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Biomedical subjects

Leonard H Sigal

Publications and source records attributed to Leonard H Sigal.

At least 19 recordsLinked to original sources
PubMed2007

A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia.

UNLABELLED: Fibromyalgia (FM) is a non-inflammatory rheumatologic disorder characterized by musculoskeletal pain, fatigue, depression, cognitive dysfunction and sleep disturbance. Research suggests that autonomic dysfunction may account for some of the symptomatology of FM. An open label trial of biofeedback training was conducted to manipulate suboptimal heart rate variability (HRV), a key marker of autonomic dysfunction. METHODS: Twelve women ages 18-60 with FM completed 10 weekly sessions of HRV biofeedback. They were taught to breathe at their resonant frequency (RF) and asked to practice twice daily. At sessions 1, 10 and 3-month follow-up, physiological and questionnaire data were collected. RESULTS: There were clinically significant decreases in depression and pain and improvement in functioning from Session 1 to a 3-month follow-up. For depression, the improvement occurred by Session 10. HRV and blood pressure variability (BPV) increased during biofeedback tasks. HRV increased from Sessions 1-10, while BPV decreased from Session 1 to the 3 month follow-up. CONCLUSIONS: These data suggest that HRV biofeedback may be a useful treatment for FM, perhaps mediated by autonomic changes. While HRV effects were immediate, blood pressure, baroreflex, and therapeutic effects were delayed. This is consistent with data on the relationship among stress, HPA axis activity, and brain function.

Adolescent↗
PubMed2006

Basic science for the clinician 36: protecting against autoimmunity: tolerance and aire, the immunologic shadow, and other mechanisms of negative selection in the thymus.

One of the miracles of immunology is tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone. Autoreactive thymocytes (the cells that would otherwise differentiate into mature autoaggressive T cells) are deleted from the emerging immunologic repertoire within the thymus; only a very small proportion of thymocytes survive the thymus--perhaps 2% to 5% emerge to become mature T cells in the periphery, the rest dying to assure tolerance. This apparent wastage somehow works to the benefit of the developing animal and if the process works, all goes well for the maturing immune system. In some autoimmune syndromes, autoreactive thymocytes are not eliminated within the thymus by either clonal deletion or activation-induced cell death; these then emerge to wreak their havoc. However, how does this deletion happen? Recent research from a number of groups has (incredibly!) identified expression of nonthymic, nonlymphoid proteins within the thymus (casting of the "immunologic shadow of self"), and this is under the control of a single protein: AIRE (autoimmune regulator). By allowing autoreactive thymocytes to encounter a broad spectrum of proteins from extrathymic organs, aire allows deletion of these cells and the maintenance of tolerance. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. These and other molecular mechanisms underlying tolerance are explored in this and the next paper in this series.

Animals↗
PubMed2006

Basic science for the clinician 37: Protecting against autoimmunity-tolerance: mechanisms of negative selection in the thymus.

As noted in previous articles in this series, tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone, is a vital characteristic of a successful (and safe) immune system. With the detection of the molecule called aire (autoimmune regulator), the mechanism whereby autoreactive thymocytes encounter extrathymic proteins within the thymus and therefore are deleted, is now far better understood; aire was the subject of a prior article in this series. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing "filtering" system. However, there are other mechanisms at work. Irregularities in expression of other proteins such as hypoxia-induced factor-1 (HIF-1) and CTLA4, have been implicated in autoimmune disease, the former in rheumatoid arthritis, the latter in autoimmune thyroid disease and lupus. Defects in intracellular factors involved in transcription of key apoptotic proteins have also been implicated in the escape of autoreactive thymocytes from the thymus, leading to autoimmune and lymphoproliferative syndromes as well. Changes in the proteins that oversee acetylation of histone lead to differential patterns of gene expression. At least 2 proteins involved in this process, HDAC and nur77, have been implicated in changes in survival of thymocytes. Yet again, there are multiple layers at work in the immune system; I have no idea how many more will be brought to light, which are phylogenetically most ancient or which will prove the most clinically relevant. For now, it is enough to bask in our new-found knowledge and know that the time from laboratory oddity, to animal model development, to therapeutic and/or diagnostic applications grows shorter each year since the molecular biologic revolution.

Antigens, CD↗
PubMed2006

Basic science for the clinician 38: B cells, factories, and immunomodulators.

