common variable immunodeficiency ( cvid ) is a heterogeneous group of diseases characterized by hypogammaglobulinemia and repeated , predominantly , bacterial infections .
b lymphocytes , however , show defects of differentiation and proliferation after antigen stimulation . the number of plasma and memory cells is reduced . as a result of this ,
the values of serum igg and iga are reduced and also irregularly the values of igm ( di renzo et al . , 2004 ) .
the antibody response to protein and polysaccharide antigens is insufficient or completely missing in some cases .
the attempts to classify cvid based on in vitro immunoglobulin ( ig ) production and b lymphocyte subsets have confirmed marked heterogeneity of this antibody defects ( weiler & bankers - fulbright , 2005 ) .
differentiation of precursor cells into mature b lymphocytes and then into plasma cells is a process regulated by products of a number of genes .
mutation of genes for inducible costimulator ( icos ) , the first single gene defect , has been described in patients with cvid ( grimbacher et al . ,
subsequently , the mutations of genes encoding transmembrane activator and calcium - modulator and cytophilin ligand interactor ( taci ) and cd19 have been found .
it ranks in the family of costimulation molecules similarly as cd28 and ctla-4 ( cd152 ) molecules .
it is encoded by three genes that are mapped to chromosome 2q33 . a great number of single nucleotide variants that participate in the icos polymorphisms have been reported .
the comparison of the frequency of single nucleotide polymorphisms between patients and healthy controls showed no significant differences ( haaning andersen et al .
, 2003 ; guzman et al . , 2005 ; ohm - laursen et al . ,
the icos and cd28 molecules share up to 20% amino acid homology and both are type i transmembrane receptors .
icos occurs as a homodimer , with an extracellular ( ig ) v like domain . unlike the cd28 molecule , which is expressed constitutively , the icos molecule is expressed only on activated t lymphocytes .
its membrane expression persists on recently activated as well as on memory th1 and th2 cd4 lymphocytes ( van berkel & oosterwegel , 2006 ; warnatz et al . , 2006 ) .
the icos expression appears to be higher on th2 cells compared to th1 cd4 t cells ( coyle et al . , 2000 ) .
the th2-mediated response is more dependent on the icos function than th1 response ( lhning et al . , 2003 ; grunig et al . ,
the density of icos membrane expression correlates with cytokine production . in case of icos gene mutation , especially the synthesis of cytokine associated with high - level icos expression ( il-10 , il-2 , il-4 , il-5 , il-13 )
within the course of viral or bacterial infections in knock - out icos/ mice , large secondary germ centres fail to develop , and specific antibody response is missing .
both the reduced proliferation th2 activity and the failure of t and b lymphocyte co - operation participate in the developed antibody defect ( van berkel & oosterwegel , 2006 ; warnatz et al . , 2006 )
( figure 1 ) . the cascade of co - stimulation signals between t and b lymphocytes .
the expression of cd154 ( cd40l ) and icos is up - regulated through constitutively surface expressed cd28 molecule and its cd80/cd86 ligands .
another support of co - stimulation ligands between t and b lymphocytes occurs through icos - icos - l which up - regulates cd154 expression .
the intracellular tail of the icos molecule contains two tyrosine residues , one of which lies within the ytyr180mem motive , which is associated with adapter molecule grow factor receptor - bound protein-2 ( grb-2 ) .
one amino acid replacement at the position in this motive includes explaining of the lack of capability to recruit grb-2 .
this molecule plays a key role during the initiation of il-2 synthesis ( harada et al . , 2003 ) .
this finding explains why activating signals coming through defective icos molecules do not lead to synthesis of il-2 ( itoh et al . , 2002 ) .
activated t lymphocytes amplify the icos - l expression on b lymphocytes through il-4 , il-5 , il-6 , granulocyte macrophage colony - stimulating factor ( gm - csf ) , ifn and tumour necrosis factor ( tnf) cytokines ( bayry et al . , 2005 ) .
icos - l expression on b lymphocytes is also up - regulated through cd40 and cd154 ligands or bacterial superantigens ( salzer et al . , 2004 ; janke et al . , 2006 ) .
the icos : icos - l interaction is necessary for il-10 , il-17 synthesis ( chtanova et al . , 2004 ; warnatz et al . ,
the icos - l molecule is encoded by one gene , which is found on the long arm of chromosome 21 ( mapped 21q22.3 ) .
the b7h2 variant is encoded by exon 17 and appears on both lymphoid and non - lymphoid cells .
