Current Allergy and Clinical Immunology - March 2008

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AN UPDATE OF THE PRIMARY ANTIBODYDISORDERSBrian Eley, MB ChB, FCPaed (SA), BSc Hons (MedBiochem)School of Child and Adolescent Health, University ofCape Town and Red Cross Children’s Hospital,Rondebosch, South AfricaABSTRACTMore than 200 primary immunodeficiency diseases(PIDs) have been described and the molecular basisof more than 120 characterised. Primary antibodydeficiencies are the most common group.Approximately 50% of patients with PIDs have aprimary antibody deficiency, and at least 80% of allprimary antibody deficiencies are due to four conditions,namely, transient hypogammaglobulinaemiaof infancy, IgG subclass deficiency, partial antibodydeficiency with impaired polysaccharide responsivenessand selective IgA deficiency (SIgAD). Many primaryantibody deficiencies either cause arrest duringearly B-lymphocyte development or impede theterminal differentiation of B lymphocytes. Severalgene mutations including Bruton’s tyrosine kinase(Btk) deficiency, µ heavy chain deficiency, λ5 deficiency,Igα deficiency and Igβ deficiency may causearrest in early development. The molecular analysisof common variable immunodeficiency (CVID) hasgained momentum. Mutations in genes encodinginducible T-cell costimulator, CD19, B-cell-activatingfactor receptor, transmembrane activator, calciummodulatingcyclophilin-ligand interactor, and thehomolog of Escherichia coli MutS have been associatedwith CVID. Genetic research has suggestedthat CVID and SIgAD are related conditions.However, significant immunological differencesbetween the two conditions exist. These observationsshould influence future CVID- and SIgAD-relatedresearch. The current classification of primaryantibody deficiencies is discussed, and recent publicationson clinical presentation and approach todiagnosis are reviewed.Correspondence: Prof B Eley, Red Cross Children's Hospital,Klipfontein Rd, Rondebosch, 7701. Tel 021-658-5111, fax 021-689-1287, e-mail Brian.Eley@uct.ac.zaINTRODUCTIONThe classic primary immunodeficiency diseases (PIDs)are relatively rare, occurring with a frequency of 1:500to 1:500 000 in the general population. 1 More than 200PIDs have been described and the molecular bases ofmore than 120 have been characterised. 2 Primary antibodydeficiencies as a group represent the most commontype of PIDs in humans. They are a heterogenousgroup of disorders in which the defining characteristicis the inability to produce an effective antibodyresponse to a pathogen. Most antibody deficiencieshave been associated with single gene mutations causingdefects in the development and function of B lymphocytes.However, some may result from environmentaltriggering in genetically predisposed individualsand a few are caused by delayed immunological maturation.3 More than 80% of confirmed antibody deficienciesthat are listed in national registries are due tofour antibody deficiencies, namely transient hypogammaglobulinaemiaof infancy, isolated IgG subclass deficiency,partial antibody deficiency with impaired polysaccharideresponsiveness and selective IgA deficiency.4 This paper reviews aspects of the primary antibodydeficiencies, particularly recent developments in thepublished literature with regard to their classification,pathogenesis, presentation and treatment.B-CELL DEVELOPMENTCharacterisation of the molecular events which directthe sequential development of lymphocytes has aidedthe elucidation of the pathogenesis of many primaryantibody deficiencies. Studies of naturally occurringmutations and molecularly engineered mouse modelshave benefited this work. 5 Haemapoeitic stem cellspass through several developmental stages beforemature B lymphocytes are produced. Development primarilyoccurs in the bone marrow compartment.Mutations in genes encoding proteins that are criticalfor the development of the B-lymphocyte lineage, particularlybetween the pro-B-cell and immature B-cellstages, may disrupt B-lymphocyte maturation leadingto partial or complete developmental arrest withdecreased B-lymphocyte number and profoundlyreduced immunoglobulin isotype (IgA, IgM, IgG, IgD,IgE) concentrations. By contrast, mutations in keygenes encoding proteins that regulate terminal differentiationand function of mature B lymphocytes mayresult in reduced immunoglobulin isotype concentrationsusually without a change in B-lymphocyte number(Fig. 1). 