In a previous article in this series, we explored how developing pre-T cells learn how to be well-behaved T cells that recognize and honor the "self versus nonself" dichotomy of the universe. B cells do much of the same sort of thing, with multipotent stem cells becoming committed to ultimately becoming B cells within the bone marrow and then, after judicious culling of the flock, going off to the spleen to learn the final lessons needed to become "well-behaved" B cells. Like with T cells, there are a large number of things that can, and do, go wrong. If there is a failure of the system and B cells do not develop properly, hypogammaglobulinemia may develop as a result of a number of immune deficiency syndromes that can be quite devastating. If autoreactive cells survive to emerge into the periphery, autoimmunity, either organ-specific or more global, may occur. If B cells in the periphery proliferate in an uncontrolled fashion, a variety of B cell lymphoproliferative syndromes may develop, recognizable by the phenotypic markers of their originating B cell lineage level of differentiation. The full details of how autoreactive B cells survive and thrive, only to cause disease, are not yet clear, but identification of many of the phenotypic surface markers and circulating growth factors identified to this point have borne therapeutic fruit.

Animals↗
PubMed2006

Basic science for the clinician 39: NF-kappaB-function, activation, control, and consequences.

Were there to be a crossroads through which all inflammatory signaling passed, controlling that junction would provide the ultimate therapeutic target for rheumatoid arthritis and many, if not all, autoimmune diseases. It now seems likely that no single cytokine or cytokine family represents such a crucial nexus. However, there is reason to believe that there may be an intracellular bottleneck that does: the family of NF-kappaB proteins. This family of proteins allows cytokine-receptor signals to enter the nucleus and either enhance or suppress the transcription of many genes involved in inflammation and in cellular survival itself. The same set of proteins is also involved in apoptosis and likely in carcinogenesis. The delicate choreography of control systems, balancing the effects of NF-kappaB proteins on the multiple DNA sites that are targeted, is also a prime target for specific therapies. Moreover, the NF-kappaB system interdigitates with other intracellular systems, eg, kinases, ubiquitin-associated protein degradation, that are critical to the normal function of cells, involved in homeostasis and inflammation, in autoimmune diseases and malignancy.

Animals↗
PubMed2006

Basic science for the clinician 40: ubiquitin, programmed protein degradation, and the proteasome.

mRNA is made from DNA. Protein is made from mRNA. Although one might say that "DNA is forever," the same cannot be said for mRNA or protein. These molecules are made in response to the cell's present needs; once the cell's circumstances change, a whole new repertoire of proteins may be needed and the previous set of proteins may be unnecessary, perhaps even deleterious. So, the cell must be able to eliminate the characters in the previous act in favor of the actors needed for the current act. In addition, there is good evidence that the DNA to mRNA to protein flow may not be efficient; abnormal proteins, as well as damaged or misfolded proteins, are quite common and must also be eliminated. This process depends on the ability of the cell to tag the protein to be eliminated with a small protein (or chain of these proteins) that targets the protein to a special structure for digestion into its constituent amino acids for recycling into new proteins. This very common protein tag was identified in the 1970s and called "ubiquitin"--it truly was everyplace! In addition, ubiquitin is crucial to targeting normal proteins to their appropriate place in or on the cell and for recycling of proteins. Ubiqutination of proteins and what follows this tagging are crucial to the normal function of cells. The complexity of these processes is being used for therapy in oncology now and perhaps in immunology and rheumatology in the near future.

Autoimmune Diseases↗
PubMed2006

Basic Science for the clinician 41: tails of cytokine receptor activation and control: JAKs, STATs, PIASs, and SOCSs.

We now have an emerging sense of the details of how cytokines deliver their signals through the specific receptors to which they bind and the means by which these messages are modulated. Using common mechanisms, many of which have been described in past articles in this series, tight controls are maintained over this signaling. A better understanding of the molecular details of these pathways has provided insights into the pathogenesis of some malignancies and immunodeficiency syndromes and may ultimately yield therapeutic agents of use in the treatment of inflammatory and autoimmune diseases.

