AID constrains germinal center size by rendering B cells susceptible to apoptosis

Abstract

IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

Role of Transgene Regulation in Ex Vivo Lentiviral Correction of Artemis Deficiency

“…[35][36][37][38] Immature B lymphocytes acquiring an excess number of nonproductive mutations undergo Fas-mediated apoptosis. 39,40 It is tempting to speculate that the coupling of these natural DNA DSB repair-inducing events with the global DNA damage accrued upon Artemis overexpression further sensitizes the cell to apoptotic stimuli. Consistent with this argument, the T lymphocyte population, which does not undergo somatic hypermutation or class switch recombination, was repopulated in EF1a-Artemistreated mice.…”

Role of activation‐induced cytidine deaminase in the progression of follicular lymphoma

“…A recent basic analysis has indicated increased proliferation and decreased apoptosis of AID ) ⁄ ) B lymphocytes in comparison with AID-expressing B lymphocytes derived from the GC. In addition, expression of AID was shown to lead to the generation of point mutations for SHM and CSR, resulting in DNA damage and apoptosis, (37) probably in the deregulated expression of anti-apoptotic factors such as bcl-2 and bcl-XL. (38) These findings suggest that cell-cycle arrest or apoptosis can be ultimately induced when sufficient AID is subsequently expressed in B lymphocytes after CSR.…”

Microenvironment Interactions in Chronic Lymphocytic Leukemia: A Delicate Equilibrium Linking the Quiescent and the Proliferative Pool

“…Thus, we could assume that these cells should undergo apoptosis once leaving the pseudo-follicles. A recent work suggesting a link between AID expression and B-cell apoptosis in GC favour this view [56]. In these conditions, the IgG pos subset could reflect the existence of an active microenvironment leading to permanent stimulation of the IgM pos pool, which would be turn on the CSR machinery maintaining this IgG pos subset in the PB.…”