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Keywords:

  • Antibody;
  • Common variable immunodeficiency;
  • IgA deficiency;
  • Primary immunodeficiency

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

Primary immunodeficiency diseases are rare disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of disorders have been described. In this review, we will focus on novel findings in antibody deficiency syndromes.

Abbreviations:
APRIL:

a proliferation-inducing ligand

BAFF:

B cell activation factor of the TNF family

CSR:

class switch recombination

CVID:

common variable immunodeficiency

HIGM:

hyper-IgM

IgAD:

IgA deficiency

IRF5:

interferon regulatory factor 5 ;

MHC2TA:

MHC class II transactivator

PID:

primary immunodeficiency disease

PTPN22:

protein tyrosine phosphatase nonreceptor-type 22

SUMO4:

small ubiquitin-like modifier 4

TACI:

transmembrane activator and CAML interactor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

Primary immunodeficiency diseases (PID) are disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of diseases have been described and the genetic basis for most of these defects is known (see 1, 2 for recent reviews).

Principally, PID can be subdivided into T cell, B cell, combined (T+B), phagocyte and complement defects. The combined immunodeficiencies (SCID) are clinically the most severe and will, if undiagnosed, lead to death of the affected child, usually within the first year of life. Other defects, numerically more prevalent and including common variable immunodeficiency (CVID) and IgA deficiency (IgAD), will result in considerable morbidity, but are rarely associated with mortality.

The above defects are all “global”, i.e. associated with susceptibility to a variety of different pathogens. However, recently, several PID have been described that are characterized by an increased frequency of infections caused by selected pathogens such as mycobacteria, pneumococci 3 and herpes simplex virus 4, 5. Such “holes-in-the-repertoire” defects (for recent review see 6) are likely to be common in the population and may, taken together, account for a substantial number of, hitherto largely undiagnosed, patients with PID.

Furthermore, a recent observation 7 shows that novel mutations in “classical” genes, i.e. those known to be involved in a given PID, may give rise to a different phenotype, suggesting that the field is getting more complex than previously recognized. In addition, the etiology of several phenotypically similar, albeit in some cases not entirely identical, PID have recently been shown to be caused by mutations in other genes than those originally implicated (examples include hyper-IgM (HIGM, see below), X-linked lymphoproliferative syndrome 8, hyper-IgE 9, 10, Omenn syndrome 11 and X-linked susceptibility to mycobacterial infections 12. Differences in glycosylation pattern may also account for selected disease phenotypes 13 and understanding the full spectrum of genetic causes of PID still requires substantial efforts. In this review, we will focus on novel findings in different B cell disorders.

Defects in early B cell development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

Mutations in genes/proteins affecting early B lymphocyte development, including Bruton's tyrosine kinase, μ, B cell linker, λ5 and Igα (CD79a), have all been described previously (for review see 14). In an early screening study by Conley and coworkers 15, eight different mutations in the μ heavy chain were identified in 19 members of 12 unrelated families. Four of the mutations were large deletions that removed more than 40 kb of DNA in the IGHC region locus. In six of the 12 families, the affected patients had an identical single base pair substitution, a G-->A, at position –1 of the alternative splice site. This mutation has occurred on at least three different Ig haplotypes, indicating that this is a hot spot for mutations. The study indicated that at least 20–30% of patients with autosomal recessive defects in B cell development have mutations in the μ heavy chain and multiple additional patients have recently been described 1618.

Interestingly, in one of the latter studies 16, two patients with compound heterozygous variations in the pre-B lymphocyte gene 1 (VpreB1) were also described. Although it cannot be ruled out that these variations represent low-frequency polymorphisms, they may be the first cases suggesting that VpreB mutations are indeed involved in the etiology of agammaglobulinemia in humans.