Animals↗
PubMed2005

Lyme arthritis synovial gammadelta T cells instruct dendritic cells via fas ligand.

gammadelta T cells participate in the innate immune response to a variety of infectious microorganisms. They also link to the adaptive immune response through their induction of maturation of dendritic cells (DC) during the early phase of an immune response when the frequency of Ag-specific T cells is very low. We observe that in the presence of Borrelia burgdorferi, synovial Vdelta1 T cells from Lyme arthritis synovial fluid potently induce maturation of DC, including production of IL-12, and increased surface expression of CD40 and CD86. The activated DC are then able to stimulate the Vdelta1 T cells to up-regulate CD25. Both of these processes are initiated primarily by Fas stimulation rather than CD40 activation of DC via high expression of Fas ligand by the Vdelta1 T cells. DC are resistant to Fas-induced death due to expression of high levels of the Fas inhibitor c-FLIP. This effect serves to divert Fas-mediated signals from the caspase cascade to the ERK MAPK and NF-kappaB pathways. The findings affirm the importance of the interaction of certain T cell populations with DC during the early phases of the innate immune response. They also underscore the view that as levels of c-FLIP increase, Fas signaling can be diverted from induction of apoptosis to pathways leading to cell effector function.

CASP8 and FADD-Like Apoptosis Regulating Protein↗
PubMed2005

Reactive arthritis.

ReA consists of sterile axial or peripheral articular inflammation,enthesitis, and extra-articular manifestations. Most patients are HLA-B27 positive, although determining the B27 status of an individual patient is irrelevant. Exposure to specific bacterial antigens is usually the inciting factor. Diagnosis usually can be made by clinical examination and history. The current standard therapy is NSAIDs and physiotherapy, but molecular biologic treatment may ultimately become the mainstay in recalcitrant and severe ReA.

Anti-Bacterial Agents↗
PubMed2005

Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.

OBJECTIVE: To review the literature on herbal preparations commonly utilized in the treatment of rheumatic indications. METHODS: Search of MEDLINE (PubMed) was performed using both the scientific and the common names of herbs. Relevant articles in English were collected from PubMed and reviewed. RESULTS: This review summarizes the efficacy and toxicities of herbal remedies used in complementary and alternative medical (CAM) therapies for rheumatologic conditions, by elucidating the immune pathways through which these preparations have antiinflammatory and/or immunomodulatory activity and providing a scientific basis for their efficacy. Gammalinolenic acid suppresses inflammation by acting as a competitive inhibitor of prostaglandin E2 and leukotrienes (LTs) and by reducing the auto-induction of interleukin1alpha (IL-1alpha)-induced pro-IL-1beta gene expression. It appears to be efficacious in rheumatoid arthritis (RA) but not for Sjogrens disease. The antiinflammatory actions of Harpagophytum procumbens is due to its action on eicosanoid biosynthesis and it may have a role in treating low back pain. While in vitro experiments with Tanacetum parthenium found inhibition of the expression of intercellular adhesion molecule-1, tumor necrosis factor alpha (TNF-alpha), interferon-gamma, IkappaB kinase, and a decrease in T-cell adhesion, to date human studies have not proven it useful in the treatment of RA. Current experience with Tripterygium wilfordii Hook F, Uncaria tomentosa, finds them to be efficacious in the treatment of RA, while Urtica diocia and willow bark extract are effective for osteoarthritis. T. wilfordii Hook F extract inhibits the production of cytokines and other mediators from mononuclear phagocytes by blocking the up-regulation of a number of proinflammatory genes, including TNF-alpha, cyclooxygenase 2 (COX-2), interferon-gamma, IL-2, prostaglandin, and iNOS. Uncaria tomentosa and Urtica diocia both decrease the production of TNF-alpha. At present there are no human studies on Ocimum spp. in rheumatic diseases. The fixed oil appears to have antihistaminic, antiserotonin, and antiprostaglandin activity. Zingiber officinale inhibits TNF-alpha, prostaglandin, and leukotriene synthesis and at present has limited efficacy in the treatment of osteoarthritis. CONCLUSIONS: Investigation of the mechanism and potential uses of CAM therapies is still in its infancy and many studies done to date are scientifically flawed. Further systematic and scientific inquiry into this topic is necessary to validate or refute the clinical claims made for CAM therapies. An understanding of the mechanism of action of CAM therapies allows physicians to counsel effectively on their proper and improper use, prevent adverse drug-drug interactions, and anticipate or appreciate toxicities. RELEVANCE: The use of CAM therapies is widespread among patients, including those with rheumatic diseases. Herbal medications are often utilized with little to no physician guidance or knowledge. An appreciation of this information will help physicians to counsel patients concerning the utility and toxicities of CAM therapies. An understanding and elucidation of the mechanisms by which CAM therapies may be efficacious can be instrumental in discovering new molecular targets in the treatment of diseases.

