Clinical Immunology (2010) 135, 193–203
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
REVIEW
Immunoglobulin class switch recombination deficiencies S. Kracker, P. Gardes, F. Mazerolles, A. Durandy⁎ INSERM, U768, Hôpital Necker-Enfants Malades, Université Paris Descartes, Faculté de Médecine Paris V-René Descartes, Paris F-75005, France Received 27 November 2009; accepted with revision 25 January 2010 Available online 18 February 2010 KEYWORDS Inherited immunodeficiencies; Class switch recombination; Somatic hypermutations CD40 ligand; CD40; NF-kB essential modulator; Activation-induced cytidine deaminase; Uracil-N-glycosylase; Post-meiotic segregation 2
Abstract Maturation of the secondary antibody repertoire is generated by means of class switch recombination and somatic hypermutation. The molecular mechanisms underlying these important processes have long remained obscure. Inherited defects in class switch recombination variably associated to defects in somatic hypermutation are a group of genetically heterogeneous diseases, the characterization of which has allowed recognition that T–B cell interaction (resulting in CD40-mediated signaling), intrinsic B cell mechanisms, and complex DNA repair machinery are involved in class switch recombination and somatic hypermutation. Elucidation of the molecular defects underlying these disorders has been essential to better understand the molecular basis of immunoglobulin diversification and has offered the opportunity to define the clinical spectrum of these diseases and to prompt more accurate diagnostic and therapeutic approaches. © 2010 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Class switch recombination and somatic hypermutation . . . . . . Ig Class switch recombination deficiencies . . . . . . . . . . . . . CSR-D caused by a defect in the CD40 signaling pathway . . . CSR-D caused by an intrinsic B cell defect . . . . . . . . . . . . CSR-D with normal in vitro B cell response to CSR activation . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. Fax: +33 1 42 73 06 40. E-mail address:
[email protected] (A. Durandy). 1521-6616/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2010.01.012
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Introduction The study of inherited immunoglobulin class switch recombination deficiencies (CSR-Ds) has greatly contributed to our understanding of the normal processes of antibody maturation. These syndromes have in common a defect in immunoglobulin (Ig) class switch recombination (CSR), as demonstrated by normal or elevated serum IgM levels, contrasting with absent or strongly decreased levels of the other immunoglobulin isotypes. Antibody maturation leads to the production of antibodies of different isotypes and formation of B cell receptors (BCR) with high affinity for antigen. This event usually takes place in the secondary lymphoid organs (spleen, lymph nodes, tonsils) in an antigenand T lymphocyte-dependent manner. When mature (but still naive) IgM+IgD+ B cells, after emigrating from the bone marrow (or fetal liver), encounter an antigen that is specifically recognized by their BCR, they proliferate vigorously and give birth to a unique lymphoid formation, the germinal center. In this location, B cells undergo the two major events of maturation: CSR and somatic hypermutation (SHM).
Class switch recombination and somatic hypermutation Class switch recombination is a process of DNA recombination between two different switch (S) regions located upstream of the constant (C) regions, while the intervening DNA is deleted by forming an excision circle [1–5]. Replacement of the Cμ region by a downstream Cx region from another class of Ig results in the production of antibodies of different isotypes (IgG, IgA, and IgE) with the same variable (V) region and thus the same antigen specificity and affinity. The different Ig isotypes vary in activities (half-life, binding to Fc receptors, ability to activate the complement system) and tissue localization (IgA is secreted by mucosal membranes). Thus CSR is necessary for an optimal humoral response against pathogens. Through SHM, mutations and, less frequently, deletions or insertions are introduced into the V regions of immunoglobulins. This process is triggered by activation of BCR and CD40 [6,7]. These mutations occur at a high frequency in the V regions and their proximal flanks (1 × 10-3 bases/generation). SHM is required as a basis for the selection of B cells expressing a BCR with a high affinity for antigen in close interaction with follicular dendritic cells [8,9]. CSR and SHM occur in germinal centers, but neither is a prerequisite for the other because IgM may be mutated whereas IgG or IgA can remain unmutated [10,11]. Schematically, three successive steps are required in the process of CSR and SHM: 1. Transcription of the targeted DNA. In S regions, this step is induced by cytokines and leads to the formation of RNA– DNA hybrids, known as stable R-loops, on the template DNA strand, leaving the single non-template strand accessible for lesion and cleavage [12–16]. However, the template DNA strand remains accessible in transcription bubbles [12]. Transcription of V regions is also required for SHM [6] but its induction remains elusive.
