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 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, 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.