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TRAF6 is a member of the TNF receptor associated factor (TRAF) family, members of which are important for signaling induced by a variety of the TNF receptor family members. TRAF6 was initially identified as a signaling adapter for CD40, but has subsequently been shown to be a critical factor for the interleukin-1 receptor~Toll-like receptor (IL-lR/TLR) family. Therefore, TRAF6 represents a central point of con- vergence for the signal transduction by the TNFR and the IL-lR/TLR superfamilies, and thus plays a critical role in the regulation of innate immune responses. Considering the importance of the TNFR and IL-RITLR family members to the regulation of the innate immune system, the extent to which TRAF6 regulates the physiology of innate immunity, as well as the connection between the innate and adaptive immune responses, is of great interest. Here we have described the potential role of TRAF6 in regulating dendritic cell fates.

The term “innate” has several functional connotations for dendritic cell (DC) biology (Table 1). DCs can mediate innate immunity directly; they also link innate and adaptive arms of the immune system during immune responses and in maintaining tolerance.

A critical but unanswered question is what defines each individual’s pre-morbid susceptibility to infection? w e propose that individuals must have an “immune haplotype” that shapes their response to infectious agents. Infection is a balance between the intrinsic virulence of the infectious agent and the host defenses. Recent viral outbreaks of SARS and influenza serve to illustrate this point as these viruses cause severe disease in certain individuals, yet there are others in whom the same infectious challenge results in minimal symptoms. On the other hand it might be that those self same people who are resistance to one particular viral infection might be susceptible to other infection challenges. Similar rules can apply to susceptibility to bacterial infections.

The immune system evolved to protect us from microbes. The antigen (Ag)-nonspecific innate immunity and Ag-specific adaptive immunity synergize to eradicate the invading pathogen through cells, such as dendritic cells (DCZ7) and lymphocytes, and through their effector proteins including antimicrobial peptides, complement, and antibodies. Its intrinsic complexity renders the immune system prone to dysfunction including cancer, autoimmunity, chronic inflammation and allergy. DCs are unique in their capacity to induce and regulate immune responses and are therefore attractive candidates for immunotherapy. However, DCs consist of distinct subsets with common as well as unique functions that lead to distinct types of immune responses. Therefore, understanding DC heterogeneity and their role in immunopathology is critical to design better strategies for immunotherapy. Indeed, what we learn from studying autoimmunity will help us induce strong vaccine specific immunity, either protective, as in the case of microbes, or therapeutic, as in the case of tumors.

Langerhans cells (LCs) through their stimulation of donor T cells likely play a key role in skin graft-versus-host-disease (GVHD), a serious complication that limits the use of allogeneic BM transplantation (1–5). LCs belong to a family of highly specialized antigen presenting cells called dendritic cells (DCs) (6, 7) and represent the only DCs of the epidermis (8). In common with all DCs, LCs are well equipped to capture environmental antigens, migrate to lymph nodes (LNs), and initiate specific T cell immune responses playing a critical role in skin immunity (6). Despite their importance, little is known about the life cycle of LCs, their precursor cell in the blood, the mechanism of LC replenishment after skin injury, and their homeostasis after allogeneic bone marrow (BM) transplantation. In this paper, we will discuss recent advances in our understanding of LC homeostasis during steady state and inflammatory conditions and the potential role of LCs in transplant immune reactions.

Humoral immune responses to foreign and self-antigens must be tightly regulated to facilitate protective immunity to pathogens while avoiding autoimmune responses. The outcome of these responses is determined in part by signals generated through the B lymphocyte antigen receptor (BCR). These signals are further supplemented and fine- tuned by other cell-surface molecules that modify and provide a context for BCR signal transduction. Such molecules, or “response regulators”, influence these events by positively or negatively biasing the context of BCR signaling, thus establishing appropriate signaling thresholds. Response regulators amplify or dampen BCR signaling by regulating the activity of intracellular kinases, phosphatases, and other effector proteins. Included among the list of BCR signal transduction response regulators is CD19, which integrates multiple intracellular signaling pathways. On the B cell surface, CD19 interacts directly with CD21 (complement receptor 2, CR2), a receptor for the C3d complement cleavage product that forms covalent bonds with foreign Ags or immune complexes to effectively link innate and acquired immunity. This review summarizes recent findings that have clarified how the CD19/CD21 receptor complex functions to regulate B cell responses in host defense and autoimmunity.

A number of recent studies have suggested that complement receptor type 2 (CR2, CD21) may play a role in the development of systemic autoimmunity. This receptor, located primarily on B cells and follicular dendritic cells in mice with a broader distribution in humans, binds C3 degradation products that have become covalently bound to antigen or immune complexes in the process of complement activation. Its role in both normal immune responses as well as systemic autoimmune disease has been supported by studies of mice in which the gene has been knocked out by homologous recombination. Furthermore, it is structurally and functionally altered in the NZM2410 mouse model of lupus, and is a strong candidate gene for lupus susceptibility in this model. Based on its known functions, several mechanisms can be hypothesized to explain its potential role in the pathogenesis of systemic lupus erythematosus.

The complement system has a significant role in innate immunity, in the inflammatory process, and in the adaptive immune response. Activated complement fragments also have the capacity to bind and damage tissues, especially in areas of inflammation. Cells must be sheltered from the harmful consequences of complement activation. To investigate the role of these molecules in vivo , we generated mice deficient in the expression of one of the molecules involved in complement regulation. The mouse Cny protein belongs to a family of molecules that regulates complement activation, protecting tissues from complement-mediated damage Crry mice do not survive pregnancy due to abnormal complement deposition in the placenta. The Cny-deficient mouse, therefore, is a valuable model to study the role of complement and complement regulators during pregnancy. Herein we describe studies that analyze further the mechanisms by which the Cny deficiency affects fetal survival, clarifying our understanding of the role of innate immune responses in pregnancy.