Update on the hyper immunoglobulin M syndromes

Abstract

The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a distant prospect. Those with a defective CSR mechanism generally do well on immunoglobulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia and, in some cases, a predisposition to lymphoid malignancy.

Fig 1

Stages of 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.

Fig 2

B cell activation to induce CSR. CTK, Cytokines; CSS, Co-stimulatory signals; TRAFS, Tumour necrosis factor receptor (family) associated factors; Iκκ, IκB kinase complex; P, phosphate. IκB(α) inhibitory protein is normally complexed with NFκB, nuclear factor κB, but upon phosphorylation by Iκκ dissociates allowing NFκB to translocate to the nucleus.

Fig 3

Class switch recombination to generate an IgG1 isotype immunoglobulin. (1) Following initiation of transcription, activation-induced cytidine deaminase (AID) is able to bind to Switch (S) regions and Variable (IGHV) genes to initiate class switch recombination and somatic hypermutation. M, D, G1, G2A etc. represent constant region heavy chain genes IGHM…., etc. S-M, S-G1 etc. represent switch regions of IGH heavy chain genes IGHM, IGHG2 etc. (2) dsDNA breaks induced in switch regions (see Fig 4). (3) Intervening DNA between switch μ region and target heavy chain constant region switch region (in this case IGHG1) is excised. (4) dsDNA repair brings IGHG1 adjacent to VDJ region. (2a and 4a) Mismatch repair enzymes and error prone DNA polymerases create frequent base substitutions in the IGHV genes to create a hypermutated VDJ region VDJ*.

Fig 4

Development of dsDNA breaks in switch regions as part CSR. (1) Transcription is initiated upstream from the IGHM switch region (S-IGHM). (2) Single strands of DNA available for action of Activation-Induced Cytidine deaminase (AID). RNA-P (ribonucleic acid polymerase) is shown associated with the template strand. (3) Cytidine (C) residues deaminated to uracil (U) by AID. Uracil N Glycosylase (UNG) excises uracil residues. (4) Apurinic/apyridinic endonuclease 1 (APE-1) creates multiple ‘nicks’ in non template DNA strand and a single nick is made in the opposing strand. (5) Mismatch Repair (MMR) enzymes convert single strand ‘nicks’ to a dsDNA break.