S. Kracker et al. 2. DNA lesion and cleavage. It is believed that during CSR, the induction of single-stranded DNA lesions is followed by a DNA cleavage step. Since both DNA strands are accessible to lesions, scattered single-strand breaks (SSBs) occurring on both DNA strands result in blunt double-stranded DNA breaks (DSBs) by a mechanism currently unknown, possibly involving exonucleases and error-prone polymerases. This error-prone DNA processing is suggested by the high frequency of mutations found in Sμ–Sx junctions [17]. 3. DNA repair. Although the first steps are shared by CSR and SHM, the following step, DNA repair, differs for both events. During CSR, histone H2AX is phosphorylated, and the repair protein 53BP1 and the complex MRE11/RAD50/ NBS1 are recruited to the site of the breaks [18,19]. Thereafter, the DNA repair machinery joins Sμ and Sx sequences by means of the widespread, constitutively expressed nonhomologous end-joining (NHEJ) enzymes [20–22]. It has been demonstrated recently that the DNA repair step in CSR can also be accomplished by an alternative end-joining pathway (XRCC4/DNA-ligase IVindependent) [23]. In contrast, DNA repair during SHM does not require NHEJ [24], but the error-prone polymerases η and mismatch repair (MMR) enzymes [25]. MMR is also implicated in CSR (see Post-meiotic segregation 2 (PMS2) deficiency section), there however in the induction and processing of DNA lesions.
Ig Class switch recombination deficiencies CSR-Ds lead to a humoral immunodeficiency characterized by normal or increased production of IgM contrasting with a marked decrease or an absence of other isotypes (IgG, IgA, and IgE), the consequence of which is an increased susceptibility to bacterial infections. Depending on the nature of the molecular defect, the CSR-D can be associated with a defect in the other process of antibody maturation, the SHM (Table 1). CSR-D caused by a defect in the CD40 signaling pathway CSR and SHM are initiated by T and B cell interaction, involving CD40 ligand (CD40L or CD154), a molecule transiently expressed on activated CD4+ follicular helper T cells, and CD40, constitutively expressed on B lymphocytes and monocytes/dendritic cells [26] (Fig. 1). X-linked CSR-D due to CD40L deficiency. The initially described and most frequent CSR-D is caused by mutations in the gene encoding the CD40L [27] (Table 1). Patients exhibit significantly reduced levels of membrane CD40L expression on in vitro activated CD4+ T cells, or no expression at all, making diagnosis of this syndrome straightforward. Due to a CD40 trans-activation defect, the patients' B cells cannot form germinal centers in secondary lymphoid organs in vivo. Impaired production of IgG and IgA is responsible for specific susceptibility to recurrent bacterial infections as observed in other severe B-cell deficiencies. No antibodies against infectious agents or vaccines are produced, but iso-hemagglutinins and antipolysaccharide IgM antibodies are normally detected. B cells are intrinsically normal, as they can be induced to proliferate and to undergo CSR upon in vitro activation by
Immunoglobulin class switch recombination deficiencies
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Table 1 Location of the CSR defect
SHM
Clinical complications
Cellular and humoral immunodeficiencies CD40L 48% X-L
–
Diminished
CD40
2%
AR
–
Diminished
NEMO#
1%
X-L
–
N or diminished
Opportunistic infections, liver damage Opportunistic infections, liver damage Opportunistic infections
Humoral immunodeficiencies AID 15%
AR
Upstream from DSB
0
UNG PMS2 AID cofactor? DNA repair?
1% 2% 10% 11%
AR AR ? ?
Upstream from DSB Upstream from DSB Upstream from DSB Downstream from DSB
N⁎ N N N
TFH defect/B cell survival?
10%
?
