus (LCMV) is an established murine model of persistent viral infection that has been instrumental in illuminating several critical ...

Immune reactivity in the retina can be critically important in inflammation and infections, but regulation of this response is essential. The retinal pigment epithelial (RPE), a unique retinal cell, displays a number of essential functions to support the health of the retina. In this review, we highlight how the RPE cell plays a pivotal role in immune defense. The RPE ...

In addition to improving vaccine formulations in order to elicit robust and long-lasting immune responses, there is also an increasing need for improving the manner in which these vaccines are delivered. As most current vaccines are administered by injection by a health care giver, there is the ever-present danger of needlestick injuries. Therefore, needle-free vaccinations are a ...

HIV infection is associated with a much higher risk for the development of non-Hodgkin lymphoma (AIDS-NHL). The principal causes of lymphomagenesis in HIV-infected individuals are thought to be the loss of immune function seen in HIV infection, which results in the loss of immunoregulation of Epstein–Barr virus-infected B cells, as well as HIV infection-associated ...

Autoimmune thyroiditis is an organ-specific autoimmune disorder characterized by infiltration of the thyroid gland by lymphocytic inflammatory cells, often followed by hypothyroidism due to destruction and replacement of the follicular tissue. Dr. Noel Rose and members of his laboratory at Johns Hopkins University have continued to study autoimmunity using autoimmune thyroiditis as a model. Autoimmune thyroiditis is multifactorial, with ...

Hematopoietic stem cells (HSCs) are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. ...

Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this ...

Hepatitis C virus (HCV) infects over 170 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. Approximately 80% of those acutely infected clear the infection, whereas the remaining 20% progress to chronic infection. Hepatitis C thus provides a model in which successful and unsuccessful responses can be compared to better understand the human response to viral ...

Due to the oncogenic potential associated with persistent infection of human gamma-herpesviruses, including Epstein–Barr virus (EBV or HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV-8), vaccine development has focused on subunit vaccines. However, the results using an animal model of mouse infection with a related rodent virus, murine gamma-herpesvirus 68 (MHV-68, γHV-68, ...

Tumor-mediated immune suppression occurs through multiple mechanisms, including dysregulation of dendritic cell differentiation. This block in differentiation results in fewer dendritic cells and an accumulation of immunosuppressive myeloid- derived suppressor cells and is thought to contribute to tumor outgrowth and to act as an impediment to successful anti-cancer immunotherapy. Tumor-mediated myeloid dysregulation is known to be Stat3 ...

An effectively orchestrated immune response to infection and disease depends on efficient trafficking of lymphocytes across vascular beds at distinct tissue sites. Local inflammation and systemic fever increase immune surveillance to immune-relevant sites throughout the body. During the initiation phase of inflammation, this tightly regulated process improves leukocyte trafficking to the secondary lymphoid organs where they undergo activation and ...

The expression of major histocompatibility complex (MHC) class I molecules on the cell surface is critical for recognition by cytotoxic T lymphocytes (CTL). This recognition event leads to destruction of cells displaying MHC class I—viral peptide complexes or cells displaying MHC class I—mutant peptide complexes. Before they can be transported to the cell surface, MHC class I molecules ...

Besides their well-characterized role as the initiator of adaptive immune responses, dendritic cells (DCs) play a critical role in the induction and maintenance of self-tolerance, the failure of which could lead to autoimmune/inflammatory diseases. Although it is clear that tolerance is a property of DCs at the steady state, the molecular mechanisms governing their generation, function and ...

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow or hematopoietic stem cell transplantation. GVHD is thought to be primarily due to the response of mature T cells transferred along with the bone marrow graft to foreign histocompatibility antigens expressed on host tissues. Recent studies, however, have challenged this paradigm set forth in the 1960s and ...

The ability of HIV to infect quiescent CD4+ T cells has been a topic of intense debate. While early studies suggested that the virus could not infect this particular T cell subset, subsequent studies using more sensitive protocols demonstrated that these cells could inefficiently support HIV infection. Additional studies showed that the kinetics of infection in quiescent cells was delayed ...

T cells bearing αβ receptors recognize antigenic peptides bound to class I and class II glycoproteins encoded in the major histocompatibility complex (MHC). Cytotoxic and helper T cells respond respectively to peptide antigens derived from endogenous sources presented by MHC class I, and exogenous sources presented by MHC II, on antigen presenting cells. Differences in the MHC class I and ...

Chronic inflammation that has been observed for malignant and non-neoplastic lung diseases of smokers has been attributed to the numerous and diverse particulate (‘tar’)-phase and gas-phase chemicals in mainstream smoke, most of which arise from the burning of tobacco. The primary cell-mediator of lung inflammation is the macrophage. Most probably, inflammation is promoted also from some ...

Novel breast tumor antigens are needed to develop T cell and antibody-based vaccine immunotherapy approach against breast cancer. To this purpose, we have previously shown that PDEF is frequently over expressed in human breast tumors and exhibits highly restricted expression in normal human tissues that is primarily limited to normal prostate. Moreover, PDEF expression correlates with poor overall survival ...

Journal: Immunologic Research - IMMUNOL RES, vol. 47, no. 1, pp. 285-285, 2010]]>http://academic.research.microsoft.com/Publication/34424620Mon, 20 May 2013 07:43:59 GMT34424620Michael Edidin(Citations:1)view publication

Here I summarize decades of work using the biophysics of class I MHC molecules to probe the patchiness and heterogeneity of cell surfaces. This program began as a study of membranes generally. MHC molecules were a convenient probe. However, in recent years, it has become clear that the lateral distribution, clustering, of class I MHC molecules in the membrane affects ...

Activation-induced deaminase (AID) is a B-cell-specific enzyme required for initiating the mechanisms of affinity maturation and isotype switching of antibodies. AID functions by deaminating cytosine to uracil in DNA, which initiates a cascade of events resulting in mutations and strand breaks in the immunoglobulin loci. There is an intricate interplay between faithful DNA repair and mutagenic DNA ...

It is now well established that most cervical cancers are causally associated with HPV infection. This realization has led to efforts to control HPV-associated malignancy through prevention or treatment of HPV infection. Currently, commercially available HPV vaccines are not designed to control established HPV infection and associated premalignant and malignant lesions. To treat and eradicate pre-existing HPV infections ...

T cell factor-1 (TCF1) critically regulates T cell development. However, signals that control TCF1 function in developing and mature T cells remain unknown. TCF1 along with β-catenin activates gene transcription and in cooperation with Groucho family of proteins mediates gene repression. It has been established that the β-catenin-dependent gene expression is often downstream of the canonical ...