Null mutations in Igα have previously been identified in a few patients with defects in B cell development 19, 20. Very recently, mutations in Igβ (CD79b) were also reported in patients with hypogammaglobulinemia. Conley and coworkers 21 identified a patient with a homozygous amino acid substitution in Igβ, a glycine to serine at codon 137, adjacent to the cysteine required for the disulfide bond between Igα and Igβ. Using expression vectors in 293T cells or Jurkat T cells, it was shown that the mutant Igβ could form disulfide-linked complexes and bring the μ chain to the cell surface as part of the B cell receptor, but that it was inefficient at both tasks. As a consequence, the patient had a very low proportion of surface IgM+ cells in peripheral blood.

Even more compelling evidence for the involvement of Igβ mutations in patients with autosomal recessive agammaglobulinemia was reported by Plebani and coworkers 22. The patient carried a homozygous nonsense mutation in Igβ, causing a replacement of the glutamine in position 80 of the protein with a stop codon. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igβ could no longer associate with Igα, and that assembly of the B cell receptor complex on the cell surface was abrogated. Consequently, there was a complete block of B cell development at the pro-B to pre-B transition in the bone marrow of the patient.

Defects in late B cell development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

HIGM

HIGM is characterized by a failure of B cells to undergo class switch recombination (CSR) and thus, the patients show normal or elevated levels of IgM but very low (or absent) levels of IgG and IgA. The prevalence is estimated to be approximately 1/500 000 in the Caucasian population. The patients suffer from recurrent respiratory tract infections and in some cases, infection by opportunistic pathogens such as Pneumocystis jiroveci. Several genetic causes underlying the development of HIGM have previously been described 23. However, although most patients with HIGM can now be diagnosed at the molecular level, it is likely that multiple additional etiologies will be found.

Recently, Durandy and co-workers 24 described a novel HIGM subtype, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) μ regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, somatic hypermutation was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique CSR deficiency phenotype could be related to an as yet uncharacterized defect in a DNA repair pathway involved in both CSR and somatic hypermutation.

Some forms of HIGM are similar in appearance to CVID (see below). Thus it is likely that there will be an overlap between the two diseases both in terms of clinical appearance and genetic background.

CVID

CVID is a clinically heterogenous disorder characterized by low or absent levels of serum IgA, reduced levels of IgG (<3 g/L) and low or normal levels of IgM. Most patients suffer from recurrent bacterial infections and autoimmune phenomena have also been suggested to be overrepresented (for review see 25). The prevalence is approximately 1/20 000–1/50 000 in the Caucasian population. Although drug-induced cases have been described, the etiology of CVID remains unknown in most patients. Other immunodeficiency disorders may occasionally be misdiagnosed as CVID. However, the availability of genetic tests for most of the latter diseases has led to a proper identification of these patients.

A major breakthrough in understanding the genetics of CVID was made in 2003, when patients with mutations in the gene encoding the “inducible T cell costimulator” (ICOS) on activated T cells, were described 26. ICOS interacts with ICOS ligand, which is expressed on the surface of B cells, thereby supporting T-B cell collaboration. Ligation of ICOS ligand to ICOS leads to a release of IL-10 from germinal center T cells, allowing B cells to undergo CSR. Furthermore, the ICOS-ICOS ligand signaling in germinal centers is critical for the development and function of the highly specialized subpopulation of chemokine CXC receptor 5+ follicular T helper cells. The loss of ICOS expression leads to absence of this cell population, consecutive failure to develop functional germinal centers and ultimately, impaired terminal B cell differentiation and hypogammaglobulinemia. This aberration (deletion of exons 2 and 3) appears to be due to a founder effect and the patients described to date (n=9) are likely to be related and are all living in the Black Forest in southern Germany or along the Danube River.

A second breakthrough was described in 2005, when CVID patients with mutations in transmembrane activator and CAML interactor (TACI) were described 27, 28. TACI belongs to a superfamily of TNF receptors consisting of the ligands B cell activation factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) and their three receptors BAFFR, B cell maturation antigen and TACI, that comprise a network that is critically involved in the development and function of humoral immunity. Failure in this complex system is associated with autoimmune disease, B lymphocyte tumors and antibody deficiency in mice. While BAFF-BAFFR interactions control peripheral B cell survival and homeostasis, the function of B cell maturation antigen seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of TACI is, however, ambiguous: while TACI-deficient mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome, accounting for 1–5% of all CVID patients.