–
N
Gene
Relative frequency+
Transmission
Lymphadenopathies, auto-immunity B cell lymphomas? Cancers Auto-immunity Auto-immunity, B cell lymphomas Auto-immunity
Relative proportion of the main CSR-D observed in our series, #could be underestimated since only sequenced in patient diagnosed with ectodermal dysplasia, DSB: double-stranded DNA breaks, N: normal, ⁎skewed pattern of nucleotide substitution.
+
CD40 agonists and appropriate cytokines [28], excluding a role for CD40L/CD40 interaction in B cell differentiation. Most, but not all, patients present reduced numbers of “memory” CD27+ B cells and a low frequency of SHM [29]. The detection of serum IgA and of SHM in some patients suggest that alternative diversification pathways can occur, for IgA production upon CpG- or proliferating inducible ligand (APRIL) activation of B cells in the gut lamina propria [30], and for SHM in a T-cell-independent manner possibly as an innate mechanism of defense [31,32]. Impaired CD40L/CD40 interaction leads to defective T cell interactions with monocytes/dendritic cells with consequences as (1) impaired full maturation of dendritic cells, (2) impaired IL-12 production by dendritic cells and macrophages, and (3) affected T cell priming, resulting in an abnormal cellular immune response [33]. As a consequence patient suffer from significant susceptibility to opportunistic
infections, which cannot be controlled by Ig substitution therapy [34] and thus adversely affect prognosis. Liver disease is very common and slerosing cholangitis, often associated with Cryptosporidium, is particularly severe and may lead to terminal liver damage. Intermittent or chronic neutropenia is also a common feature of X-linked CD40L deficiency and may result from a defective “stress”-induced CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules [35]. Other complications, such as auto-immune manifestations or cancers, reported in some cases, are not frequent. Albeit mutations affect the entire CD40L gene, they are irregularly distributed with a majority in exon 5, which contains most of the TNF homology domain [36]. No strict relationship between genotype and phenotype is established. Although the CD40L gene is located on the X chromosome, some female patients are rarely affected
Figure 1 T–B cell cooperation in germinal centers. TFH: T follicular helper, TCR: T cell receptor, MHC II: major histocompatibility complex class II, CXCR5: CXC-chemokine receptor-5, ICOSL: ICOS ligand, CD40L: CD40 ligand, IL-R: interleukin receptor, CSR: Ig class switch recombination, SHM: somatic hypermutation, AID: activation-induced cytidine deaminase, UNG: uracil-N-glycosylase.
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S. Kracker et al.
because of a skewed pattern of X inactivation [37] or chromosomal translocation [38].
step, in contrast normal detection of DSBs suggests a defect in DNA repair.
Autosomal recessive CSR-D due to CD40 deficiency. The defect in CD40 has been reported in a very few patients as an autosomal recessive (AR) inherited disease and was diagnosed based on the lack of expression of CD40 on the surface of B lymphocytes and monocytes. The clinical and immunological findings of these patients are identical to those reported in CD40L deficiency. However, in contrast with what is reported in CD40L deficiency, CD40-deficient B cells are unable to undergo in vitro CSR upon activation with CD40 agonists and cytokines [39]. Despite efficient Ig substitution and prophylactic antibiotics, the long-term prognosis of both CD40L and CD40 deficiencies is very severe and death can occur because of infections early in life and later on because of severe liver damage. Hematopoietic stem cell transplantation (HSCT) should be considered if an HLA-identical sibling as a donor is available. Results of HSCT with matched unrelated donors are less satisfactory [40].
