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B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders. [ABSTRACT FROM AUTHOR]

One of these is I AICDA i , encoding activation-induced cytidine deaminase (AID), which is highly expressed by GC B cells in vivo, and is induced in B cells in vitro in response to CD40L and cytokines such as IL-4 or IL-21 [[3], [5]]. After these initial events, some responding B cells will also form germinal centers (GC) where somatic hypermutation (SHM) of Ig variable region genes expressed by Ag-specific B cells occurs. Despite these similarities, there are key differences in function of these mutant AID proteins, as heterozygous-truncated AID-exon 5 protein maintained peripheral B cell tolerance, but the AR I c.428-1G i > I T AICDA i variant did not. Interestingly, ~ 25% of individuals with AR AID deficiency also develop IgM-mediated autoimmune phenomena (cytopenia, AIHA), revealing a key role for AID in maintaining peripheral B cell tolerance [[9]]. [Extracted from the article]

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG , is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells. [Display omitted] • Human FLT3L deficiency underlies bone-marrow failure and infectious diseases • Human and mouse FLT3L deficiencies impair dendritic and B cell development • FLT3L deficiency impairs monocyte development in humans but not mice • FLT3L deficiency impairs NK cell development in mice but not in humans Adult humans with inherited, complete FLT3L deficiency enable valuable insights into the role of the hematopoietic growth factor FLT3L in human hematopoiesis, revealing that FLT3L deficiencies impair monocyte, dendritic, and B cell development but not NK cell development. This study reveals key differences in the role of FLT3L in humans versus mice. [ABSTRACT FROM AUTHOR]