Results from clinical trials of biologic anti-TNF drugs performed in the late 1990s confirmed the biological relevance of TNF function in the pathogenesis of chronic noninfectious inflammation of joints, skin and gut, which collectively affects 2-3% of the population. Up to April 2009, more than two million patients worldwide have received the first marketed drugs, namely the monoclonal anti-TNF antibodies infliximab and adalimumab and the soluble TNF receptor etanercept. All three are equally effective in rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, but, for not clearly defined reasons, only the monoclonal antibodies are effective in inflammatory bowel disease. About 60% of patients who do not benefit from standard nonbiologic treatments for these diseases respond to TNF antagonists. Less than half of responding patients achieve complete remission of disease. Importantly, some of those patients with rheumatoid arthritis in whom long-term anti-TNF therapy induced disease remission remain disease-free after discontinuation of any kind of treatment. There are not yet reliable predictors of which patients will or will not respond on anti-TNF therapy, whereas subsequent loss of an initial clinical response occurs frequently. The spectrum of efficacy anti-TNF therapies widens to include diseases such as systemic vasculitis and sight-threatening uveitis. While paradoxical new adverse effects are recognized, i.e. exacerbation or development of new onset psoriasis, reactivation of latent tuberculosis remains the most important safety issue of anti-TNF therapies. Clinical practice guidelines and consensus statements on the criteria of introduction, duration of treatment and cessation of TNF antagonists, including safety issues, are under constant revision as data from longer periods of patient exposure accumulate. It is hoped that more efficacious drugs that will ideally target the deleterious proinflammatory properties of TNF without compromising its protective role in host defense and (auto)immunity will be available in the near future.

TNF is essential to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while defective TNF production results in uncontrolled infection. The critical role of TNF in the control of tuberculosis has been illustrated recently by primary and reactivation of latent infection in some patients under pharmacological anti-TNF therapy for rheumatoid arthritis or Crohn's disease. In this review, we discuss results of recent studies aimed at better understanding of molecular, cellular and kinetic aspects of TNF-mediated regulation of host-mycobacteria interactions. In particular, recent data using either mutant mice expressing solely membrane TNF or specific inhibitor sparing membrane TNF demonstrated that membrane TNF is sufficient to control acute M. tuberculosis infection. This is opening the way to selective TNF neutralization that might retain the desired anti-inflammatory effect but reduce the infectious risk.

Obesity, an epidemic of our times with rates rising to alarming levels, is associated with comorbidities including cardiovascular diseases, arthritis, certain cancers, and degenerative diseases of the brain and other organs. Importantly, obesity is a leading cause of insulin resistance and type 2 diabetes. As emerging evidence has shown over the last decade, inflammation is one of the critical processes associated with the development of insulin resistance, diabetes and related diseases, and obesity is now considered as a state of chronic low-grade inflammation. Adipose tissue, apart from its classical role as an energy storage depot, is also a major endocrine organ secreting many factors, whose local and circulating levels are affected by the degree of adiposity. Obesity leads to infiltration of the expanded adipose tissue by macrophages and increased levels in proinflammatory cytokines. The first indication for increased cytokine release in obesity was provided by the identification of increased expression of TNF-alpha, a proinflammatory cytokine, in the adipose tissue of obese mice in the early 1990s. TNF-alpha is expressed in and secreted by adipose tissue, its levels correlating with the degree of adiposity and the associated insulin resistance. Targeting TNF-alpha and/or its receptors has been suggested as a promising treatment for insulin resistance and type 2 diabetes. This review will summarize the available knowledge on the role of TNF-alpha in obesity and related processes and the potential implications of the above in the development of new therapeutic approaches for obesity and insulin resistance. Recent data from clinical studies will also be described together with late findings on the pathogenesis of obesity and insulin resistance.