A CSR defect located upstream from the double-stranded DNA breaks in S regions Activation-induced cytidine deaminase (AID) deficiency. Activation-induced cytidine deaminase (AID) deficiency is the most frequent of autosomal recessive CSR-D (OMIM #605258). It is caused by mutations in the AICDA gene, which encodes AID, a molecule specifically expressed in activated B cells. It belongs to the large cytidine deaminase family, able to deaminate cytidine into uridine [47]. Its Cterminal domain also contains a leucine-rich region that may be important for protein–protein interaction [48–50]. Recently, a nuclear localization signal (NLS) and a nuclear export signal (NES) have been described, respectively, in the N and C termini of the molecule, although the function and localization of the NLS is still debated [51–53]. A subsequent report suggested active import of AID and an NLS dependent on the conformation of AID [49]. An APOBEC-1-like domain is also described but its function remains unknown. The mechanism of action of AID remains open to debate. Because the sequence of AID is similar to that of the RNA-editing enzyme APOBEC-1, it was originally proposed that AID edits an mRNA encoding a substrate common to CSR and SHM, probably an endonuclease [54,55]. Conversely, several pieces of evidence strongly indicate that AID exerts its cytidine deaminase activity directly on DNA [12–15,56]. Whatever its mode of action is, AID plays a crucial role in B cell terminal differentiation as the inducer of DNA lesion in both S and V regions and its defect leads to complete lack of CSR and SHM in AID-deficient patients and AID-/- mice [57,58]. Analysis of the CSR-induced DSB occurrence in Sμ regions clearly located the defect upstream from the DNA lesion and cleavage [46]. Apart from bacterial infections of the respiratory and digestive tracts, lymphoid hyperplasia is a prominent feature of this disease and is due to massive enlargement of germinal centers, which are filled with actively proliferating B cells that coexpress CD38, sIgM, and sIgD, all markers of germinal center founder cells. Such lymphoid hyperplasia, affecting Peyer's patches as a consequence of intestinal microbial infections, is also described in AID knock-out mice [59]. Autoimmunity (hemolytic anemia, thrombocytopenia, hepatitis, SLE) affects about 20% of the patients, with the presence of auto-antibodies of IgM isotype [60]. AICDA mutations, scattered all along the gene, lead to the same defect impairing both CSR and SHM, although the percentage of CD27+ B cells remains normal. Interestingly, several mutations, located in the C-terminal part of the AICDA gene, which retain normal cytidine deaminase activity, result in complete lack of CSR, whereas SHM is not affected [61]. This observation suggests that, in addition to its cytidine deaminase activity, AID acts on CSR by binding a CSR-specific cofactor. Furthermore, a CSR-specific cytoplasmic AID cofactor has been strongly suggested by recent data using artificial mutants [48,49]. Because mutations in Sμ regions [62] and DSBs [48] are normally found in Sμ regions of AIDΔC murine B cells stimulated to undergo CSR, a defect in synapse formation of the S regions or in DNA repair is more likely than an abnormality of AID targeting to S regions. Another unexpected finding reported [63] is that hete-
X-Linked CSR-D due to defective NF-κB activation. Crosslinking of CD40 results in activation of the NF-κB signaling pathway, the role of which is critical in CSR as shown by the description of patients affected with ectodermal dysplasia associated with immunodeficiency (EDA-ID) [41– 43]. Although heterogeneous, this syndrome can be characterized by normal to increased IgM levels, low levels of serum IgG and IgA, and impaired antibody responses, particularly to polysaccharide antigens. Susceptibility to mycobacterial infections is frequent. EDA-ID is inherited as an X-linked trait, and caused by hypomorphic mutations most frequently found in the zinc-finger domain of the NF-κB essential modulator (NEMO, also known as IKKγ) [44], a scaffolding protein that binds to IKKα and IKKβ, two kinase proteins, required for NF-κB activation and nuclear translocation. Likely because of genetic heterogeneity, in vitro CSR and SHM can be either normal or defective [45] (Durandy, unpublished results). However, the defect is not restricted to CD40 activation since NF-κB nuclear translocation is required for many signaling pathways, including the T and B cell receptors. The ectodermal dysplasia, a key feature of this syndrome, results from NEMO deficiency as ectodysplasin receptor expressed on tissues derived from the ectoderm