2,5,6PRIMARY ANTIBODY DISORDERSThe International Union of Immunological SocietiesPrimary Immunodeficiency Diseases ClassificationCommittee recently published an updated classificationof all known PIDs. The classification of the primary antibodydeficiencies has undergone several revisionssince 1990 as a result of the molecular advances. Sixcategories have been defined (Table I). 7Btk deficiency and related conditionsOne of the significant advances in recent times wasthe elucidation of deficiencies associated with thearrest of early B-lymphocyte development. Bruton'styrosine kinase (Btk) deficiency or X-linked or agammaglobulinaemia,an X-linked recessive condition, was thefirst antibody deficiency to be recognised in 1952. 8 Themolecular defect in Btk deficiency was described in1993. 9 Although Btk is expressed during all stages ofB-lymphocyte development except for plasma cells,deficiency causes arrest at the pre-B-cell stage. Thismay be detected on bone marrow analysis (Fig. 1). Btkdeficiency is fully penetrant, only males are affectedand the condition exhibits considerable clinical heterogeneity.However, the majority of patients are diagnosedbefore the age of 5 years. 10 Recently, the mutationof a large family with Btk deficiency in Cape Townwas characterised. 11 About 85% of patients with earlyonsetinfections, profound hypogammaglobulinaemiaand markedly reduced B-lymphocyte number, have BtkCurrent Allergy & Clinical Immunology, March 2008 Vol 21, No. 1 13
IgαIgβIgµλ5BLNKBtkCD40LCD40AIDUNGIKK-γCVIDICOSCD19TACIMsh5BAFFRPlasma cellpro-B cellpre-B cellImmatureB cellMatureB cellMatureB cellIgM+IgM+ IgD+IgG, IgA or IgECommonlymphoidprecursorMemoryB cellHaematopoieticstem cellFig. 1. B-lymphocyte development and associated primary antibody deficiencies. Igα, Igβ, µ heavy chain (Igµ), λ5,B-cell linker protein (BLNK) and Bruton's tyrosine kinase (Btk) deficiencies affect early B-lymphocyte development.Deficiencies affecting terminal B-lymphocyte function include inhibitor-of-nuclear-factor-κB kinase (IKK-γ), conditionscausing hyper-IgM syndrome (CD40 and CD40 ligand (CD40L)), activation-induced cytidine deaminase (AID)and uracil-DNA glycosylase (UNG) deficiencies), and disorders associated with common variable immunodeficiency(CVID) including inducible costimulator (ICOS), CD19, transmembrane activator and calcium-modulatingcyclophilin-ligand interactor (TACI), homolog of Escherichia coli MutS (Msh5), and possibly B-cell-activating-factorreceptor (BAFFR).deficiency. Deficiencies of several components of thepre-B-cell receptor complex may also cause this phenotype,including mutations in the genes encoding µheavy chain, λ5 and Igα and Igβ . In addition, mutationsin the gene encoding the scaffold protein, B-cell linkerprotein (BLNK); may produce a similar phenotype.Unlike Btk deficiency all of these deficiencies are transmittedby autosomal recessive inheritance. 12-15Hyper-IgM syndromesDuring a primary infection, antigen binds to B lymphocytes,displaying cell-surface-bound IgM. Thereafter, BTable I. Current classification of primary antibody deficienciesI. Severe reduction in all serum immunoglobulin isotypes with profoundly reduced or absent B lymphocytes.Bruton’s tyrosine kinase (Btk) deficiencyµ heavy chain deficiencyλ5 deficiencyIgα deficiencyIgβ deficiencyB-cell linker protein (BLNK) deficiencyThymoma with immunodeficiencyMyelodysplasiaII.Severe reduction in serum IgG and IgA with normal, low or very low numbers of B cellsCommon variable immunodeficiency disorders (Mutations in transmembrane activator and calcium-modulatingcyclophilin – ligand interactor (TACI), B-cell-activating-factor receptor (BAFFR) and Msh5 may act as contributing polymorphisms)Inducible costimulator (ICOS) deficiencyCD19 deficiencyX-linked lymphoproliferative syndromeIII. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cellsCD40 ligand deficiencyCD40 deficiencyActivation-induced cytidine deaminase deficiencyUracil-DNA glycosylase (UNG) deficiencyIV. Isotype or light chain deficiencies with normal numbers of B cellsIg heavy chain deletionsκ chain deficiencyIsolated IgG subclass deficiencyIgA deficiency associated with IgG subclass deficiencySelective IgA deficiencyV. Specific antibody deficiency with normal immunoglobulin concentrations and normal numbers of B cellsVI. Transient hypogammaglobulinaemia of infancy with normal numbers of B cells14 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1
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