Antirheumatic Agents↗
PubMed2005

Basic science for the clinician 34: Interleukins of current clinical relevance (part II).

As you saw in the first part of this description of interleukins, normal orchestration of wound healing, the protective immune response and inflammation involves many cells that must effectively communicate with each other. The means of this communication is often soluble messengers (cytokine) and many of them bear the title interleukin. Although all these messengers have a role in normal immune homeostasis, it is apparent that many are involved in tissue damage in a variety of disease, eg, rheumatoid arthritis, osteoarthritis. I dealt with interleukins (IL) 3 to 16 in the first part of this project. We now pick up the story with IL-17. Turns out, much of the most exciting recent work in rheumatology has focused on IL-17 and IL-18. The disparate effects of the interleukins may be confusing, often a single cytokine producing multiple effects seemingly at crossed purposes, but we are in our infancy when it comes to insights into the molecular biology of normal immune function, homeostasis, inflammation, and disease.

Humans↗
PubMed2005

Basic science for the clinician 26: Tolerance--mechanisms and manifestations.

Usually the immune system monitors our internal milieu, protecting us from external and internal risks, silently watching over the rest. Pathologic autoimmunity is usually avoided, except in certain animal models and certain immunogenetically predisposed people. On the other hand, "salutary autoimmunity" occurs in the interaction of immune systems with themselves or other immune pathways as part of control or recognition mechanisms, eg, idiotype network, epitope-MHC complex binding with B- or T-cell antigen receptors. There are means by which dangerous autoimmune reactants are eliminated from the repertoire before birth; some of these are described here. However, potentially dangerous autoimmune effectors can be identified in the immunologic repertoire of certain adult animal strains but not damage the animal; these latent autoimmune effector pathways are held in check in adult animals/humans by active suppressive mechanisms.The identification and control of autoimmunity may well be the holy grail of rheumatology. Autoimmunity may also be an active participant in a number of other organ systems and diseases, so lessons learned in immunology may apply broadly throughout medicine. Once a better understanding of the normal processes and aberrancies that lead to disease are had, one can look forward to interventions to reestablish tolerance, perhaps by something as simple as a capsule containing the appropriate self antigen-containing molecules--"oral tolerizing" as a cure for autoimmune diseases! There is much promising evidence in favor of the efficacy of oral tolerance in animal models, but as of yet, human disease has proven a harder nut to crack. Although the concept of oral tolerance is nearing its centennial, there is still much to learn!

Animals↗
PubMed2005

Basic science for the clinician 27: Toll-like receptors and nucleotide oligomerization domains.

Ancient protective mechanisms are in place, deep within our defenses against infection and malignancy, often unappreciated until homologous proteins found within less phylogenetically advanced organisms are identified. Such is the case with 2 major recent finds, the Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) families of innate immunity molecules. These families of receptors have high specificity, limited heterogeneity, and no plasticity; nonetheless, they play a pivotal role in rapid initial defenses against pathogens. Moreover, studies of the mechanisms of TLRs and NODs show how they and IL-1 and IL-18 stand at the threshold of the adaptive immune response and help to accelerate specific immune responsivity. Nonspecific reactivity of these preprogrammed receptors may be how relatively nonpathogenic organisms like yersinia and chlamydia may drive the inflammation of reactive arthritis and atherosclerosis. The inflammation of rheumatoid arthritis may be magnified, if not initiated, by these innate mechanisms as well.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Basic science for the clinician 30: The immunologic synapse.

Interactions between discrete and independent cells, immune or otherwise, present a variety of potential problems. How do you make sure the cells can communicate effectively? How do you preclude neighboring cells from "listening in on a conversation" that may be meant only for one set of "ears"? How can you sharpen the hearing of those ears so they will be capable of detecting small signals but not get distracted by random noise in the system? How can you selectively enhance the sense of hearing in times of great need or urgency and then diminish the "gain" of the system when it is not immediately required? How can you assure that the call will be terminated at the end of the conversation? Passage of communication molecules and/or interaction of cell surface markers require close and stable apposition of the cell delivering the message with the receiving cell. In the nervous system, these problems were successfully addressed in the nerve-nerve or nerve-myocyte (neuromuscular junction) synapses. Not surprisingly, given the parsimony of nature, the immune system uses some of the same design features, even some of the same molecules, to achieve an effective communication strategy. The term "immunologic synapse" was coined only 2 decades ago, but the structure it describes has become a very hot topic in immunology and cell biology. The immunologic synapse allows the activation of a unique T cell, with an antigen receptor recognizing its antigen in the grasp of the antigen-presenting cell's (APC's) major histocompatibility complex (MHC). A better understanding of this transient immune cell-cell interactive structure allows one to weave the functions of T cell antigen receptors, lipid rafts, adaptor molecules, and nuclear signaling molecules together into one cohesive, flowing communication supersystem. Appreciation of the intricacies of the synapse also identifies targets that one day may be used to interfere with antigen-specific immune responses, eg, autoimmunity.