activate NF-κB, via the IKKα/β NEMO complex [42]. CSR-D caused by an intrinsic B cell defect Other CSR-Ds are caused by an intrinsic B cell defect, resulting in increased susceptibility to bacterial infections (but not to opportunistic infections) that can be effectively controlled by regular intravenous Ig substitution. SHM can be either normal or defective, according to the molecular defect. B cells are intrinsically defective for CSR; although they proliferate normally they are unable to undergo CSR after activation by CD40L and appropriate cytokines. In such in vitro activation studies, it is possible to locate the CSR defect by employing a ligated-mediated PCR technique that allows detection of DNA-DSBs, which are normally occurring during CSR in switch regions [46]. The absence of DSB indicates a defect located upstream from the DNA cleavage
Immunoglobulin class switch recombination deficiencies rozygous nonsense mutations, located in the C-terminal domain and resulting in the loss of the nine last amino acids of NES (AIDΔNES) lead to a variable CSR-D transmitted as an autosomal dominant (AD) disease. Haploinsufficiency, although reported in mice with weak consequences on Ig levels [64,65], is highly unlikely because all other human subjects heterozygous for AID deficiency always exhibit normal Ig levels. A dominant negative effect exerted by the mutated allele could be explained if AID acts in a homomeric complex, which is however still controversially discussed [48,49]. The prognosis for the patients is rather good upon regular infusion of Ig for treatment that, however, does not control the lymphoid hyperplasia and the auto-immune complications. Uracil-N-glycosylase (UNG) deficiency. The Uracil-Nglycosylase deficiency is a rare cause for CSR-D (OMIM #608106, gene ⁎ 191525) since only three patients have been reported in the literature [66]. UNG belongs to the family of uracil-DNA-glycosylases capable of deglycosylating uracil residues that are misintegrated into DNA. Following removal of uracil residues by UNG, abasic sites are created that can be attacked by apurinic-apyrimidinic endonucleases leading to SSB. The processing and repair of the DNA nicks complete both CSR and SHM [66,67]. In the absence of UNG, this pathway is impaired, resulting in defective CSR and abnormal SHM as shown by the phenotype of both UNG-deficient patients [66] and ung-/- mice [67]. All three patients had a history of frequent bacterial infections of the respiratory tract that are easily controlled by regular IVIG infusions. Lymphadenopathy was observed in two of three patients, with transient enlargement of mediastinal or cervical lymph nodes. The adult patient has developed Sjögren syndrome in recent years. All 3 patients do suffer from a drastic CSR defect in vivo and in vitro, the latter being located upstream from the DSB occurrence [66]. Interestingly enough, SHM was normal in frequency but characterized by a skewed pattern of nucleotide substitution. The excess of transitions occurring on C:G residues probably arise from the replication of U: G lesions in the absence of U removal. Mismatch repair (MMR) enzymes may also recognize and repair these mismatches, thereby introducing mutations on neighboring nucleotides that result in both transitions and transversions on A:T residues [68]. Four different mutations affecting the catalytic domain of UNG1 and UNG2 have been found. Two patients have small deletions leading to a premature stop codon (homozygous mutation in one patient born from a consanguineous family and two heterozygous mutations in the other). The third patient carries a homozygous missense mutation. UNG expression and function were defective in Epstein–Barr virus (EBV) B cell lines, providing evidence for the lack of any compensatory UNG–DNA glycosylase activity, at least in B cells. Patients are well controlled with Ig substitution. However, UNG is part of the DNA base excision repair involved in the repair of spontaneously occurring base lesions and therefore constitutes an anti-mutagenic defense strategy. UNG-deficient mice do develop B cell lymphomas when aging [69]. It is thus possible that UNG deficiency predisposes to such tumors in adulthood. Another consequence of UNG deficiency has also been reported in ung-deficient mice since post-ischemic brain injury is much more severe than in control mice, a
