B cells and antibodies are indispensable for host immunity. Our understanding of the mechanistic processes that underpin how B cells operate has left an indelible mark on the field of clinical pathology, and recently has also dramatically reshaped the therapeutic landscape of diseases that were once considered incurable. Evaluating patients with primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) that primarily affect B cells, offers us an opportunity to further our understanding of how B cells develop, mature, function and, in certain instances, cause further disease. In this review we provide a brief compendium of IEI that principally affect B cells at defined stages of their developmental pathway, and also attempt to offer some educated viewpoints on how the management of these disorders could evolve over the years.

We present a unique and unusual case of a male patient diagnosed with two coexisting and typically unassociated X-linked conditions: he was initially diagnosed with X-linked agammaglobulinemia (XLA) followed by a diagnosis of X-linked chronic granulomatous disease (XCGD) and an as of yet unpublished hypomorphic gp91phox variant in the CYBB gene. The latter was tested after the finding of granulomatous gingivitis. Hematopoietic stem cell transplant (HSCT) was performed due to severe colitis and nodular regenerative hyperplasia (NRH) of the liver. Following transplant, complete donor engraftment was observed with the restoration of a normal oxidative burst and full restoration of normal levels of circulating, mature CD19+ B cells. This case is singular in that it does not involve a contiguous gene syndrome in which deleted genes are in close proximity to either BTK and CYBB, which has been previously reported. To our knowledge, this is the first reported case of XLA and XCGD co-existing in a single patient and of having both inborn errors of immunity successfully treated by HSCT.

Background: Very early onset-inflammatory bowel disease (VEO-IBD) can arise from monogenic defects affecting immune regulation. We report a male child with VEO-IBD caused by a homozygous, loss-of-function IL10RB variant (c.562T>G; p.C188G) that has not been previously reported for this disorder.Case Presentation: A male infant of Hispanic descent was admitted to our hospital at the age of 8 months due to intractable colitis, perianal fistulas and growth faltering. Endoscopy at nine months of life revealed pancolitis and gastritis. Despite multiple courses of steroids and use of sulfasalazine, their disease remained active. Standard biologic therapies (infliximab and adalimumab) were trialed in the second year of life without improvement. Given the very early onset and severe phenotype, functional testing by phosflow to evaluate the IL-10 signaling pathway demonstrated the absence of STAT3 phosphorylation in response to IL-10 and follow up genetic testing identified a novel homozygous IL10RB missense variant (c.562T>G; p.C188G). Subsequent protein structure analysis using AlphaFold corroborated this loss-of-function phenotype. The patient’s condition was partially controlled with anakinra (IL-1 receptor antagonist) as a bridge therapy. At the age of 3 years, the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an unrelated umbilical cord blood donor; however, they experienced engraftment failure, likely due to persistent hyperinflammation and the choice of cord blood for HSCT. The patient continues to have active disease requiring on-going medical management and supportive care.Conclusion: We report a novel, loss-of-function IL10RB variant causing VEO-IBD, thus expanding the genotypic spectrum of this condition. This case highlights the diagnostic and therapeutic challenges of IL-10R deficiency–related VEO-IBD. It also underscores the importance of early recognition of monogenic causes of IBD, use of interim immunomodulatory therapies, and the need for optimal timing and donor selection for HSCT.

Background: X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation (XMEN) disease is an inborn error of immunity (IEI) affecting the Magnesium Transporter 1 ( MAGT1) gene. In this report, we present the diagnostic odyssey for a patient harboring a novel MAGT1 variant resulting in XMEN disease. Case presentation: A 6y old male child of Caucasian ancestry presented at the immunology clinic in our hospital with a history of recurrent upper respiratory tract infections, as well as significant atopy and viral skin lesions. Genetic testing identified a novel, hemizygous pathogenic variant in the magnesium transporter 1 ( MAGT1 ) gene (c.580dup; p.Ser194Phefs*3). Follow-up testing by flow cytometry revealed the canonical disruption in Natural Killer Group 2D (NKG2D) surface expression on CD8 T cells and NK cells, and clinical testing for congenital disorders of glycosylation (CDG) additionally verified the hallmark defect in glycosylation that underpins XMEN disease. Subsequent in silico analyses using AlphaFold provided an in-depth view of the resulting aberrant protein structural variant and its inability to tether itself to the OST-B complex, a pre-requisite for optimal enzymatic activity of the MAGT1 protein. Disease management included infection control and prophylaxis, steroids and immunotherapy for the patient’s asthma and atopy, topical antiviral treatment for the warts and molluscum, as well as biannual EBV load monitoring (the patient is EBV negative). Conclusion: This case illustrates how a synergistic multi-disciplinary team approach established a diagnosis of XMEN disease in a patient with an atypical clinical presentation. This case also highlights a growing trend where established diagnostic tools such as flow-cytometry and genomics can be complemented with newer, sophisticated analytical approaches such as AlphaFold to further elucidate the functionally crippling effects of novel variants described in the setting of IEI.