Current directions in autoimmunity最新文献

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.

Lichen planus (LP) is an idiopathic inflammatory disease of the skin and mucous membranes, characterized by an autoimmune attack on the epidermis by skin-infiltrating T cells. It remains unknown, however, how such autoaggressive T cells could be activated in vivo to cause epidermal damage; we hypothesize that memory T cells specific for a previously encountered virus could cross-react with other antigens, including contact allergens, drugs and other heterologous viruses in the absence of cognate antigen, and cause epidermal damage. This hypothesis provides an explanation for an intimate relationship between exposure to a number of exogenous agents, such as viruses and drugs, and the development of LP. In addition to T cells migrating from the circulation, T cells indigenously residing in the epidermis, such as intraepidermal CD8+ T cells, would also be involved in tissue damage. This population is typically detected at high frequencies in the resting lesion of fixed drug eruption, which is a simplified disease model for LP. Fucosyltransferase VII, essential for generating E-selectin ligand, is shown to play an indispensable role in inducing the accumulation of relevant skin-homing T cells at sites of LP lesions; however, the alternative notion should be appreciated that T cell recruitment to the skin is also crucial for host defense and that T cells frequently found in LP lesions could display beneficial properties for the host.

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.

This chapter summarizes the evidence that defined compartments of the hair follicle (HF) and nail epithelium maintain an area of relative immune privilege (IP). HF and nail IP is chiefly characterized by absent or very low level of expression of major histocompatibility complex class Ia antigens, complemented by a number of factors, such as the local production of potent immunosuppressive agents, dysfunction of professional antigen-presenting cells and inhibition of natural killer cell activities. In the hair bulb, IP is seen only in the anagen stage of HF cycling, while the nail apparatus continuously maintains an IP site in its proximal nail matrix, since the nail apparatus does not cycle. Possibly, the (non-cycling) bulge area of human scalp HFs also enjoys some relative, stably maintained IP, even though it is not as pronounced as the IP of the anagen hair bulb. A collapse of HF and nail IP likely plays a key role in the pathogenesis of one of the most common organ-specific autoimmune diseases, alopecia areata. Therefore, the therapeutic restoration of IP collapse promises to be a particularly effective future strategy for the treatment of alopecia areata.

Pemphigus foliaceus (PF) and its endemic form fogo selvagem (FS) are autoimmune diseases characterized clinically by transient cutaneous superficial blisters. As opposed to pemphigus vulgaris (PV), patients lack mucosal involvement. Acantholysis in the upper epidermis is appreciated histologically. The serologic hallmark of PF and FS is the demonstration of IgG autoantibodies against the cell surface of keratinocytes. The specific target of these autoantibodies is desmoglein (Dsg) 1, one of the four known desmosomal cadherins, a family of transmembrane glycoproteins that play an important role in the dynamic regulation of intercellular adhesion. Compelling evidence has been compiled suggesting anti-Dsg1 autoantibodies in patients with PF and FS are pathogenic. The mechanism by which anti-Dsg autoantibodies induce loss of cell-cell adhesion in PF is under active investigation and is beginning to be elucidated. The study of the pathogenesis of PF and FS provides a unique opportunity to uncover insights that may contribute to our greater understanding of autoimmunity.

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.

Psoriasis is one of the most common chronic inflammatory disorders with a strong genetic background. Recent progress in the understanding of both the immunological as well as the genetic basis has provided an unprecedented opportunity to move scientific insights from the bench to bedside. Based on insights from laboratory research, targeted immunotherapies are now available for the benefit of patients suffering from psoriasis. The success of these therapies has validated insights into disease pathogenesis and also provides the opportunity to increase our understanding about the pathways underpinning autoimmune-type inflammation in the skin.

The pemphigoid group of autoimmune blistering diseases includes distinct entities (bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA dermatosis and lichen planus pemphigoides) that are characterized by relatively consistent clinical, histologic and immunopathologic findings. Patients with these disorders have antibasement membrane autoantibodies that often display pathogenic (blister-forming) activity following passive transfer to experimental animals. Interestingly, such autoantibodies target important structural proteins that promote adhesion of epidermis to epidermal basement membrane in human skin. Autoimmune blistering diseases are characterized by substantial morbidity (for example pruritus, pain, disfigurement) and in some instances mortality. Treatment with systemic immunosuppressives has reduced morbidity and mortality in patients with these diseases.

The prototypic autoimmune diseases involving skin (lupus, dermatomyositis) typically result in epithelial injury and autoantibodies to characteristic cellular antigens. Disease-specific autoantibodies are also found in scleroderma, but scleroderma is different from other cutaneous autoimmune diseases because epithelial injury does not occur. Multiple factors and combinations of factors (immune system, vascular and extracellular matrix abnormalities) are the most likely triggers in an individual with a genetic predisposition to scleroderma. These lead to increased synthesis of normal collagen in skin, lungs and gut in the systemic form of scleroderma, systemic sclerosis. The hypotheses for the pathophysiology of scleroderma are diverse and include abnormal immunologic processes such as cytokine and chemokine dysregulation, abnormal T cell signaling, B cell dysfunction, injury due to autoantibodies to endothelial cells, persistent wound healing condition due to dysregulation of matrix homeostasis, abnormalities in the fibrinolytic system, polymorphisms in critical molecules of the immune system and matrix homeostasis, and microchimerism due to fetal/maternal placental exchange of HLAcompatible cells. Systemic sclerosis/scleroderma is chronic and progressive. To date, no definitive therapy is effective for any of the scleroderma variants, although agents for the vascular dysfunction have some utility. Hematopoietic bone marrow or stem cell transplantation before significant tissue fibrosis has occurred may be the most effective treatment.