197 likely consequence of the mitochondrial DNA repair defect [70]. Post-meiotic segregation 2 (PMS2) deficiency. It has been recently shown that homozygous mutations in the PMS2 gene, known to be responsible for early occurrence of cancers, result in a CSR-D, which can be the main symptom for several years [71]. PMS2 belongs to the MMR pathway that recognizes and repairs mismatched nucleotides on DNA. MMR is known to play a role in CSR in mice, as shown by abnormal switched isotype levels and switch junctions [72,73]. There are two main MMR components: the MutS homologue (MSH1– 6) and the MutL homologue (PMS2/MLH1/PMS1). The MSH2– MSH6 complex appears to recognize AID-induced DNA mismatches in the absence of UNG, leading to backup CSR and SHM, as shown by the phenotype of a double UNG–MSH2 and UNG–MSH6 knockout mutant [68,74]. Recently, it has also been reported that MSH5 variants in humans can be associated with common variable immunodeficiency and IgA deficiency phenotypes, including abnormal switch junctions that are characteristic of DNA repair defects [75], although these results are controversial [76]. The role of the PMS2– MLH1 complex is less clear. It has been proposed that the MMR system can convert DNA SSBs into DSBs in Sμ regions upon CSR activation [77]. In the SHM process, the repair of V regions requires the MMR and error-prone DNA polymerases. The MSH2–MSH6 complex is essential in SHM for recognizing the AID-induced U/G mismatch, and recruiting exonuclease (EXO1) and polymerase η [78]. The role of the PMS2–MLH1 complex in SHM remains subject to debate [79,80]. Whereas heterozygous PMS2 mutations are associated with colon carcinoma in adulthood [81] homozygous mutations are responsible for high susceptibility to various cancers (colon adenocarcinoma, T lymphoma, T acute lymphoid leukemia) [82]. Moreover, a variable CSR-D can even worsen the prognosis, as recently shown in six patients carrying homozygous nonsense mutations in PMS2 gene, leading to either a truncated protein or a lack of expression. Indeed, one of the patients has suffered from bacterial infections from the first years of age, leading to the diagnosis of CSR-D with high IgM levels, decrease of IgG, and absence of IgA. Whereas she has been treated by Ig substitution for 2 years, she developed a colon carcinoma that lead to the diagnosis of PMS2 deficiency. The five other patients, already known to suffer from a PMS2 deficiency because of early occurrence of cancers, have no remarkable history of repeated infections; however, they all lack IgG2 and IgG4. IgA and IgG3 were also decreased in one. SHM was found normal in all with a normal nucleotide substitution pattern. This observation underlies the role of PMS2 in CSR but not in SHM in humans, as already shown in mice [72,79]. Interestingly, it was also shown that DNA DSBs do not normally occur in Sμ regions in PMS2-deficient B cells upon CSR activation [71]. Expression of MLH1, PMS2 partner in MutLa, was slightly reduced but still present in the nuclei likely because of dimerization with PMS1. The decrease occurrence of DSBs in Sμ regions upon CSR activation in PMS2-deficient human B cells strongly suggests a role for PMS2 in DNA cleavage, likely through its endonuclease domain [83]. Since UNG-deficient patients exhibit a drastic CSR defect, it appears that PMS2
198 does not play a role in CSR as an alternative pathway but acts downstream from UNG in the very same pathway [71]. Indeed, the main symptom of PMS2 deficiency is the occurrence of cancers during childhood. Nevertheless, the CSR-D, which appears constant in all the studied patients, could be the main feature for several years and this diagnosis has to be considered when CSR-D due to an intrinsic B cell defect is not associated with AICDA or UNG mutations. Ig CSR deficiencies with unknown molecular defect (s). Half of Ig CSR deficiencies due to an intrinsic B cell defect are related neither to AID, UNG nor PMS2 deficiency. Although most of the observed cases are sporadic, the mode of inheritance observed in a few multiplex or consanguineous families is compatible with an autosomal recessive (AR) pattern. The clinical phenotype is similar to that of AID deficiency, including increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts. Lymphoid hyperplasia is milder and less frequent (50%), consisting of moderate follicular hyperplasia without the giant germinal centers typical of AID deficiency. Autoimmune manifestations are reported [84]. The CSR defect appears to be milder as compared with AID or UNG deficiency since residual serum levels of IgG can be detected in some patients. It is located downstream from S-region transcription and upstream from the S-region DNA cleavage, as no detectable CSR-induced DSB are detected in Sμ regions of patients' B cells. The defect is restricted to CSR, as SHM is normal in both frequency and pattern in the CD27+ B cell subset, which is represented in normal numbers. This