A variety of mutations in TACI causing CVID have been described and whereas homozygous mutations will cause disease, heterozygous mutations, in particular the C104R and A181E, only constitute risk factors 29. Recently, Geha and coworkers 30 showed that the former mutation dominantly interferes with TACI signaling. This effect is dependent on pre-association of the mutants with wild-type TACI in the absence of ligand. The mutant protein does, however, not interfere with ligand binding by wild-type TACI, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACI pre-assembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how heterozygous C104R TACI mutations can potentially lead to CVID. However, the study was based on an in vitro overexpression system in 293 cells, which was limited to the measurement of induction of NF-κB. Rigorous proof of a dominant-negative effect awaits the results of transgenic or knock-in mice.

A third genetic cause of CVID, mutations in the CD19-encoding gene, was also recently described 31. The CD19 protein forms a complex with CD21, CD81 and CD225 in the membrane of mature B cells. Together with the BCR, this complex signals the B cell to decrease its threshold for activation by the antigen. Four patients have been described to date with homozygous mutations in the CD19 gene. Levels of CD19 were undetectable in one patient and substantially decreased in the other three. The composition of the precursor B cell compartment in bone marrow and the total numbers of B cells in blood were normal whereas the numbers of CD27+ memory B cells and CD5+ B cells were decreased.

Several other candidate genes as well as genetic regions have been suggested (for recent review see 32), and it is likely that CVID, similar to HIGM, will be due to a variety of underlying genetic causes and the future nomenclature will have to encompass these new findings, i.e. classifying CVID into CVID type 1 (ICOS), type 2 (TACI), type 3 (CD19) etc.

IgAD

IgAD, defined as <0.07 g/L of IgA in serum, is the most prevalent PID in Caucasians with an estimated frequency of 1/600 in the general population. Although some individuals with IgAD are asymptomatic, many suffer from an increased frequency of respiratory and gastrointestinal tract infections. The genetic cause of IgAD still remains elusive although a strong association/linkage to genes within the MHC (HLA), in particular the class II and/or the class III regions, has been suggested (for review see 25).

MSH5, encoded by a gene within in the central MHC class III region, and its obligate heterodimerization partner MSH4, play critical roles in regulating meiotic homologous recombination. One of the recently identified human MSH5 alleles contains two missense polymorphisms (L85F and P786S), and the variant protein encoded by this allele shows impaired binding to MSH4. Ig switch region joints from IgAD and CVID patients carrying the disease-associated MSH5 alleles show an increased donor/acceptor microhomology, involving pentameric DNA repeat sequences, and lower mutation rates than controls. These findings suggest that MSH4/5 heterodimers contribute to CSR and support a model whereby MSH4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical non-homologous end-joining mechanism and that defects in MSH5 may thus result in immunodeficiency 33. These mutations are carried on the ancestral HLA B14, DR1 haplotype and although this haplotype has previously been shown to be associated with IgAD, it nevertheless accounts only for a small proportion of cases (1–2%). Thus, a search for additional susceptibility genes within the MHC region is clearly warranted.

Mutations in TACI were initially described in IgAD patients 27. However, enlarged series of patients have shown no association 23, 29.

Negative association studies in IgAD/CVID

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

Although the clinical hallmark of PID is an increased susceptibility to infections, many forms of PID are also characterized by autoimmunity and/or aberrant inflammatory responses 34. While autoimmune manifestations have been reported in various forms of PID, irrespective of the nature of the immune defect primarily involved in the disease, the molecular and cellular mechanisms responsible for autoimmunity may vary in different forms of PID. In addition, several mechanisms may be involved even within the same form of PID. In particular, the notion that autoimmunity results from a failure of self tolerance applies only to some of the autoimmune manifestations associated with PID.

