Springer seminars in immunopathology最新文献

Numerous studies in several species have shown that certain subsets of T and B lymphocytes express antigen receptors which are either semi-invariant, or germline encoded, and often autoreactive. In the case of B cells they appear to use a distinct immune recognition strategy during developmental selection and functional activation. These B cells respond to foreign antigens, and have the ability to protect against a variety of infections; however, they can also react with self or neoself antigens. They appear to use the latter as positively selecting ligands facilitating their entry into and maintenance in a functional repertoire, as well as providing cues for positioning themselves in strategic microenvironmental niches in the immune system and at interfaces with the environment. These innate-like B cell subsets form a bridge between the rapidly occurring innate immune responses, and the slower acting primary, T cell-dependent, adaptive antibody response by providing a rapid T cell-independent antibody response.

Natural antibodies produced by CD5+ B-1 B cells include those with specificity for senescent erythrocytes (anti-BrMRBC, anti-PtC) and for thymocytes (anti-thymocyte autoantibody, ATA). Here we describe work from our laboratories studying two prototypic examples, V(H)11Vkappa9-encoded anti-BrMRBC and V(H)3609Vkappa21c-encoded ATA. Using V(H)11-mu transgenic mice, we discovered that certain natural autoantibodies utilize V(H) genes that are selected against in bone marrow B cell development, but not fetal liver, effectively restricting their generation to fetal/neonatal life. Studies with ATA-mu transgenic mice demonstrated a critical requirement for self antigen in the accumulation of B cells with this specificity and for the production of high levels of serum ATA. Finally, analysis of B cell development in ATA-mu kappa transgenic mice revealed two distinct responses by B cells to expression of this B cell receptor (BCR): most developing B cells in spleen of adult mice were blocked at an immature stage and only escaped apoptosis by editing their BCR to eliminate the ATA specificity; nevertheless, high levels of serum ATA were observed, indicating that some B cells differentiated to antibody-forming cells without altering their specificity. Thus, our studies reveal mechanisms for restricting the generation of B cells producing natural autoantibodies, demonstrate a key positive selection step in their development, and show that most developing B cells in adult mice bearing such specificities fail to reach a mature stage.

Mucosal lymphocyte homeostasis involves the dynamic interaction of enteric microbiota, the intestinal host epithelium, and the mucosal immune system. Dysregulation of mucosal lymphocyte homeostasis results in a variety of intestinal disorders, notably inflammatory bowel diseases like ulcerative colitis and Crohn's disease. One key cellular component regulating homeostasis are B lymphocytes that reside in gut-associated lymphoid tissue. This compartment includes Peyer's patches, isolated lymphoid follicles, lamina propria, and mesenteric lymph nodes. Recent data have pointed to two new and exciting aspects of B cells in the gut. First, there has been progress on identification and functional analysis of abundant isolated lymphoid follicle B cells that are key mediators of IgA genesis. Second, several groups have now clarified the functional identification and characterization of immunoregulatory B cells in the gut. This review examines the novel aspects of these B cells, and examines how each plays a role in mediating mucosal homeostasis in this bacteria-laden compartment.

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.

Natural antibodies are produced at tightly regulated levels in the complete absence of external antigenic stimulation. They provide immediate, early and broad protection against pathogens, making them a crucial non-redundant component of the humoral immune system. These antibodies are produced mainly, if not exclusively, by a subset of long-lived, self-replenishing B cells termed B-1 cells. We argue here that the unique developmental pattern of these B-1 cells, which rests on positive selection by self antigens, ensures production of natural antibodies expressing evolutionarily important specificities that are required for the initial defense against invading pathogens. Positive selection for reactivity with self antigens could also result in the production of detrimental anti-self antibodies. However, B-1 cells have evolved a unique response pattern that minimizes the risk of autoimmunity. Although these cells respond rapidly and strongly to host-derived innate signals, such as cytokines, and to pathogen-encoded signals, such as lipopolysaccharide and phosphorylcholine, they respond very poorly to receptor-mediated activation. In addition, they rarely enter germinal centers and undergo affinity maturation. Thus, their potential for producing high-affinity antibodies with harmful anti-self specificity is highly restricted. The positive selection of B-1 cells occurs during the neonatal period, during which the long-lived self-renewing B-1 population is constituted. Many of these cells (B-1a) express CD5, although a smaller subset (B-1b) does not express this surface marker. Importantly, B-1a cells should not be confused with short-lived anergic B-2 cells, which originate in the bone marrow in adults and initiate CD5 expression and programmed cell death following self-antigen recognition. In summary, we argue here that the mechanisms that enable natural antibody production by B-1 cells reflect the humoral immune system, which has evolved in layers whose distinct developmental mechanisms generate complementary repertoires that collectively operate to maximize flexibility in responses to invading pathogens. B-2 cells, present in what may be the most highly evolved layer(s), express a repertoire that is explicitly selected against self recognition and directed towards the generation of high-affinity antibody response to external antigenic stimuli. B-1 cells, whose repertoire is selected by recognition of self antigen, belong to what may be earlier layer(s) and inherently maintain production of evolutionarily important antibody specificities that respond to pathogen-related, rather then antigen-specific signals.

