Springer seminars in immunopathology最新文献

In the most simplistic terms, immune tolerance can be envisioned as a balance with autoreactive cells that arise naturally in all individuals on one side and regulatory mechanisms designed to counter those autoreactive processes on the other. A tilt of the balance toward the autoreactive side, either by increasing the number or function of autoreactive cells or by diminishing regulatory mechanisms, is manifested as autoimmunity. In contrast, tilting of the balance toward increased regulation could conceivably cause immunodeficiency. Regulatory T cells (T(REG)), and particularly the naturally arising CD4(+)CD25(+) subset of T(REG) cells, provide a substantial component of the autoimmune counterbalance. The identification of forkhead box P3 (FOXP3) as a critical determinant of CD4(+)CD25(+) T(REG) development and function has provided new opportunities and generated expanded interest in studying the delicate balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. Identification of both human and mouse syndromes in which FOXP3 is mutated, and consequently CD4(+)CD25(+) T(REG) cells are absent, has led to a rapid accumulation of knowledge regarding T(REG) development and function over the past 5 years. The recent development of antibody reagents to specifically identify CD4(+)CD25(+) T(REG) cells by their FOXP3 expression has provided new tools to identify these elusive cells and investigate their role in human disease. This review will focus on the current state of knowledge regarding the role of T(REG) in human autoimmune diseases and on specific human immunodeficiencies that provide interesting models of autoimmunity.

Among the cells of the immune system involved in the pathogenesis of autoimmune disease, T cells have received the most attention. The central role of these cells in several animal models of autoimmune diseases and in human disease counterparts has provided the rationale for specific therapeutic targeting of T cell subsets, especially CD4 T cells. So far, the applicability of this approach has not been clearly evident in clinical trials, which was also the case when nondepleting "coating" anti-CD4 monoclonal antibodies was used. In the past several years, experimental evidence supporting a major role of B cells in systemic autoimmune disease has grown. This includes the pathogenicity of certain autoantibodies, the potential of B cells to present antigen in the context of MHC Class II and to signal via costimulatory molecules, and to secrete proinflammatory cytokines. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibodies. The depletion of B cells by targeting the surface marker CD20 has been shown to be effective in treating rheumatoid arthritis with a good side effect profile. Series of cases with other systemic autoimmune diseases indicate that this strategy may be effective in these conditions too. The clinical data add weight to the importance of B cells in the pathogenesis of autoimmune diseases.

Biologics are used in solid organ allografting and hematopoietic stem cell transplantation (HSCT) for the induction and maintenance of immunosuppression. In solid organ transplantation, antibodies targeting T cells are part of induction protocols administered for initiation of immunosuppression during organ transfer and during sustained post transplant periods for prevention of graft rejection. Several clinical trials in renal allografting provide data for the efficacy and safety of biologics in this clinical setting. Application of biologics also allows the reduction of calcineurin inhibitors, thereby reducing toxicity and improving long-term graft function. In acute rejection periods, anti T cell antibodies are established in steroid-resistant cases. Strategies interfering with the activity of soluble cytokines are less frequently applied for solid organ transplantation. In HSCT, T cell directed antibodies as part of conditioning protocols improve engraftment and reduce the incidence of detrimental graft vs host disease (GvHD). In acute GvHD, both antibodies targeting T cells and cytokines like TNF-alpha are established therapeutics for remission induction.

The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1beta has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

Recent studies have provided new insight into aberrations in the immunological interplay between mother and fetus and their potential role in the development of recurrent fetal loss and preeclampsia. The action of anti-phospholipid antibodies in recurrent fetal loss is now proposed to involve the complement system, neutrophil activation and the production of TNFalpha by immune bystander cells. A clear involvement of the immune system is emerging in preeclampsia, involving mainly the innate arm, especially neutrophils. The activation of peripheral neutrophils by placentally released inflammatory debris triggers the induction of neutrophil extracellular traps (NETs), which may lead to an occlusion of the intervillous space, thereby further promoting a condition of placental hypoxia. It has, hence, been suggested that new therapeutic strategies be developed, including the possible use of TNFalpha antagonists in cases of recurrent miscarriage. These strategies need to be addressed with caution due to the possible induction of fetal congenital abnormalities.

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-alpha), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-alpha, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-alpha is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.

The concept of costimulation, the requirement for an independent accessory cellular activation signal that supplements the signal delivered to a lymphocyte by antigen, has been a focal point of progress in understanding the regulation of the immune system. While considerable attention has been directed to new developments related to the activation of cells of the innate immune system through Toll-like receptors, resulting in the production of soluble mediators, augmented expression of cell surface costimulatory molecules on antigen-presenting cells is arguably the most significant early outcome of immune system activation. It is those cell surface molecules that provide the essential afferent costimulatory signals to T cells of the adaptive immune response. Once fully activated, T cells express their own cell surface accessory molecules that permit those T cells to instruct interacting B cells, macrophages, and dendritic cells to further implement an effective immune response. Significantly for patients with autoimmune diseases, the manipulation of costimulatory signals represents a rational and effective approach to modulating the chronic immune system activation that characterizes those diseases. Further elucidation of the complexities of members of the accessory molecule families and their functions should lead to an ever greater capacity for therapeutic modulation of the immune response in autoimmune and inflammatory diseases.