Several “classical” autoimmune diseases, such as systemic lupus erythematosus, insulin-dependent diabetes mellitus, Graves disease and celiac disease, are associated with an increased prevalence of IgAD. The question remains whether the very same genes are involved in both diseases or whether in the case of genes within the MHC region, the two diseases are due to different genes in linkage disequilibrium. Recently, a number of non-MHC susceptibility genes have been identified in various autoimmune disorders, including interferon regulatory factor 5 (IRF5), protein tyrosine phosphatase nonreceptor-type 22 (PTPN22), small ubiquitin-like modifier 4 (SUMO4) and MHC class II transactivator (MHC2TA) 3538. This has prompted a search for an association in PID patients not only for genes involved in B cell development or immune regulation, but also genes primarily thought to be involved in the development of autoimmunity. No significant association has, however, been observed thus far for the tested genes (see Table 1 for IgAD and Table 2 for CVID) 37, 3942.

Table 1. Negative gene association studies in IgAD
GeneSNPa)NucleotidealterationAmino acidalterationNumberof patientsReference
  1. a) SNP: single-nucleotide polymorphism.

  2. b) Unpublished data are from the authors’ laboratory. The Institution Review Board at the Karolinska Institute, Stockholm, Sweden, had approved the study and informed consent was obtained from all patients.

  3. c) Sequencing of all exons.

APRILrs38038001028A-GN96S164Unpublishedb)
51c)Unpublished
BAFFR62C-GP21R228Unpublished
475C-TH159Y197Unpublished
CD45rs17612648263C-G (77C-G)P57P232Unpublished
16542
IRF5rs109542132191A-GIntron198Unpublished
rs2004640T-GIntron177Unpublished
MHC2TArs3087456–168A-GIntron249Unpublished
PTPN22rs24766011858C-TR620W25937
197Unpublished
SUMO4rs237025196A-GM55V197Unpublished
TACIIns204A23729
228G-A R72H23829
273T-AI87N203Unpublished
rs34557412323T-CC104R23929
377C-TR122W24029
444C-AS144X238Unpublished
555C-AA181E23229
55c)29
Table 2. Negative gene association studies in CVID
GeneSNPa)NucleotidealterationAmino acidalterationNumberof patientsReference
  1. a) SNP: single-nucleotide polymorphism.

  2. b) Unpublished data are from the authors’ laboratory.

  3. c) Sequencing of all exons.

APRILrs38038001028A-GN96S76Unpublishedb)
23c)Unpublished
BAFF78c)40
BAFFR62C-GP21R4841
475C-TH159Y
IVS2–33T-C
CD45rs17612648263C-G (77C-G)P57P91Unpublished
14242
CTLA-4exon-1 +49 A/GIntron4739
IRF5rs109542132191A-GIntron84Unpublished
rs2004640T-GIntron76Unpublished
MHC2TArs3087456–168A-G97Unpublished
SUMO4rs237025196A-GM55V61Unpublished
TACI228G-AR72H11529
377C-TR122W11429
618G-AR202H11529

These negative association studies include candidate genes such as APRIL, where the corresponding mouse knock out shows impaired IgA class switching 43, and the BAFFR, where the initial study suggested an association with CVID in a German family 44. The association of unusual PID case presentations in patients carrying the CD45 C77G polymorphism in a heterozygous form is intriguing 45. However, as this is also seen in a similar proportion both in IgAD/CVID patients and controls 42, its relevance may be questioned.

Negative association studies rarely get published. Nevertheless, information gathered on genes shown not to be associated with PID may be quite valuable as they may point to, or exclude, particular pathways that are being used in the disease process. Furthermore, publication of these data will prevent unnecessary duplication of research efforts.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defects in early B cell development
  5. Defects in late B cell development
  6. Negative association studies in IgAD/CVID
  7. Concluding remarks
  8. Acknowledgements
  9. Appendix

As efficient therapy exists for the majority of PID patients, efforts should be made to increase the awareness of the existence of these diseases among pediatricians and infectious disease doctors. It is now also time to look at novel approaches to therapy for PID, based on the disease mechanisms. This is not restricted to gene therapy, but also includes bypassing biochemical and/or cellular defects, and exploiting the use of chemical compounds to allow reading-through nonsense mutations or correction of splice-site mutations 46.

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