Bone is subject to permanent remodeling during development and through life. This activity is essential for (a) proper shaping and growth of each bone during development; (b) maintenance of bone mass as well as structural integrity of the micro architecture of bone through adult life, and (c) tissue repair needed for healing of fracture as well as of micro-damage. In addition to genetically linked rare developmental diseases, disturbances in bone remodeling are causing common bone pathologies, which severely impair the quality of life of patients. Among them are postmenopausal osteoporosis and local as well as systemic bone loss observed in chronic inflammatory diseases such as rheumatoid arthritis. The role of TNF-alpha in mediating bone remodeling will be presented and discussed in this chapter.

TNF-alpha (TNF) is a pleiotropic cytokine which can have proinflammatory or immunosuppressive effects, depending on the context, duration of exposure and disease state. The basis for the opposing actions of TNF remains elusive. The growing appreciation of CD4+FoxP3+ regulatory T cells (Tregs), which comprise approximately 10% of peripheral CD4 cells, as pivotal regulators of immune responses has provided a new framework to define the cellular and molecular basis underlying the contrasting action of TNF. TNF by itself can overcome the profound anergic state of T cell receptor-stimulated Tregs. Furthermore, in concert with IL-2, TNF selectively activates Tregs, resulting in proliferation, upregulation of FoxP3 expression and increases in their suppressive activity. Both human and mouse Tregs predominantly express TNFR2, making it possible for TNF to enhance Treg activity, which helps limit the collateral damage caused by excessive immune responses and eventually terminates immune response. TNFR2-expressing CD4+FoxP3+ Tregs comprise approximately 40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered.

TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function.

TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-beta-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells.

TNF is a potent cytokine with an important role in the regulation of a multitude of cellular responses and in coordinating immune and inflammatory reactions. TNF exerts its effects by binding to the TNFR1- and TNFR2-specific cell surface receptors, which activate a number of intracellular signaling cascades including the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways. Activation of NF-kappaB mediates many of the functions of TNF by transmitting information from the cell surface TNF receptors to the nucleus, where it coordinates a gene expression program that allows the cell to survive and elicit its responses. The intimate interplay of TNF with the NF-kappaB signaling pathway is highlighted by results obtained in transgenic and knockout mice with defects in NF-kappaB signaling components, where TNF has been shown to contribute to different pathologies observed in these mice. This chapter focuses on the function of TNF in pathologies induced by NF-kappaB deficiency and discusses the implications of these findings for our understanding of inflammatory diseases.

The relationship between TNF and immune pathology forced an intense research into the regulation of its biosynthesis that extends to multiple mechanisms controlling the utilization of its mRNA. These posttranscriptional mechanisms gradually and variably impose a series of flexible rate-limiting controls to modify the abundance of the TNF mRNA and the rate of its translation in response to environmental signals. Mechanistically, these controls consist of signaling networks converging to RNA-binding proteins and microRNAs, which in turn target a code of secondary or tertiary ribonucleotide structures located on the TNF mRNA. The outcome of these interactions is the stringent control of this mRNA's maturation, localization, turnover and translation. A wealth of molecular and genetic data highlighted that if these posttranscriptional interactions fail, they perturb cellular responses to provide the impetus for TNF-mediated inflammatory disease. Here, we highlight the parameters guiding the posttranscriptional regulation of TNF mRNA and their relevance to homeostasis and pathology.

The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor kappaB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus.

The TNF/TNF receptor (TNFR) system has a prominent role in the pathogenesis of chronic inflammatory and autoimmune disorders. Extensive research in animal models with deregulated TNF expression has documented that TNF may initiate or sustain inflammatory pathology, while at the same time may exert immunomodulatory or disease-suppressive activities. The TNF/TNFR system encompassing both the soluble and the transmembrane form of TNF with differential biological activities, as well as the differential usage of its receptors, mediating distinct functions, appears to confer complexity but also specificity in the action of TNF. The inherent complexity in TNF-mediated pathophysiology highlights the requirement to address the role of TNF taking into account both proinflammatory tissue-damaging and immunomodulatory functions in a cellular and receptor-specific manner. In this review, we discuss our current understanding of the involvement of TNF in chronic inflammation and autoimmunity, focusing on TNF-mediated cellular pathways leading to the pathogenesis or progression of joint and intestinal inflammatory pathology. Knowledge of the mechanisms by which TNF either initiates or contributes to disease pathology is fundamentally required for the design of safe and effective anti-TNF/TNFR therapies for human inflammatory and autoimmune disorders.