type of CSR-D could thus be caused by a direct or indirect impairment of AID targeting on S regions. Although targeting factors of AID are presently unknown, they might exist because AID deaminates cytosines specifically in the S and V regions in B cells. AID shares sequence similarity with the RNA-editing enzyme APOBEC-1, which is only expressed in the gut and requires a cofactor, ACF (APOBEC-1-cofactor), which targets APOBEC-1 on a unique C residue in ApoB mRNA. In addition, specific switch factors have been described in CSR-activated B cells. Although their role remains elusive, it has been proposed that these cofactors act as docking proteins for the recruitment of the recombinase complexes to DNA-specific regions [85,86]. A CSR defect located downstream from the double-stranded DNA breaks in S regions. Conversely, a group of CSR-D due to an intrinsic B cell defect is caused by a defect located downstream from the DNA lesion and cleavage step since DSB normally occur in Sμ regions in CSR-activated B cells. Thus a defect in DNA repair can be suggested. Ig CSR deficiencies associated to an unknown DNA repair defect. This CSR deficiency appears to be transmitted as an AR disease since the M:F ratio is around 1 and consanguinity is observed in 20% of the cases. As other CSR-D, patients suffer from susceptibility to bacterial infections, lymphadenopathies, and auto-immune manifestations. Some residual IgG or IgA are often observed but the in vitro CSR upon CD40 activation together with cytokines is strongly reduced. This CSR defect is located downstream from the DNA cleavage step, suggesting a DNA repair defect of switching B cells, a hypothesis reinforced
S. Kracker et al. by the observation of tumor occurrence (non-EBV-induced B cell lymphomas) in 4 out of 45 patients [87]. Moreover, a strong decrease of CD27+ B cells, a defect in switch junctions repair with a preferential usage of microhomology, and especially a significant increased radiosensitivity of fibroblasts and EBV B cell lines strongly argue in favor of this hypothesis [88]. DNA repair of S regions is achieved through a complex mechanism: it has been shown that upon CSR activation and in an AID-dependent manner, the conformation of the Ig locus is modified, leading the Sμ–Sx regions to be in close proximity [89]. The maintenance of this synapse requires a multimolecular complex involving the phosphorylated γH2AX- and the 53BP1 protein, the complex MRE11/RAD50/ NBS1 and ATM [18,19,90–93], leading to (1) cell cycle arrest and (2) DNA repair through the NHEJ pathway [21,22,94]. Since the involvement of all these molecules has been excluded in these patients, it is likely that (an)other(s) molecule(s), up to now undefined and deficient in these patients, plays a role in CSR-induced DNA repair of S regions. Although this condition is not molecularly defined, it is important to diagnose it in order to prompt an accurate follow-up of patients because of the risk of lymphomas. Ig CSR deficiencies as part of a known DNA repair factor defect. As ATM and the MRE11/RAD50/NBS1 (MRN) complex are involved in DSB DNA repair, a CSR-D is not unexpected in these syndromes caused by a defect in one of these molecules. ATM (ataxia–telangiectasia: AT), MRE11 (AT-like disease), and NBS1 (Nijmegen breakage syndrome) deficiencies are associated with variable CSR-D, a symptom sometimes preceding the neurological abnormalities in AT [95–97]. Study of recombined switch junctions in the Ig gene locus indicates that the DNA repair does not occur properly during CSR [98,99]. Normal SHM generation and pattern in AT confirms that ATM is not essential for DNA repair of V regions [100]. Conversely, an SHM defect has been reported in Nijmegen breakage syndrome [101]. An Ig CSR-D phenotype has also been observed as part of combined immunodeficiencies linked to leaky mutations in genes encoding NHEJ factors, such as Cernunnos, DNA ligase IV or Artemis [102–105]. CSR-D with normal in vitro B cell response to CSR activation Interestingly, several patients affected with a CSR-D display normal in vitro CSR. CD40L defect has been excluded by normal protein expression and gene sequence. The phenotype of this group of patient is indeed quite different from that of CD40L-deficient patients since there is no susceptibility to opportunistic infections but only to bacterial infections that are controlled by Ig substitution. Lymphadenopathies with enlarged germinal centers (but no giant germinal centers that are typical of AID deficiency) are observed and SHM is found normal in frequency and pattern. Several possible causes have been excluded, such as congenital rubella, in which a defect of T cell activation leads to defective CD40L expression on CD4+ T cells [106], or major histocompatibility complex (MHC) class II deficiency in which diminished expression of CD40L by activated CD4+ T cells can also be responsible for an in vivo CSR-D [107]. Deficiencies in ICOS, a T cell activation