Antigen-Presenting Cells↗
PubMed2005

Basic science for the clinician 32: T-cells with regulatory function.

Tolerance is one of the major requirements of a successful immune system: destroy invaders but recognize self and the benign environment to leave them alone. Central tolerance is achieved by deletion of T-cells with T-cell antigen receptors that recognize self-antigens too well. However, within the population of T-cells that actually survive the harrowing experience of passage through the thymus (wherein over 98% of all pre-T-cells perish), there persist T-cells capable of inducing autoimmune damage. How then to avoid autoaggression? One theory in the 1970s was that there were peripheral T-suppressor cells that actively dampened these autoimmune proclivities. One problem presented itself, however; despite the fact that such an immunologic activity could be measured, no one could identify the cells that mediated the activity and so the concept fell into disfavor. However, the concept of peripheral regulation by a distinct (at last identifiable!) population of T-cells is now back in vogue. These T-regulatory (T-reg) cells have an important function in immune homeostasis. T-reg demand our attention as we try to manipulate the molecular biology of immune responses and inflammation to control autoimmune disorders and enhance transplantation efficiency.

CD4-Positive T-Lymphocytes↗
PubMed2005

Basic science for the clinician 35: CD1, invariant NKT (iNKT) Cells, and gammadelta T-cells.

As noted in previous articles in this series, the very heterogeneous MHC class I and II molecules present peptide antigens to T-cells. However, there is another family of less heterogeneous MHC-related molecules. CD1 molecules present lipid antigens, oftentimes to 2 other distinct families of T-cells: gammadelta T-cells (named because they bear a T-cell antigen receptor consisting of a gamma chain and a delta chain rather than the alpha chain/beta chain heterodimer on most T-cells) and iNKT cells (T-cells that bear markers previously defined on natural killer cells). CD1 molecules and the gammadelta T-cells and iNKT cells to which they present antigens have fundamental responsibilities for immune surveillance over intracellular pathogens and serve other roles that place them at the boundary between innate and acquired immunity. The gammadelta T-cell has been implicated in the pathogenesis of many diseases, rheumatologic and otherwise, suggesting that better understanding of these cells, and of CD1 molecules, may help us explain the immunopathogenesis of some inflammatory diseases and how to craft more targeted therapies in many fields of medicine.

Antigens, CD1↗
PubMed2004

Molecular biology and immunology for clinicians 29: lipid domains, lipid rafts, and caveolae.

The development of an antigen-specific immune response depends on the peptide-loaded MHC molecule on the surface of the antigen-presenting cell being found by the antigen-specific receptor on the cell about to be activated (the T-cell antigen receptor for T-cells or the membrane-bound immunoglobulin molecule on B-cells). The details of this process are becoming clear now with the appreciation of the supramolecular organization of the structures that make this cell-cell interaction. In the last 6 years has come an appreciation of the heterogeneity of the lipid bilayer membrane (a concept first put forth over 20 years ago), with certain lipids and membrane-bound proteins segregating into discrete ships called "lipid rafts" sailing in the surrounding more liquid lipid bilayer membrane. Knowledge of these microscopic structures leads to a better understanding of how antigen-specific responses are triggered and how aberrant responses are avoided; as one leader in the field put it, "keeping T-cells rested but ready."Membrane heterogeneity directly contributes to the rapid development of a more formalized cell-cell interaction that has been termed the "immunologic synapse." It is at this synapse that the acquired immune response, antigen specificity, is learned. In addition to antigen presentation, lipid rafts have also been implicated in signaling through a large number of receptors, endocytosis, cell interactions with pathogens and toxins, budding of viruses from host cell membrane, and the pathogenesis of prion disorders. Yet again, an insight in one discrete field of cell biology is proving to be of great relevance in a host of other areas of study.

Journal Article↗