Our increased understanding of the mechanisms of immune-mediated skin disease has led to the growth of therapeutic options for these diseases. Treatment options impact the various levels of the immune response, including the activation and effector function of immune cells. In this review, we give a broad outline of the steps in the immune process that can be altered by immunomodulatory therapy as well as a working model for the potential areas of intervention for new treatments.

Autoimmune diseases present with varied and broad-ranging cutaneous manifestations. Connective tissue disorders have a plethora of skin manifestations such as rheumatoid nodules in rheumatoid arthritis, psoriatic plaques in psoriatic arthritis, acne and pustulosis in SAPHO syndrome, livedo reticularis and ulceration in antiphospholipid antibody syndrome and xerosis in Sjögren syndrome. Cutaneous manifestations of autoimmune vasculitides such as polyarteritis nodosa, Kawasaki disease, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, Behcet disease, Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome range from papules, subcutaneous nodules and livedo reticularis, to palpable purpura, hemorrhagic bulla and ulcerating lesions. Pathological skin manifestations in autoimmune endocrinopathies include pretibial myxedema/dermopathy in Graves' disease, diabetic dermopathy and necrobiosis lipoidica in type I autoimmune diabetes mellitus, candidiasis, ectodermal dysplasia, vitiligo and alopecia areata in APECED and uniform hyperpigmentation of the skin in Addison's disease. Autoimmune gastrointestinal disorders such as inflammatory bowel disease (with erythema nodosum), gluten-sensitive enteropathy (with dermatitis herpetiformis), autoimmune hepatitis and primary biliary cirrhosis (with jaundice and pruritus), hematologic/oncologic disorders such as acute and chronic graft-versus-host disease (with skin manifestations ranging from pruritic maculopapular eruptions and lichen planus-like lesions to generalized scleroderma), and paraneoplastic autoimmune dermatoses are discussed as well.

The mode of action of intravenous immunoglobulin (IVIg) is complex. An ongoing research continues to elaborate and identify novel mechanisms. Recent advances have demonstrated that IVIg has direct effect on keratinocytes, the target cells of autoimmune blistering diseases. IVIg protects keratinocytes from pathogenic autoantibodies by preventing the autoantibody-induced of apoptosis and oncosis. This anti-apoptotic action of IVIg helps explain how IVIg works in severe, life threatening dermatologic conditions that are resistant to traditional systemic treatments, such as toxic epidermal necrolysis and Stevens-Johnson syndrome. Thus, the actions of IVIg are varied and complex, and the primary mechanisms of action may be different in different diseases.

Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Although thought to be autoimmune in origin, many questions remain as to the etiopathogenesis of this disease. DM has classically been considered a humorally mediated disease. Current evidence, however, seems to increasingly support alternative (though not mutually exclusive) mechanisms of pathogenesis, including cell-mediated and innate immune system dysfunction. Pathologic findings of DM in muscle include infarcts, perifascicular atrophy, endothelial cell swelling and necrosis, vessel wall membrane attack complex deposition, and myocyte-specific MHC I upregulation. As for the skin, histopathologic findings include hyperkeratosis, epidermal basal cell vacuolar degeneration and apoptosis, increased dermal mucin deposition, and a cell-poor interface dermatitis. Autoantibodies, particularly those that bind nuclear or cytoplasmic ribonucleoprotein antigens, are also commonly found in DM, although their importance in pathogenesis remains unclear. Defective cellular clearance, genetic predilection and environmental exposures, such as viral infection, may also play an important role in the pathogenesis of DM. The seminal work regarding the pathogenesis of DM is reviewed and an update on the recent basic and molecular advances in the field is provided.