SummaryOne would assume that the anti-inflammatory activity of α1-anti-trypsin (AAT) is the result of inhibiting neutrophil enzymes. However, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition or by reduced inflammatory parameters. Targets outside the serineprotease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is over-emphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumour susceptibilities, stunt B lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acutephase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds interleukin (IL)-8, ADAM metallopeptidase domain 17 (ADAM17) and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity -'relative AAT deficiency'. Unlike immunosuppression, AAT appears to help the immune system to distinguish between desired responses against authentic threats, and unwanted responses fuelled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force: cell injury.

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In conclusion, we have reported a syndromic patient with combined immune deficiency and a homozygous MAN2B2 variant p.Asp38Asn associated with abnormalities of glycosylation and lysosomal involvement that were reversed in vitro upon lentivirus-mediated transfer of wild-type MAN2B2. We propose MAN2B2 biallelic p.Asp38Asn as a novel pathogenic variant leading to combined immune deficiency, abnormal glycosylation, and lysosomal involvement. Patients have normal transferrin isoelectric focusing profiles, and mild glycosylation changes by electrospray-ionization quadrupole time-of-flight in blood. At the age of 5 years, the patient received hematopoietic stem cell transplantation from her phenotypically HLA-matched father after reduced-intensity conditioning with fludarabine, busulfan, and rabbit antithymocyte globulin. Six months after hematopoietic stem cell transplantation, improvement in Tcell count and function, and in immunoglobulin production (with independence from intravenous immunoglobulins), was observed (Table E1), and stabilization of the disease was achieved, with resolution of infections. Our findings imply MAN2B2 deficiency as a novel CDG. On the basis of our data, we recommend screening for putative pathogenic variants in the MAN2B2 gene in pediatric patients presenting with combined immune deficiency and severe growth delay with intellectual or developmental disability.

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