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Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A>G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface "self-associated molecular patterns" that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed ∼2-3 Ma, possibly contributing to the origins of the genus Homo. The mutation likely altered human self-associated molecular patterns, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some gene-encoding Sia-sensing proteins suggested a "hotspot" in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence ∼0.6 Ma. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, Natural Killer(NK) cells, and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6 and 2 Ma, potentially affecting human evolution., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m 2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen., Implications for Practice: Gemtuzumab ozogamicin (GO) 3 mg/m 2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m 2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

As we age, the composition of our peripheral leukocytes changes dramatically. Many of these alterations contribute to the general immune dysfunction that burdens the elderly, which in turn, contributes to increased susceptibility to disease. MDSCs represent a heterogeneous population of immunosuppressive leukocytes that are elevated in the peripheral blood of cancer patients. Given the relation between cancer incidence and age, this study examined the frequency of peripheral blood CD33(+)HLA-DR(-) MDSCs across three cohorts: healthy adults (19-59 years old), community-dwelling seniors (61-76 years old), and frail elderly (67-99 years old). This analysis is the first to demonstrate that MDSCs and specifically the CD11b(+)CD15(+) MDSC subset are increased with age. Proinflammatory cytokines that are required for the differentiation of MDSCs (e.g., TNF-α, IL-6, and IL-1β) were similarly found to be increased in the serum of the frail elderly. Furthermore, the proportion of MDSCs and the CD11b(+)CD15(+) subset were found to be elevated significantly in elderly donors with a history of cancer. This age-related elevation in the frequency of MDSCs may contribute to the increased cancer incidence that occurs with age. Further investigation into the functional consequences of elevated MDSCs will provide valuable insight into the progression of age-related pathologies.