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Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.

Péron S, Metin A, Gardès P, Alyanakian MA, Sheridan E, Kratz CP, Fischer A, Durandy A - J. Exp. Med. (2008)

Bottom Line: In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation.Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase.CSR was found partially defective in vivo and markedly impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U768, 75015 Paris, France.

ABSTRACT
Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell-intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation.

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In vivo and in vitro Ig-CSR deficiency in patients. (A) B cell phenotype. IgM and IgD expression was studied on CD19+CD27+ gated PBLs. Very few IgM+IgD+ cells were observed in P1, P2, and P3 (n = 1) compared with controls (n = 7). A reduction of IgA+ B cells on CD19+-gated PBLs was observed in P3 compared with an age-matched control (n = 2). (B) Defective IgE and IgA production by CSR activated patients' PBLs. PBLs were activated by sCD40L plus IL-4 for 12 d or sCD40L plus IL-10 for 10 d for CSR toward IgE (P1, n = 2; P2 and P3, n = 1; controls, n = 10) and IgA (P1 and P3, n = 1; controls, n = 5), respectively. Proliferation was assessed after a 5-d stimulation with sCD40L plus IL-4 by measuring [3H]thymidine incorporation. Error bars represent one SD (P1 and P3, n = 1; controls, n = 10).
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fig3: In vivo and in vitro Ig-CSR deficiency in patients. (A) B cell phenotype. IgM and IgD expression was studied on CD19+CD27+ gated PBLs. Very few IgM+IgD+ cells were observed in P1, P2, and P3 (n = 1) compared with controls (n = 7). A reduction of IgA+ B cells on CD19+-gated PBLs was observed in P3 compared with an age-matched control (n = 2). (B) Defective IgE and IgA production by CSR activated patients' PBLs. PBLs were activated by sCD40L plus IL-4 for 12 d or sCD40L plus IL-10 for 10 d for CSR toward IgE (P1, n = 2; P2 and P3, n = 1; controls, n = 10) and IgA (P1 and P3, n = 1; controls, n = 5), respectively. Proliferation was assessed after a 5-d stimulation with sCD40L plus IL-4 by measuring [3H]thymidine incorporation. Error bars represent one SD (P1 and P3, n = 1; controls, n = 10).

Mentions: Blood CD19+ B lymphocyte numbers were normal in all three patients. CD27+ memory B cells were low in P1 and P2 and normal in P3 (Table I). In all three patients, virtually all CD19+CD27+ B cells were IgM+IgD+ (Fig. 3 A), and very few IgA+ (switched) B cells were detected (P3; 2 vs. 8% in an age-matched control; Fig. 3 A), pointing to a defective in vivo CSR toward IgA. In vitro activation of P1, P2, and P3 B cells with sCD40L plus IL-4 or sCD40L plus IL-10 led to a poorly efficient CSR toward IgE and IgA, respectively, although potent B cell proliferation could be detected when tested for (Fig. 3 B). These observations point to a CSR defect located downstream of the transcription step, because IgE germline transcripts were normally expressed in CSR-activated B cells from P1 and P2 (Fig. 1).


Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.

Péron S, Metin A, Gardès P, Alyanakian MA, Sheridan E, Kratz CP, Fischer A, Durandy A - J. Exp. Med. (2008)

In vivo and in vitro Ig-CSR deficiency in patients. (A) B cell phenotype. IgM and IgD expression was studied on CD19+CD27+ gated PBLs. Very few IgM+IgD+ cells were observed in P1, P2, and P3 (n = 1) compared with controls (n = 7). A reduction of IgA+ B cells on CD19+-gated PBLs was observed in P3 compared with an age-matched control (n = 2). (B) Defective IgE and IgA production by CSR activated patients' PBLs. PBLs were activated by sCD40L plus IL-4 for 12 d or sCD40L plus IL-10 for 10 d for CSR toward IgE (P1, n = 2; P2 and P3, n = 1; controls, n = 10) and IgA (P1 and P3, n = 1; controls, n = 5), respectively. Proliferation was assessed after a 5-d stimulation with sCD40L plus IL-4 by measuring [3H]thymidine incorporation. Error bars represent one SD (P1 and P3, n = 1; controls, n = 10).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2571921&req=5

fig3: In vivo and in vitro Ig-CSR deficiency in patients. (A) B cell phenotype. IgM and IgD expression was studied on CD19+CD27+ gated PBLs. Very few IgM+IgD+ cells were observed in P1, P2, and P3 (n = 1) compared with controls (n = 7). A reduction of IgA+ B cells on CD19+-gated PBLs was observed in P3 compared with an age-matched control (n = 2). (B) Defective IgE and IgA production by CSR activated patients' PBLs. PBLs were activated by sCD40L plus IL-4 for 12 d or sCD40L plus IL-10 for 10 d for CSR toward IgE (P1, n = 2; P2 and P3, n = 1; controls, n = 10) and IgA (P1 and P3, n = 1; controls, n = 5), respectively. Proliferation was assessed after a 5-d stimulation with sCD40L plus IL-4 by measuring [3H]thymidine incorporation. Error bars represent one SD (P1 and P3, n = 1; controls, n = 10).
Mentions: Blood CD19+ B lymphocyte numbers were normal in all three patients. CD27+ memory B cells were low in P1 and P2 and normal in P3 (Table I). In all three patients, virtually all CD19+CD27+ B cells were IgM+IgD+ (Fig. 3 A), and very few IgA+ (switched) B cells were detected (P3; 2 vs. 8% in an age-matched control; Fig. 3 A), pointing to a defective in vivo CSR toward IgA. In vitro activation of P1, P2, and P3 B cells with sCD40L plus IL-4 or sCD40L plus IL-10 led to a poorly efficient CSR toward IgE and IgA, respectively, although potent B cell proliferation could be detected when tested for (Fig. 3 B). These observations point to a CSR defect located downstream of the transcription step, because IgE germline transcripts were normally expressed in CSR-activated B cells from P1 and P2 (Fig. 1).

Bottom Line: In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation.Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase.CSR was found partially defective in vivo and markedly impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U768, 75015 Paris, France.

ABSTRACT
Immunoglobulin (Ig) class switch recombination (CSR) deficiencies are rare primary immunodeficiencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR deficiencies can be associated with abnormal somatic hypermutation. Analysis of CSR deficiencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell-intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation.

Show MeSH
Related in: MedlinePlus