the hgl-50 variant is encoded by exon 16 and 8 , and is found only on lymphoid cells ( ohm - laursen et al . , 2005 ; warnatz et al . ,
interaction of icos  icos - l molecules is important for differentiation of naive b lymphocytes into memory and plasma cells .
icos - l ligand shares up to 20% homology with cd80 and cd86 molecules ( receptors for cd28 and ctla-4 molecules ) ( salzer et al . , 2004 ; van berkel & oosterwegel , 2006 ) .
the clinical phenotype includes recurrent and serious bacterial infections , autoimmune phenomena , splenomegaly , lymphadenopathy and malignancy .
patients with cvid , based on icos defect , have mild b lymphopaenia and significantly reduced number of memory cd19/cd27 b lymphocytes ( warnatz et al . , 2002 ; piqueras et al . ,
this laboratory finding is not , however , characteristic for icos mutations because up to 75% of patients with cvid have a reduced number of memory isotype - switched cd19/cd27/igm b lymphocytes ( schejbel et al . , 2005 ) .
however , patients with icos deficiency belong to cvid type i group ( freigburg classification ) ( warnatz et al . , 2002 ; carsetti et al . , 2005 ) .
icos deficiency , based on one point mutation , was the first example of an autosomal recessive disorder that occurs only in a small amount of patients with cvid ( approximately 2% ) ( warnatz et al . , 2006 ) .
in order to ensure physiological antibody response after antigen stimulation , other activation signals mediated by both intracellular interactions and soluble factors are important ( kroczek et al . , 2004 ) . class switch recombination ( csr ) of ig synthesis requires four signals .
the first one is mediated by il-3 , il-4 , il-5 , il-6 , il-13 cytokines , which participate in ch genes transcription regulation . in case of a t - cell  dependent antibody response , the interaction of cd40l ( cd154 ) molecule expressed on activated t lymphocytes with cd40 molecule on b lymphocytes is necessary ( mcheyzer - williams , 2003 ) .
costimulatory icos  icos - l interaction constitutes the third necessary stimulus for sufficient antibody production .
the fourth signal is mediated by other interactions of molecules , which belong to the superfamily of tnf molecules ( b - cell  acting factor of the tnf family ( baff ) , a proliferation - inducing ligand ( april ) ) , and their receptors ( b - cell maturation antigen ( bcma ) , baff receptor ( baff - r ) , taci ) .
the baff and april are among these molecules ( castigli et al . , 2005a ) .
baff is present predominantly on monocytes / macrophages , dendric cells and t lymphocytes ( mackay & ambrose , 2003 ) . on the contrary
, it is not expressed on b lymphocytes although this molecule has been detected on b - cell  derived chronic lymphatic leukaemia ( novak et al . , 2002 ) .
the april molecule is expressed on a large variety of cells , monocytes / macrophages , dendritic cells and activated t lymphocytes .
baff and april molecules create both homotrimers and heteromers capable of stimulating b lymphocyte differentiation ( wu et al . , 2000 ;
it has been proved that april and baff molecules interfere with csr of t - independent antibody response ( litinskiy et al . , 2002 ; martin & vishva , 2005 ) .
both april and baff molecules bind two type iii membrane receptors , bcma , taci ( schneider et al . , 1999 ) .
bcma is expressed exclusively on b lymphocytes while taci is expressed both on b lymphocytes and activated t lymphocytes .
the third receptor belonging to the tnf - r family is the baff - r , which is the unique receptor for baff ( bodmer et al . , 2002 ; losi et al . ,
this membrane molecule is predominantly expressed on b lymphocytes and only on part of activated t lymphocytes ( schneider & tschopp , 2003 ; martin & vishva , 2005 ) . interactions of april and baff , expressed on monocytes and macrophages , with their receptors on b lymphocytes are evidence of the significance of natural immunity for the correct antibody response ( mcheyzer - williams , 2003 ; de durana et al . , 2006 ) .
the absence of any of the previously mentioned signals is the cause for defect of terminal differentiation of a mature b lymphocyte into plasmatic and memory cells , which are manifested by antibody immunodeficiency ( salzer & grimbacher , 2005 ) ( figure 2 ) .
tnf receptor family members , baff - r , bcma and taci , and their ligands baff and april check terminal differentiation of b lymphocytes and/or csr of ig synthesis .
tnf receptors and their ligands regulate both the survival and the apoptosis during immune system development and immune responses .
