Limits...
Targeting plasma cells in autoimmune diseases.

Tarlinton DM, Hodgkin PD - J. Exp. Med. (2004)

Bottom Line: Antibodies specific for self-antigens mediate life-threatening pathology in several autoimmune diseases.Clearly the ability to target the plasma cells (PCs) producing the autoantibodies would be of great clinical benefit.However, recent results question this assumption and suggest that optimizing the treatment of severe autoimmune conditions will require a significant investment in elucidating the details of PC biology.

View Article: PubMed Central - PubMed

Affiliation: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. tarlinton@wehi.edu.au

ABSTRACT
Antibodies specific for self-antigens mediate life-threatening pathology in several autoimmune diseases. Clearly the ability to target the plasma cells (PCs) producing the autoantibodies would be of great clinical benefit. Current immunosuppressive therapies are based on the premise that autoreactive PCs are short-lived and replenished from ongoing immune responses. However, recent results question this assumption and suggest that optimizing the treatment of severe autoimmune conditions will require a significant investment in elucidating the details of PC biology.

Show MeSH

Related in: MedlinePlus

The tangled web of PCs and their precursors. Schematic representation of PC subsets and their postulated or proven precursors and products. SL, short-lived; LL, long-lived; Ag, antigen.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211780&req=5

fig1: The tangled web of PCs and their precursors. Schematic representation of PC subsets and their postulated or proven precursors and products. SL, short-lived; LL, long-lived; Ag, antigen.

Mentions: Next is the question of the cellular origin of PCs. Are particular PC phenotypes or the PCs found in particular locations associated with distinct cellular origins? Such relationships may determine the pathogenicity of the antibodies being produced. For example, PCs derived from germinal centers (GCs) may secrete antibody of a mature (IgG) isotype and of high affinity for antigen, both factors that may exacerbate tissue damage. Thus, knowing the etiology of a PC may identify points and means of clinical intervention. There are several developmental schemes for PCs that collectively encompass virtually every possible connection (Fig. 1). Although plasmablasts are potential PC precursors of long standing (7), several other populations have joined them recently. The GC is broadly accepted to produce PCs that are high affinity, long-lived, and that reside primarily in the bone marrow (13, 22). Defining the developmental processes that drive a GC B cell toward becoming a long-lived bone marrow PC may identify points at which the development of pathogenic autoantibodies can be interrupted, assuming that the long-lived PC-secreting pathogenic autoantibodies in the bone marrow are GC derived, which may not always be the case (23). If, for example, the process of PC differentiation depends on antigen-induced signaling (24), the creation of environmental niches (25), and chemokine gradients (26), then modulating any of these may be sufficient to modulate disease severity. One must include also the traditional memory B cell population as containing PC precursors since such cells rapidly differentiate into short-lived PC upon reexposure to antigen (27, 28). In mouse, two additional precursor populations have been identified: both B220− and both concentrated in the bone marrow. One of these is cycling (29) and therefore presumably susceptible to the treatment applied by Hoyer et al. (6) that failed to block anti-DNA antibody production. The role of this population in the maintenance of long-lived autoreactive PCs in the bone marrow therefore remains open. The other B220− population is derived from the GCs, lacks expression of CD138, is developmentally dependent on a transcriptional regulator of PC development, Blimp1 (30, 31), and is responsive to antigen, which long-lived PCs are not (14). Again, the role of this population in the maintenance of long-lived PCs is unresolved. In humans, PC precursor diversity is less well defined, although stages of maturation have been identified in blood ranging from a plasma cell precursor (32) to more discrete stages within committed PC (33, 34). Interestingly, one of these studies noted a significant increase in plasma cell precursor frequency in the blood of children with SLE (32), which complements other studies reporting a correlation between disease activity and circulating PCs (35). These data raise the possibility that aspects of the immune response are dysfunctional in these patients, and if the developmental origin of the PC were known, it may be possible to intervene in a relatively precise manner. The definition of relationships between precursors and PCs is going to be crucial if selective therapies are to be developed that target only the relevant PC subset.