Marginal zone B cells and B-1 cells have been termed innate-like B cells as they express limited repertoires that play special roles in immune defenses against common infections. These B cells are the sources of natural antibodies and are capable of highly accelerated clonal responses that help counter blood-borne infections. We have characterized a class of microbial product with highly adapted binding interactions with host immunoglobulins/B cell receptors (BCRs), which enable the targeting of large supra-clonal sets of B cells for activation-associated apoptotic death. In recent studies, we have shown that all B cells with V region-targeted BCRs are susceptible. However, compared to follicular B cells, in vivo exposure preferentially causes innate-like B cells to undergo induced death with subsequent long-lasting supra-clonal depletion and immune tolerance. Based on these properties, it is likely that B cell superantigens influence the pathogenesis of some common infections, but also may provide novel therapeutic opportunities to treat B cell neoplastic and autoimmune diseases.

Natural (i.e. low-affinity, preimmune) IgM has a wide range of actions in the immune system. That IgM is important in defence against infection has been recognised for many years but recently, due to the generation of mouse models specifically deficient in serum IgM, other functions of serum IgM have been revealed. The participation of natural IgM in autoimmunity has been a subject of speculation for some time, but there is recent definitive evidence that demonstrates its protective role. This review focuses on these new areas of research, which also show that many pathologies not normally recognised as having an immunological basis are modulated by serum IgM.

Antibodies (Abs) and enzymes are structural and functional relatives. Abs with promiscuous peptidase activity are ubiquitous in healthy humans, evidently derived from germline variable domain immunoglobulin genes encoding the serine protease-like nucleophilic function. Exogenous and endogenous electrophilic antigens can bind the nucleophilic sites covalently, and recent evidence suggests that immunization with such antigens can induce proteolytic antibodies. Previously, Ab catalytic activities have been linked to pathogenic autoimmune reactions, but recent studies indicate that proteolytic Abs may also serve beneficial functions. An example is the rapid and selective cleavage of the HIV-1 coat protein gp120 by IgMs found in uninfected humans. The selectivity of this reaction appears to derive from recognition of gp120 as a superantigen. A second example is the cleavage of amyloid beta-peptide by IgM and IgG from aged humans, a phenomenon that may represent a specific proteolytic response to a neurotoxic endogenous peptide implicated in the pathogenesis of Alzheimer's disease.

In recent years, the subject of natural antibodies has been revisited and the immunobiological roles of these humoral factors are being better defined. These antibodies are secreted by distinct sets of innate-like B cells, B-1 cells and marginal zone B cells, which arise early in development to become the sources of "natural immune memory". Due to their interactions with a variety of self-determinants, natural antibodies have previously been postulated to play roles in the maintenance of host homeostasis. A central paradigm has recently been developed from the demonstration that oxidation derived epitopes on apoptotic cells and oxidized low-density lipoproteins are recognized by the phosphorylcholine-specific germline encoded B-1 cell natural antibody, T15, which has provided important insights into possible "house-keeping" functions under both normal and pathological conditions. In this review, the potential functions of natural antibodies in the pathogenesis and progression of the chronic inflammatory condition of atherosclerosis are discussed, as well as their capacities for apoptotic cell binding and clearance. These interactions of natural antibodies and oxidation-epitopes from phospholipids appear to provide a dynamic immunobiological connection linking host responses in infection, autoimmunity and atherosclerosis.