receptor taci molecules are encoded by the tnfrsf13b gene , which is situated at the short arm of chromosome 17 ( 17p11.2 ) .
the described mutations affect taci molecule in its extracellular ( c104r , s144x ) , transmembrane ( a181e ) and intracellular parts ( s194x , r202h , ins204 ) ( castigli et al .
tnfrsf13b mutations are associated with antibody deficiencies ( salzer et al . , 2005 ) .
this suggests that taci deficiency may manifest in autosomal dominant as well as in recessive traits in familial and in sporadic cvid . in the case of heterozygous mutations , the clear evidence that they are the cause of humoral deficiencies has not been shown .
it is not possible to exclude that heterogeneous mutations may be the only modifying factor that leads to the manifestation of other defects .
the taci mutations show a range of clinical symptoms from no infection to very severe infections , suggesting that other genetic and environmental factors contribute to the variable disease spectrum .
in addition , taci deficiency may also represent a common genetic defect for cvid and selective iga deficiency ( sigad ) , which has been long proposed to be based on the clinical observations in cvid / sigad families ( salzer & grimbacher , 2006 ) .
the numbers of b cells in homozygous taci deficiency are normal or tend to be slightly reduced .
patients with homozygous mutations in taci showed selective impairment of april and baff - induced b - cell proliferation and csr .
they have low numbers of cd19/cd27/igm b lymphocytes and suffer from severe infections caused by encapsulated microbes .
the vaccination with non - conjugated vaccines is not effective . in the case of homozygous taci mutations ,
polysaccharide antigens are followed by a disturbance in the proliferation of b lymphocytes ( castigli et al . , 2005b ) . unlike knock - out taci/ mice ,
in which spontaneous development of lymphomas occur , only one case of malignant lymphoma has been described in patients with taci mutation ( seshasayee et al . , 2003 ) .
the increased incidence of lupus - like disease seen in taci/ mice was not observed in cvid patients with the same defect . in case of patients with cvid ,
the incidence of autoimmune manifestations in patients with and without taci defect is the same .
the incidence of tnfrsf13b mutations is estimated to be in 510% of patients with cvid ( salzer & grimbacher , 2006 ) .
the cd19 molecule is detectable in the cytoplasm of b lymphocyte precursors , and from the stage of immature b lymphocytes it is imbedded in the cell membrane .
it participates in feedback regulation of signals which come through bcr . on the other hand ,
it facilitates the recognition of antigen - antibody complexes that link to bcr and the cd21 molecule .
together with the cd21 molecule , it ensures another communication between natural immunity and b lymphocytes .
van zelm described the homozygous mutation in the cd19 gene in four members of a family with antibody deficiency that complies with classification criteria for cvid .
the encoding gene is situated on the short arm of chromosome 16 ( mapped 16p11.2 ) ( van zelm et al . , 2006 ) .
its real frequency is unknown in patients with cvid because the findings discovered up to now are rare .
the numbers of peripheral b lymphocytes are normal or only slightly reduced in affected individuals .
cd19 expression on b lymphocytes is missing and as a result of this , the expression of cd21 surface molecules is reduced .
the hypersomatic mutation process proceeds in a normal way ; however , cd27 b lymphocytes are missing .
autoimmune and lymphoproliferative symptoms were not observed ( van zelm et al . , 2006 ) .
in 1953 janeway described a case of a 39-year - old woman with hypogammaglobulinaemia , which is considered the first mention of cvid .
more than 50 years have passed during which separate pathological units , as for example hyper igm syndrome linked and unlinked to x - chromosome and autosomal recessive agammaglobulinaemia , have been excluded . in the last 3 years , mutations of genes encoding icos , taci and cd19 have been described .
these defects are found in less than 15% of the patients and for this reason the etiology of most of the patients with cvid remains unknown .
the described mutations and findings of other expected gene defects will probably cause disintegration of this heterogeneous antibody deficiency syndrome .
 common variable immunodeficiency ( cvid ) is the most frequent clinically manifested primary immunodeficiency . according to clinical and laboratory findings , cvid is a heterogeneous group of diseases . 
 recently , the defects of molecules regulating activation and terminal differentiation of b lymphocytes have been described in some patients with cvid . in this study 
 , we show the overview of deficiencies of inducible costimulator , transmembrane activator and calcium - modulator and cytophilin ligand interactor , cd19 molecules , their genetic basis , pathogenesis and clinical manifestations . 
Introduction
ICOS deficiency
TACI deficiency
CD19 molecule deficiency
Conclusion