Andrea T. Borchers

Probiotics and immunity

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.

Mushrooms, Tumors, and Immunity: An Update

There is significant interest in the use of mushrooms and/or mushroom extracts as dietary supplements based on theories that they enhance immune function and promote health. To some extent, select mushrooms have been shown to have stimulatory action on immune responsiveness, particularly when studied in vitro. However, despite their widespread use for potential health benefits, there is a surprising paucity of epidemiologic and experimental studies that address the biologic activities of mushrooms after oral administration to animals or humans. There have been a number of studies that have addressed the ability of mushrooms to modulate mononuclear cell activation and the phenotypic expression of cytokines and their cognate receptors. There have also been a number of attempts to determine antitumor activities of mushrooms. Such studies are important because many of the components of mushrooms do potentially have significant biologic activity. All data, however, should be tempered by the Possibility that there are toxic levels of metals, including arsenic, lead, cadmium, and mercury as well as the presence of radioactive contamination with 137Cs. In this review, we will Present the comparative biology with respect to both immunological and antitumor activities of mushroom extracts and also highlight the need for further evidence-based research.

The geoepidemiology of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by absolute insulin deficiency resulting from the progressive immune-mediated destruction of pancreatic islet beta cells. It is thought to be triggered by as yet unidentified environmental factors in genetically susceptible individuals, the major genetic contribution coming from loci within the HLA complex, in particular HLA class II. The worldwide incidence of T1D varies by at least 100-fold, being highest in Finland and Sardinia (Italy) and lowest in Venezuela and China. The incidence has been increasing worldwide at an annual rate of approximately 3%. While genetic factors are thought to explain some of the geographic variability in T1D occurrence, they cannot account for its rapidly increasing frequency. Instead, the declining proportion of newly diagnosed children with high-risk genotypes suggests that environmental pressures are now able to trigger T1D in genotypes that previously would not have developed the disease during childhood. Although comparisons between countries and regions with low and high-incidence rates have suggested that higher socioeconomic status and degree of urbanization are among the environmental factors that play a role in the rising incidence of T1D, the findings are too inconsistent to allow firm conclusions. Morbidity and mortality as well as causes of death also show considerable geographic variation. While glycemic control has been identified as a major predictor of the micro- and macrovascular complications of T1D and shows considerable geographical variability, it does not appear to be the only factor involved in the regional differences in complication rates. The role of genetics in susceptibility to nephropathy, retinopathy and other diabetic complications largely remains to be explored.

Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life threatening, diseases characterized by widespread epidermal necrosis, and are predominantly medication-induced. Unfortunately, though they are often associated with long-term debilitating sequelae, there are currently no efficacious pharmaceutical interventions proven through large clinical trials. It has been well established that the epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific T cells are implicated in this process, our understanding of the immunopathology is far from complete. The scenario suggested by todays literature points towards drug-specific CD8+ cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently, there may be an expansion of apoptosis involving the interaction of either membrane-bound or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains controversial, with both peripheral lymphocytes and keratinocytes themselves as potential candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better understanding of the underlying immunological mechanisms is required to identify appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug hypersensitivity to prevent SJS/TEN.

Lupus nephritis: A critical review

Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role of type I interferons is increasingly recognized; new insights have been gained into the contribution of immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents, including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials that established the equivalency of these agents in the induction and/or maintenance therapy of lupus nephritis, culminating in the recent publication of new treatment guidelines by the American College of Rheumatology. Although newer biologics have been approved and continue to be a focus of research, they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.

The implications of autoimmunity and pregnancy

There are multiple epidemiological studies that document the potential adverse affects of autoimmunity on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease. Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism? Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).

The Immunobiology of Mushrooms

There has been enormous interest in the biologic activity of mushrooms and innumerable claims have been made that mushrooms have beneficial effects on immune function with subsequent implications for inhibition of tumor growth. The majority of these observations are anecdotal and often lack standardization. However, there remains considerable data on both in vitro and in vivo effects that reflect on the potential of mushroom compounds to influence human immunity. A number of these effects are beneficial but, unfortunately, many responses are still characterized based on phenomenology and there is more speculation than substance. With respect to tumor biology, although many neoplastic lesions are immunogenic, tumor antigens frequently are self antigens and induce tolerance and many patients with cancer exhibit suppressed immune responses, including defective antigen presentation. Therefore, if and when mushroom extracts are effective, they more likely function as a result of improved antigen presentation by dendritic cells than by a direct cytopathic effect. In this review we attempt to place these data in perspective, with a particular focus on dendritic cell populations and the ability of mushroom extracts to modulate immunity. There is, at present, no scientific basis for the use of either mushrooms or mushroom extracts in the treatment of human patients but there is significant potential for rigorous research to understand the potential of mushrooms in human disease and thence to focus on appropriate clinical trials to demonstrate effectiveness and/ or potential toxicity.

Drug-induced lupus.

Abstract:  Drug‐induced lupus (DIL) is a rare adverse reaction to a large variety of drugs with features resembling those of idiopathic systemic lupus erythematosus (SLE). It usually develops only after months and, quite commonly, years of treatment with the offending agent, although latencies of days or weeks have been described in some instances. There are some indications that the risk of DIL can increase with higher daily and cumulative doses and with longer duration of therapy. There are no definitive and commonly accepted diagnostic criteria for DIL, but the following guidelines have been proposed: (a) sufficient and continuing exposure to a specific drug, (b) at least one symptom compatible with SLE, (c) no history suggestive of SLE before starting the drug, and (d) resolution of symptoms within weeks (sometimes months) after discontinuation of the putative offending agent. In addition, it is frequently suggested that the presence of ANA is required for the diagnosis of DIL. However, negative ANA test results should not automatically preclude such a diagnosis, particularly if a patient has other autoantibodies associated with SLE/DIL.

Giant cell arteritis: A review of classification, pathophysiology, geoepidemiology and treatment

Giant cell arteritis is a chronic vasculitis affecting large and medium-sized arteries, most commonly the temporal and other cranial arteries. Temporal artery biopsy has long been the gold standard for establishing the diagnosis of giant cell arteritis. There is growing evidence that simultaneous color Doppler and duplex ultrasonography of temporal arteries of GCA patients represents a valid alternative for this somewhat invasive procedure. Ultrasonography and other imaging modalities such as magnetic resonance imaging and positron emission tomography have also provided evidence that involvement of the aorta and its proximal branches is much more common in giant cell arteritis than previously appreciated; it will be important to clarify whether these patients need to be treated more aggressively. It has long been known that patients with giant cell arteritis face a markedly increased risk of developing aortic aneurysms and of dying from aortic dissection. This raises important questions as to whether patients should be screened regularly for extra-cranial large-vessel involvement and whether and how treatment of patients with positive screening results should be adjusted. In this review we discuss the pathophysiology of this disease and also the issues of epidemiology and sex differences.

The SAPHO Syndrome

OBJECTIVE To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. METHODS We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. RESULTS The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. CONCLUSIONS The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.