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Comment on Lanzi , page 5867 A new guise for hyper-IgM syndrome

The hyper-IgM syndromes (HIGMs) are immunodeficiencies that have taught us much about the details of humoral immunity. In this issue of Blood, Lanzi et al characterize a rare subset of HIGM patients and demonstrate that these disorders may also teach us about endoplasmic reticulum (ER) storage diseases.1 The primary HIGMs comprise genetic deficiencies in CD154 (HIGM1), CD40 (HIGM3), or AICDA (HIGM2) and share a phenotype of absent or reduced serum immunoglobulin G (IgG) and IgA, normal to elevated levels of IgM, impaired humoral responses to T cell– dependent antigens and generation of the B-cell memory compartments, and recurrent bacterial infections. Curiously enough, HIGM2 patients also present with systemic autoimmune disease.2 CD154, a type II transmembrane protein of the tumor necrosis factor (TNF) superfamily, is transiently expressed by activated CD4 T cells. CD154 is the ligand of CD40, a type I TNFR family member, constitutively expressed on B lymphocytes and myeloid antigenpresenting cells. Cognate interactions between antigen-activated T and B lymphocytes include CD154:CD40 ligation, leading to CD40 trimerization and the generation of NFB signals crucial for B-cell survival, proliferation, and AICDA expression. In the absence of CD154:CD40 interaction, incomplete cognate interactions abrogate B-cell responses to T cell–dependent antigens. In HIGM1 and HIGM3 patients, germinal centers do not form and memory B-cell generation is greatly impaired. In contrast, HIGM2 patients fully support cognate T:B lymphocyte interaction but cannot express the AICDA gene product, AID, and are unable to initiate Ig class-switch recombination (CSR) and somatic hypermutation (SHM). Thus, whereas all HIGM patients are unable to produce IgG and IgA antibody, plasmacytes, and memory B cells, HIGM2 patients are characterized by lymphadenopathy associated with exaggerated germinal center responses. In this issue, Lanzi and colleagues have now detailed the molecular characteristics of 5 rare HIGM3 patients and identify a subset of genetic hypomorphs carrying missense mutations or small in-frame deletions.1 In the 3 hypomorphs, mutant CD40 polypeptide is synthesized but retained—to various degrees—in the Secretory and endocytic pathways of mammalian cells. CD40 molecules synthesized in the ER are delivered to the cell surface via the trans-Golgi network and vesicles that subsequently fuse with the plasma membrane. Some CD40 mutants carrying missense mutations or small in-frame deletions cannot complete this pathway but are retained instead in the ER. The 3 novel CD40 mutants identified by Lanzi et al in this issue exhibit distinct fates in the ER: (1) the P4 mutant does not leave the ER and is promptly degraded by ERAD; (2) the P2 mutant CD40 persists in the ER and activates UPR as determined by increased HSP production and XBP-1 splicing; and (3) the P5 mutant accumulates in the ER but neither is degraded nor elicits UPR. The P5 CD40 mutant is a candidate for therapies based on pharmacologic chaperones. (Professional illustration by Kenneth X. Probst.)