Overview of Hyper IgM Syndromes
The hyper IgM (HIGM) is characterized by elevated or normal IgM, and low IgA and IgG. HIGM patients present with a variety of bacterial and opportunistic infections. Six forms of HIGM are currently known, which can generally be divided into those that result from mutations in the genes encoding CD40L and/or CD40, and defects in genes encoding intrinsic factors involved in CSR and SHM in B cells. Mutations in five genes have so far been identified as causing these syndromes, namely, genes that encode CD40 ligand, CD40, nuclear factor (NF)-κB essential modulator (NEMO) activation-induced cytidine deaminase (AID), and uracil-DNA glycosylase (UNG). HIGM caused by genetic defects of CD40L or CD40 presents with features of cellular and humoral immunodeficiencies while those caused by intrinsic B-cell defects are pure humoral immunodeficiencies. In physiological conditions, CD4+ T cell CD40L interaction with B cell CD40 promotes germinal center development in B cells, which is required for CSR. The CD40L-CD40 interaction results in the activation of TNF receptor-associated factors, and NFκB downstream, which signals to the nucleus. This eventually results in the relocation of the V(D)J from the constant region gene IGHM of IgM, to other regions encoding IgG (IGHG region), IgA (IGHA region), or IgE (IGHE region).
Fig. 1 Mutated genes and the affected pathways involved in HIGM syndrome. (Yazdani, 2019)
Treatment of Hyper IgM Syndromes
Distinguishing between the different HIGM types is very important for the management of the affected patients because of different prognoses. HIGM1 and HIGM3 are the most severe cases so have features of HIGM hyper IgM. In general, the treatment of hyper IgM involves corrective therapy with stem cell transplantation in cases of CD40 signaling defects, and immunoglobulin replacement therapy in cases involving intrinsic B cell defects. Continuous prophylaxis for the prevention of opportunistic infections is recommended in patients at high risk. Infections as the major complications in HIGM syndrome are treated and controlled by conventional courses of antibiotics. Immune-suppressive therapy could be considered as an approach for patients with autoimmune and inflammatory disorders. The success of gene therapy in the treatment of X-linked severe combined immunodeficiency disease (X-SCID) and adenosine deaminase deficient (ADA) SCID is a stimulus for the treatment of other immune deficiency diseases including HIGM syndromes. Up to now, gene therapy for HIGM syndromes seems to be more complicated than that of X-SCID, as the expression of the CD40L gene is highly regulated, current methods of gene transfer result in constitutive gene expression, which may be harmful.
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- Yazdani, R.; et al. The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin Immunol. 2019, 198: 19-30.
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