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Others specialized B cell subsets include marginal zone B cells, which localize to the region between the red and white pulp in the spleen, and B1 cells, which. (2) is based on several surrogate markers of B cell differentiation (B, PNA- binding, CD38 Both memory B cells and memory plasma cells express affinity- matured, 5 A of the paper (2), there is no difference between day 0 and day 7 with. Kipps T.J. Kipps, Thomas south-park-episodes.infoons of B Lymphocytes and Plasma Cells in . Exposed between constant-region globular domains, the hinge region is attacked SP: DNA double-strand breaks: Signaling, repair and the cancer connection.
It is also expressed on malignant plasma cells in multiple myeloma. Compared with CD, which disappears rapidly ex vivo, the expression of CD is considerably more stable.
This is a type of safeguard to the system, almost like a two-factor authentication method. First, the B cells have to encounter a foreign antigen, and are then required to be activated by T helper cells before they differentiate to specific cells. Upon stimulation by a T cell, which usually occurs in germinal centers of secondary lymphoid organs like the spleen and lymph nodesthe activated B cell begins to differentiate into more specialized cells.
Germinal center B cells may differentiate into memory B cells or plasma cells. Most of these B cells will become plasmablasts or "immature plasma cells"and eventually plasma cells, and begin producing large volumes of antibodies. Some B cells will undergo a process known as affinity maturation.
Selecting B cells and plasma cells to memory
Immature plasma cells[ edit ] The most immature blood cell that is considered of plasma cell lineage is the plasmablast. Function[ edit ] After the process of affinity maturation in germinal centers, plasma cells have an indeterminate lifespan, ranging from days to months.
Recently they have been shown to reside for much longer periods in the bone marrow as long-lived plasma cells LLPC.
They secrete high levels of antibodies, ranging from hundreds to thousands of antibodies per second per cell. Those individuals with genetic vulnerabilities can lose tolerance to citrullinated protein motifs and develop anticitrullinated peptide antibodies ACPAs. These appear to be T-cell-dependent, antigen-driven responses with autoantibodies undergoing class switching. Rheumatoid factors RFs also develop and may indicate the presence of immune complexes IC or other aspects of immune dysregulation.
Long-lived antibody-producing cells and circulating autoantibodies may be present for many years before clinically detectable synovitis [ 9 ]. Patients tend to accumulate autoantibodies to additional citrullinated peptide antigens over time, suggesting epitope spreading.
Events that are more proximal to the development of inflammatory arthritis involve systemic inflammation as detected by increased circulating proinflammatory cytokines.
It is likely that exaggerated citrullination of proteins in the synovia [ 14 ], possibly as a result of PAD secretion by neutrophils and macrophages [ 15 ], triggers a local autoimmune response.
All along these steps toward RA, B lymphocytes and long-lived PC play a role that is still incompletely understood. Furthermore, the role of innate immunity and stromal cells in shaping the acquired immune response remains under investigation.
Production of autoantibodies The development and presence of autoantibodies is a hallmark of RA. These are typically IgM antibodies and are not highly specific for RA.
They can be identified in many instances of hypergammaglobulinemia occurring in other autoimmune diseases e. They are also commonly detected in clinical situations of chronic antigenemia and IC formation associated with viral e. Recent advances have helped identifying specific motifs of autoantigens in RA, which can lead to the production of disease-specific autoantibodies and increasing the current availability of detectable autoantibodies relevant to RA diagnosis.
Citrullination conversion of arginine into citrulline of certain peptides can occur in many proteins [ 18 ]. These citrullinated autoantigens can be both intracellular and extracellular proteins. It is noteworthy that although citrullination is a biochemical modification catalyzed by the PAD enzymes and occurs under healthy steady-state conditions, activity of the PAD enzymes and increased citrullination can be enhanced by certain external stimuli like cigarette smoke.
So far, most ACPAs that have been characterized belong to the IgG and IgA isotypes [ 2324 ], which underscores how autoreactive B cells must have been selected to reach a mature PC fate and have undergone isotype switching during the process. Somatic hypermutation is likely to be involved in the development of ACPAs, as reversion of citrulline-specific antibodies cloned from the synovium B cells of RA patients to their corresponding germline configuration results in loss of citrulline-specific antigen binding [ 8 ].
Citrullination is also increased at sites of inflammation including synovial tissues and atherosclerotic plaques, and it is thought that initial ACPA development may occur through priming at distant sites such as the lung or gingival tissues, while clinical RA and its complications may develop when citrullination occurs in RA target organs [ 2930 ].
A highly relevant question, therefore, is the mechanism underlying citrullination in these tissues. Romero and colleagues recently reported hypercitrullination of cells in rheumatoid synovial fluid [ 15 ].
Neutrophils are the first immune cells to enter the arthritic joint [ 31 ], but it remains unclear what specific processes target neutrophils or cytotoxic cells to the joints.
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It is also plausible that IC involving either RF or ACPAs could locally activate complement leading to the establishment of a local autoimmune response involving hypercitrullinated proteins derived from neutrophils.
Anticarbamylated protein antibodies anti-CarPon the other hand, are directed towards peptides that are catalyzed by a nonenzymatic transformation that involves lysine and N-terminal addition of homocitrulline [ 32 ], which largely resembles citrulline but is one methylene group longer [ 33 ].
