This may reflect deficiencies of signalling pathways other than through CD40. Handling of cytomegalovirus (CMV) contamination can be problematic in these patients WS3 (Levyet al, 1997;Winkelsteinet al, 2003) and disseminated contamination can be seen as an initial presenting illness (Beneschet al, 2000). M (HIGM) syndromes are a group of main immunodeficiency disorders in which defective immunoglobulin (Ig) class switch recombination (CSR) prospects to deficiency of IgG, IgA and IgE with preserved or elevated levels of IgM. A number of different gene products are involved in this process and WS3 defects of a number of these have now been explained (Leeet al, 2005). Studies of patients affected by these conditions have helped elucidate the process of CSR and the related process of somatic hypermutation (SHM). Most, but not all, patients with CSR defects also show defective SHM. The genetic disorders can be broadly classified into defects restricted to B cells and defects that additionally impact the functions of other cells, including monocytes, macrophages and dendritic cells, whose function requires signalling through the CD40 receptor. The former cause a real humoral immunodeficiency while the latter are associated with an additional defect of cell-mediated Rabbit polyclonal to AP2A1 immunity and a consequent susceptibility to opportunistic infections. In addition to the classical forms of HIGM, other more complex defects of the DNA repair mechanism can also lead to a HIGM-like immunological pattern as part of a more generalized disorder. Additionally, other antibody deficiency disorders, such as common variable immunodeficiency (CVID) or occasionally X-linked agammaglobulinaemia, can present with a picture of low IgG and IgA with preserved IgM thus mimicking HIGM. A secondary HIGM pattern of immunodeficiency can be seen with congenital rubella contamination, malignancy or in patients on antiepileptic medication. This review WS3 will not address these forms of the disorder. An understanding of the details of B cell development and the generation of diverse antibodies of different isotypes is helpful in explaining the different causes of HIGM and will be explained here. == B cell development == Maturation from the common lymphoid precursor to a class-switched immunoglobulin-producing B cell or a terminally differentiated plasma cell entails antigen-independent and -dependent phases (Fig 1). This has been explained in previous reviews (Ghiaet al, 1998;LeBien, 1998). The antigen-independent phase occurs in the liver during fetal life and thereafter in the bone marrow.IGgene rearrangement of the germline DNA to produce unique antibody specificities commences at the pro (precursor)- B cell stage and is completed in the pre- B cell stage. The process of Ig gene rearrangement is initiated by the recombination activating genes (RAG1andRAG2), which bind to specific recombination signal sequences to initiate double stranded (ds) DNA breaks. There is excision of intervening DNA to bring the required genes into juxtaposition followed by dsDNA repair using the non homologous end-joining (NHEJ) apparatus. Genetic defects inRAGgenes or in the genes encoding proteins involved in the NHEJ dsDNA repair process (for example Artemis or Ligase IV) result in a failure to generate T and B cell receptors and a clinical picture of severe combined immunodeficiency rather than HIGM (de Villartay, 2009). Exceptions to this are Ataxiatelangiectasia and Nijmegen breakage syndrome, both affecting NHEJ, and sometimes resulting in a HIGM picture (observe below). == Fig 1. == Stages of WS3 B cell development. CLP, Common Lymphoid Precursor; Pro B E/M/L, Precursor B cell early/mid/late; B Mem, Memory B cell; CSR, Class switch recombination. Immunoglobulin heavy chain gene (IGH) rearrangement usually results in the beginning in the association of VDJ sequences with the chain constant region gene,IGHM. Mature nave B cells express surface IgM and IgD. == Class switch recombination == The second antigen-dependent stage of B cell development occurs in the periphery and is continued in the germinal centres of lymphoid tissue (MacLennan, 1994;Rajewsky, 1996). This stage is dependent on a number of signals including antigen engagement of the B cell receptor and co-stimulatory signals through the effects of cytokines and direct conversation with T cells. B cells may progress to become plasma cells or follow a route of germinal centre maturation (including CSR) to become memory B cells which express CD27. CD40Ligand/CD40 conversation promotes germinal centre development of.