Differential Expression Patterns of Recombination-activating Genes in Individual Mature B Cells in Juvenile Idiopathic Arthritis

Overview

Journal Ann Rheum Dis

Specialty Rheumatology

Date 2006 Mar 1

PMID 16504994

Citations 7

Authors

C Faber

H Morbach

S K Singh

H J Girschick

Affiliations

Soon will be listed here.

Abstract

Background: Re-expression of the recombination-activating genes (RAG) in peripheral B cells may be relevant in the development of autoreactive antibodies in autoimmune diseases. The presence of antinuclear antibodies (ANA) as a hallmark of oligoarticular juvenile idiopathic arthritis (o-JIA, early-onset type) indicates a breakdown in immunological tolerance.

Aim: To examine the expression of RAG genes in peripheral blood mature B lymphocytes in patients with o-JIA.

Methods: 777 memory B cells from peripheral blood, CD19+ CD27+ CD5+ or CD19+ CD27+ CD5-, isolated from three ANA+ children with o-JIA and three healthy age-matched children, were examined for the expression of RAG1 and RAG2 mRNA. mRNA transcripts of activation-induced cytidine deaminase and immunoglobulin G were searched to further determine their developmental stage.

Results: mRNA was present for any of the two RAG genes in the B cells of children with JIA and controls. However, the predominance of RAG1 or RAG2 was different. A significantly decreased frequency of RAG2-expressing memory B cells in both CD5+ and CD5- populations was noted in children with JIA (p<0.001), whereas the number of RAG1-expressing B cells was slightly increased. The coordinate expression of both the RAG genes was a rare event, similar in the CD5+ populations (1% in controls, 2% in children with JIA), but different among the CD5- compartments (5% v 0%; p<0.01).

Conclusion: These results argue for a reduced coordinate RAG expression in the peripheral CD5- memory B cells of patients with o-JIA. Thus, it was hypothesised that impaired receptor revision contributes to autoimmune pathogenesis in JIA.

Citing Articles

B Cells on the Stage of Inflammation in Juvenile Idiopathic Arthritis: Leading or Supporting Actors in Disease Pathogenesis?.

Moura R, Fonseca J Front Med (Lausanne). 2022; 9:851532.

PMID: 35449805 PMC: 9017649. DOI: 10.3389/fmed.2022.851532.

B Cells as a Therapeutic Target in Paediatric Rheumatic Disease.

Wilkinson M, Rosser E Front Immunol. 2019; 10:214.

PMID: 30837988 PMC: 6382733. DOI: 10.3389/fimmu.2019.00214.

Phosphorothioate-modified CpG oligodeoxynucleotides mimic autoantigens and reveal a potential role for Toll-like receptor 9 in receptor revision.

Doster A, Ziegler S, Foermer S, Rieker R, Heeg K, Bekeredjian-Ding I Immunology. 2013; 139(2):166-78.

PMID: 23289794 PMC: 3647183. DOI: 10.1111/imm.12063.

B-cell pathology in juvenile idiopathic arthritis.

Wiegering V, Girschick H, Morbach H Arthritis. 2011; 2010:759868.

PMID: 22076178 PMC: 3199973. DOI: 10.1155/2010/759868.

Abatacept in difficult-to-treat juvenile idiopathic arthritis.

Kuemmerle-Deschner J, Benseler S Biologics. 2009; 2(4):865-74.

PMID: 19707464 PMC: 2727897. DOI: 10.2147/btt.s3355.