Immunoglobulin class switch recombination deficiencies molecule, or in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a receptor expressed on B cells for the activation molecules BAFF and APRIL, have also been excluded. Although reported as responsible for AR or dominant common variable immunodeficiencies or IgA deficiencies [108– 110], both defects can present with normal serum IgM levels and decrease of IgG and IgA. In ICOS deficiency, the defective CSR could be caused by defective TH2 cytokine production and/or defective generation of CXC-chemokine receptor-5 (CXCR5)+ follicular helper T cells as shown in patients and ICOS-deficient mice [111,112]. In TACI deficiency, the defective CSR results from impaired TACI activation as it has been demonstrated that BAFF and APRIL are inducing CSR to IgG and IgA via TACI activation in naive B cells [113]. A defect in the generation of follicular helper T cells, their activation, and/ or their interaction with follicular B cells could be suspected in this CSR-D condition. Conversely, abnormalities in survival signaling of switched B cells could underlie this condition. Molecular interactions are known to be essential for B cell survival, including that of BAFF (B cell activating factor) with its B cell receptor, BAFF-R [114,115]. However, increased IgM levels are not reported in patients with a defect in the BAFF-R [116], which might be due to the general decrease of naive mature B cells in these patients. A response to DNA damage leading to inappropriate cell death should be considered. In cells other than germinal center B cells, DSB activates p53 and p21, resulting in cell cycle arrest and apoptosis. In contrast, in germinal centers, the p53 response to DNA damage is directly inhibited by the highly expressed transcriptional regulator B cell lymphoma 6 (BCL6), while p21-induced cell cycle arrest is suppressed through interaction of its transcriptional activator Miz1 (protein inhibitor of activated STAT2) with BCL6. Both these events enable intense proliferation of B cells undergoing CSR [117,118]. Fitting in with this observation, BCL6-deficient mice are depleted of germinal centers because of a strong B cell apoptosis [119]. Such a defect in transcriptional repression of proteins involved in cell cycle arrest induced by DNA damage could also underlie this Ig CSR deficiency. In favor of this last hypothesis is the occurrence of auto-immunity in 20% of patients. Another hypothesis is related to the described role of phosphoinositide-3 kinase (PI3K) acting as a negative regulator of CSR [120]. However, the normal expression of AICDA transcripts, AID protein, and in vitro CSR by activated B cells from these patients do not support this hypothesis. It is likely that this group of patients is quite heterogeneous, and a precise phenotypical characterization is necessary for a better understanding of the defects underlying this CSR-D with normal in vitro CSR.
Concluding remarks The ongoing delineation of inherited CSR-D is shedding new light on the complex molecular mechanisms that T and B cell interaction govern CSR and SHM. Natural mutants observed in human immunodeficiencies have, in some cases, been described before the generation of the
199 appropriate mouse model. The molecular characterization of CD40L and of NEMO deficiencies, before the generation of the corresponding deficient mice, provided clear evidence that the CD40 activation pathway, including the activation and nuclear translocation of NF-κB transcription complex, was essential in both events of antibody maturation, CSR and SHM. AID-deficient humans and mice were described concomitantly, demonstrating the key role of this molecule in the generation of the secondary antibody repertoire. These examples emphasize the important contribution made by studies of primary immune deficiencies to improving our understanding of the physiology of immune responses. Moreover, a precise diagnosis of the CSR-D aids in assessment of prognosis and prompts to accurate forms of treatment.
Acknowledgments We acknowledge Mrs. M. Forveille for her excellent technical assistance. This work was supported by INSERM, CEE EUROPAD Contract 7th Framework Program (n201549), and Association Nationale pour la Recherche (MRAR-016-01). S. Kracker is supported by the EUROPAD contract.
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