The extent to which ACPAs are causative agents of disease and not only epiphenomena of other immune dysregulation processes is still under debate. Additionally, ACPAs can contribute to the generation of ICs, which are characteristic of other autoimmune disorders [ 35 ]. One of the keys to understanding how the innate and adaptive immune responses interact relies in the roles of ICs and the complement system in RA.
ICs can contain inflammatory molecules embedded in a cluster of antibodies, and it is possible that during disease progression some of the newly generated ICs contain autoantibodies and ACPAs.
Additionally, the ICs can retain autoantigens and allow for their persistence, migration and presentation in places remote to their origin. This suggests a potential role of citrullination in increasing the potency of an endogenous innate immune ligand.
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Whether ICs can have different impacts, depending not only on the composition of the proinflammatory and antigenic molecules they carry but also on the specificity of their antibodies, has not been rigorously investigated.
Concomitant to the presence of autoantigens, autoantibodies, ICs and a proinflammatory environment, alterations in the complement activation system have been well described. The anatomical location where autoantibody production actually occurs can be difficult to track. Selection of B cells occurs in the bone marrow BM and spleen, but priming and further differentiation into distinct B cell subsets strongly differs in localization and costimulatory requirements.
First, a B cell with a certain degree of self-reactivity has to be selected and receive the sufficient survival signals to escape negative selection.
Additionally, that same B-cell clone needs to avoid becoming fully anergic or if so, retain the capacity to revert from the functionally silenced state. Hence, breaking tolerance for B-cell responses in RA is highly likely to happen at more than one site and may need a combination of consecutive factors to be enabled at precise time points. The transition of a mature B cell into an autoreactive PC can occur in different ways as well.
Lymphoid neogenesis in the synovium is a well-characterized reversible process that is associated with inflammation during RA [ 38 ].
Not surprisingly, several of the features associated with ELS are also illustrated in other autoimmune diseases where tertiary lymphoid organs contain B cells and can promote B-cell selection, such as the pancreas during type 1 diabetes [ 42 ]. Additionally, among all cells with phagocytic and APC characteristics, only B cells possess the capacity to recognize a specific Ag through its clonally restricted BCR, and hence drive a BCR-mediated Ag capture and incorporation, and even concentrate antigens present at low level, all of which imbues them with the capacity to potentially become Ag-specific APCs.
Different phenotypically defined B-cell subsets exist both in mice and humans. We will not discuss in detail the role of follicular B cells as we consider that it has been properly addressed in recent reviews [ 543 ]. When compared with canonical B2 B cells, all of them, to a different degree, populate specific niches, possess different reactivities to pathogenic self or non-self antigens, generate faster humoral responses and confer quick protective responses to certain microorganisms.
Therefore, innate-like B cells constitute a link between innate and adaptive immune responses throughout evolution, anatomical locations and types of responses [ 44 — 46 ]. MZ B cells constitute a population of splenic B cells that are characterized by hyporesponsiveness to Ag-driven signals through their BCRs and CD40 but hyperresponsiveness to several innate-like and proinflammatory signals [ 4748 ].
MZ B cells also respond rapidly to blood-borne antigens and can behave in both innate- and adaptive immune response fashions. Expansion of MZ B cells has been observed in many autoimmune diseases, and compared with follicular B cells they are more potent APCs when driving T-cell proliferation [ 6 ].
MZ B cells can also regulate antigen capture by MZ macrophages [ 49 ]. A different type of B cells, B1 cells, are also altered in many autoimmune diseases, and although their ontogeny, anatomical location and functional capacities are very different from all other B-cell populations, they share some characteristics with MZ B cells, including cell surface markers, responsiveness to toll-like receptor TLR ligands and certain pathogens, and partial overlap in the molecular pathways activated upon BCR stimulation [ 44 ].
Both MZ and B1 cells have distinctive phagocytic and Ag-presenting capacities [ 454950 ]. All these characteristics suggest that MZ and B1 cells can become critical partners in misleading immune responses that may result in the development of autoimmunity, especially in the context of a chronic inflammatory environment.
B cells are currently also appreciated as significant contributors to the cytokine and chemokine milieu in given microenvironments. In normal homeostatic conditions, there is balance among pro- and anti-inflammatory B cells, but this equilibrium is disrupted during RA. Some B-cell-specific cytokines also have autocrine effects, as is the case of IL-4, IL-6 and many of the cytokines that tightly regulate the maturation of naive B cells into plasmablasts or PCs [ 5152 ].
Interestingly, some of the cytokines, such as IL, that are relatively decreased during RA either systemically or in the joint are considered anti-inflammatory or Th2-promoting cytokines [ 953 ]. A special mention is required for a newly redefined subset of B cells that fall under the term regulatory B cells Bregswhich share several phenotypical markers with both MZ and B1 cells, although there is no absolute or exclusive overlap among all of them.
The immunomodulatory capacity of Bregs depends critically on their competence to secrete IL, independently of how they are phenotypically characterized or named. Bregs can strongly suppress autoimmunity in many different murine models [ 54 ], and their suppressive capacity is not always exclusive to the endogenous production of IL Interestingly, transient production of IL occurs when B cells differentiate into antibody secreting cells ASCs [ 57 ].
Moreover, a defect in Breg function has been found in RA patients regarding their capacity to enhance Th1 bias [ 5859 ], and patients with new-onset RA have decreased numbers of circulating Bregs [ 59 ].