Targeting plasma cells in autoimmune diseases.

Tarlinton DM, Hodgkin PD - J. Exp. Med. (2004)

The tangled web of PCs and their precursors. Schematic representation of PC subsets and their postulated or proven precursors and products. SL, short-lived; LL, long-lived; Ag, antigen.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211780&req=5

fig1: The tangled web of PCs and their precursors. Schematic representation of PC subsets and their postulated or proven precursors and products. SL, short-lived; LL, long-lived; Ag, antigen.
Mentions: Next is the question of the cellular origin of PCs. Are particular PC phenotypes or the PCs found in particular locations associated with distinct cellular origins? Such relationships may determine the pathogenicity of the antibodies being produced. For example, PCs derived from germinal centers (GCs) may secrete antibody of a mature (IgG) isotype and of high affinity for antigen, both factors that may exacerbate tissue damage. Thus, knowing the etiology of a PC may identify points and means of clinical intervention. There are several developmental schemes for PCs that collectively encompass virtually every possible connection (Fig. 1). Although plasmablasts are potential PC precursors of long standing (7), several other populations have joined them recently. The GC is broadly accepted to produce PCs that are high affinity, long-lived, and that reside primarily in the bone marrow (13, 22). Defining the developmental processes that drive a GC B cell toward becoming a long-lived bone marrow PC may identify points at which the development of pathogenic autoantibodies can be interrupted, assuming that the long-lived PC-secreting pathogenic autoantibodies in the bone marrow are GC derived, which may not always be the case (23). If, for example, the process of PC differentiation depends on antigen-induced signaling (24), the creation of environmental niches (25), and chemokine gradients (26), then modulating any of these may be sufficient to modulate disease severity. One must include also the traditional memory B cell population as containing PC precursors since such cells rapidly differentiate into short-lived PC upon reexposure to antigen (27, 28). In mouse, two additional precursor populations have been identified: both B220− and both concentrated in the bone marrow. One of these is cycling (29) and therefore presumably susceptible to the treatment applied by Hoyer et al. (6) that failed to block anti-DNA antibody production. The role of this population in the maintenance of long-lived autoreactive PCs in the bone marrow therefore remains open. The other B220− population is derived from the GCs, lacks expression of CD138, is developmentally dependent on a transcriptional regulator of PC development, Blimp1 (30, 31), and is responsive to antigen, which long-lived PCs are not (14). Again, the role of this population in the maintenance of long-lived PCs is unresolved. In humans, PC precursor diversity is less well defined, although stages of maturation have been identified in blood ranging from a plasma cell precursor (32) to more discrete stages within committed PC (33, 34). Interestingly, one of these studies noted a significant increase in plasma cell precursor frequency in the blood of children with SLE (32), which complements other studies reporting a correlation between disease activity and circulating PCs (35). These data raise the possibility that aspects of the immune response are dysfunctional in these patients, and if the developmental origin of the PC were known, it may be possible to intervene in a relatively precise manner. The definition of relationships between precursors and PCs is going to be crucial if selective therapies are to be developed that target only the relevant PC subset.

Bottom Line: Antibodies specific for self-antigens mediate life-threatening pathology in several autoimmune diseases.Clearly the ability to target the plasma cells (PCs) producing the autoantibodies would be of great clinical benefit.However, recent results question this assumption and suggest that optimizing the treatment of severe autoimmune conditions will require a significant investment in elucidating the details of PC biology.

View Article: PubMed Central - PubMed

Affiliation: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. tarlinton@wehi.edu.au

ABSTRACT
Antibodies specific for self-antigens mediate life-threatening pathology in several autoimmune diseases. Clearly the ability to target the plasma cells (PCs) producing the autoantibodies would be of great clinical benefit. Current immunosuppressive therapies are based on the premise that autoreactive PCs are short-lived and replenished from ongoing immune responses. However, recent results question this assumption and suggest that optimizing the treatment of severe autoimmune conditions will require a significant investment in elucidating the details of PC biology.

Show MeSH
Related in: MedlinePlus