References

Nagafuchi H, Yoshikawa H, Takeba Y, Nara K, Miura K, Kurokawa M . Recombination activating genes (RAG) induce secondary Ig gene rearrangement in and subsequent apoptosis of human peripheral blood circulating B lymphocytes. Clin Exp Immunol. 2004; 136(1):76-84. PMC: 1808993. DOI: 10.1111/j.1365-2249.2004.02423.x. View

Petty R, Southwood T, Manners P, Baum J, Glass D, Goldenberg J . International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004; 31(2):390-2. View

Shinkai Y, Rathbun G, Lam K, Oltz E, Stewart V, Mendelsohn M . RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992; 68(5):855-67. DOI: 10.1016/0092-8674(92)90029-c. View

Mombaerts P, Iacomini J, Johnson R, Herrup K, Tonegawa S, Papaioannou V . RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992; 68(5):869-77. DOI: 10.1016/0092-8674(92)90030-g. View

Schatz D, Oettinger M, Schlissel M . V(D)J recombination: molecular biology and regulation. Annu Rev Immunol. 1992; 10:359-83. DOI: 10.1146/annurev.iy.10.040192.002043. View

Tiegs S, Russell D, Nemazee D . Receptor editing in self-reactive bone marrow B cells. J Exp Med. 1993; 177(4):1009-20. PMC: 2190975. DOI: 10.1084/jem.177.4.1009. View

Lin W, Desiderio S . Cell cycle regulation of V(D)J recombination-activating protein RAG-2. Proc Natl Acad Sci U S A. 1994; 91(7):2733-7. PMC: 43444. DOI: 10.1073/pnas.91.7.2733. View

Bensimon C, Chastagner P, Zouali M . Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements. EMBO J. 1994; 13(13):2951-62. PMC: 395182. DOI: 10.1002/j.1460-2075.1994.tb06593.x. View

Lin W, Desiderio S . V(D)J recombination and the cell cycle. Immunol Today. 1995; 16(6):279-89. DOI: 10.1016/0167-5699(95)80182-0. View

10.

Schwarz K, Gauss G, Ludwig L, Pannicke U, Li Z, Lindner D . RAG mutations in human B cell-negative SCID. Science. 1996; 274(5284):97-9. DOI: 10.1126/science.274.5284.97. View

11.

Hikida M, Mori M, Takai T, Tomochika K, Hamatani K, Ohmori H . Reexpression of RAG-1 and RAG-2 genes in activated mature mouse B cells. Science. 1996; 274(5295):2092-4. DOI: 10.1126/science.274.5295.2092. View

12.

Han S, Zheng B, Schatz D, Spanopoulou E, Kelsoe G . Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science. 1996; 274(5295):2094-7. DOI: 10.1126/science.274.5295.2094. View

13.

Han S, Dillon S, Zheng B, Shimoda M, Schlissel M, Kelsoe G . V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science. 1997; 278(5336):301-5. DOI: 10.1126/science.278.5336.301. View

14.

Suzuki N, Mihara S, Sakane T . Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus. FASEB J. 1997; 11(12):1033-8. DOI: 10.1096/fasebj.11.12.9337156. View

15.

Hikida M, Nakayama Y, Yamashita Y, Kumazawa Y, Nishikawa S, Ohmori H . Expression of recombination activating genes in germinal center B cells: involvement of interleukin 7 (IL-7) and the IL-7 receptor. J Exp Med. 1998; 188(2):365-72. PMC: 2212440. DOI: 10.1084/jem.188.2.365. View

16.

Hertz M, Kouskoff V, Nakamura T, Nemazee D . V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signalling. Nature. 1998; 394(6690):292-5. PMC: 4523147. DOI: 10.1038/28419. View

17.

Meffre E, Papavasiliou F, Cohen P, de Bouteiller O, Bell D, Karasuyama H . Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells. J Exp Med. 1998; 188(4):765-72. PMC: 2213359. DOI: 10.1084/jem.188.4.765. View

18.

Dorner T, Foster S, Farner N, Lipsky P . Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus. J Clin Invest. 1998; 102(4):688-94. PMC: 508930. DOI: 10.1172/JCI3113. View

19.

Klein U, Rajewsky K, Kuppers R . Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998; 188(9):1679-89. PMC: 2212515. DOI: 10.1084/jem.188.9.1679. View

20.

Sandel P, Monroe J . Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity. 1999; 10(3):289-99. DOI: 10.1016/s1074-7613(00)80029-1. View