B Lymphocyte Physiology: The Beginning and the End

Nossal, G. J. V.

doi:10.1002/9780470515280.ch15

Cited by 5 publications

(3 citation statements)

References 29 publications

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“…Because of the irreversible reactivity, the CRAs are predicted to saturate BCRs more readily compared to conventional antigens. BCR saturation is thought to tolerize B cells [80][81][82] and the CRAs offer a potential route to induction of antigen-specific tolerance.…”

Section: Cra Inactivation Of Pathogenic Antibodiesmentioning

confidence: 99%

Theory of proteolytic antibody occurrence

et al. 2006

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Section: Cra Inactivation Of Pathogenic Antibodiesmentioning

confidence: 99%

Theory of proteolytic antibody occurrence

et al. 2006

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“…If a naive B‐cell is exposed to soluble self protein or an unconjugated chemical molecule such as a free hapten, then little or no antibody response is induced, because there is no B‐cell receptor (BCR) crosslinking and no T‐cell help (). During the germinal center reaction, soluble protein induces apoptosis, further eliminating antibody responses to soluble antigens (67). Even memory B cells are poorly responsive to soluble foreign proteins in the absence of T‐cell help (38), and this property may be important because it reduces the amount of antibody directed towards self‐antigens or induction of antibody responses to environmental or irrelevant antigens.…”

Section: Repeated Infection or Booster Vaccination Modelsmentioning

confidence: 99%

Mechanisms that determine plasma cell lifespan and the duration of humoral immunity

Amanna

Slifka

2010

Immunological Reviews

275

254

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Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane-bound form that serves as the antigen-specific B-cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface-bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre-existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody-secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long-term antibody production are not fully understood. Here, we examine several models of long-term humoral immunity and present a new model, described as the 'Imprinted Lifespan' model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B-cell signaling that occurs during the induction of an antigen-specific humoral immune response. This represents a testable hypothesis and may explain why some antigen-specific antibody responses fade over time whereas others are maintained essentially for life.

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“…Antigen binding to the antigen receptor (immunoglobulins complexed to signal transducing proteins) drives maturation of B lymphocytes into Absecreting cells. Saturation of the antigen receptor induces B cell apoptosis and immune tolerance (48,49). Administration of very large amounts of FVIII on the order of grams induces immune tolerance to FVIII in a subpopulation of HA patients (10,11).…”

Section: Discussionmentioning

confidence: 99%

Covalent Inactivation of Factor VIII Antibodies from Hemophilia A Patients by an Electrophilic FVIII Analog

Planque

Escobar

Smith

et al. 2008

Journal of Biological Chemistry

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dissociation by SDS treatment and boiling, procedures that dissociate noncovalent Ab-antigen complexes. The rate-limiting step in the reaction was formation of the initial noncovalent complexes. Conversion of the initial complexes to the irreversible state occurred rapidly. The antigenic epitopes of E-FVIII were largely intact, and most of the Abs were consumed covalently. E-FVIII expressed poor FVIII cofactor activity in clotting factor assays. Nonspecific interference by E-FVIII in clotting factor function was not evident. Treatment with E-FVIII, and to a lesser extent E-C2, irreversibly relieved the FVIII inhibitory effect of HA IgG in clotting factor assays. Small FVIII peptides did not display useful reactivity, highlighting the diverse epitope specificities of the Abs and the conformational character of FVIII epitopes. E-FVIII is a prototype reagent able to attain irreversible and specific inactivation of pathogenic Abs. Specific antibodies (Abs)2 to individual antigens are thought to cause harmful effects in autoimmune diseases, transfusion of incompatible blood products, and organ transplantation. Inhibitory Abs to Factor VIII (FVIII) in hemophilia A (HA) are a well characterized example. HA is a chromosome X-linked genetic disorder characterized by the synthesis of functionally inactive FVIII. This impairs the intrinsic pathway of blood coagulation. The primary therapy for control of bleeding in HA patients is infusion of recombinant or plasma-derived FVIII (1). About 20 -30% of patients receiving FVIII replacement therapy produce antibodies (Abs) to FVIII that inhibit FVIII cofactor activity. These are referred to clinically as "inhibitors." The inhibitory effect is thought to derive from reversible steric hindrance of FVIII interactions with phospholipids and other coagulation factors, including thrombin, Factor IXa (FIXa), and von Willebrand factor (2). In addition, some Abs inactivate FVIII permanently by catalyzing its proteolytic breakdown (3). Epitope mapping studies using FVIII fragments (heavy chain, light chains, and A2, A3, C1, and C2 domains) and FVIII hybrid molecules have suggested that many Abs are directed to conformational epitopes (4, 5). Most inhibitor positive patients mount a highly diverse immune response consisting of Abs to multiple FVIII epitopes located in the A2, C1, C2, and A3 domains (2, 6, 7).The Abs pose major problems in managing acute bleeding episodes and surgical procedures in the patients. Short term bleeding in inhibitor-positive patients can be controlled by infusing activated prothrombin complex concentrates or recombinant factor VIIa, agents that bypass the requirement for FVIII in the coagulation pathway (8, 9). Refractory bleeds occur in about 20% of inhibitor-positive HA patients receiving bypass therapy, and an overdose carries the risk of inducing thrombotic events (9). In principle, FVIII itself could be infused to saturate the Abs and restore the coagulation pathway. However, massive quantities of FVIII are required to overcome the inhibitory effect of the ...

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B Lymphocyte Physiology: The Beginning and the End

Cited by 5 publications

References 29 publications

Theory of proteolytic antibody occurrence

Theory of proteolytic antibody occurrence

Mechanisms that determine plasma cell lifespan and the duration of humoral immunity

Covalent Inactivation of Factor VIII Antibodies from Hemophilia A Patients by an Electrophilic FVIII Analog

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