Biomedical subjects

Albert C Shaw

Publications and source records attributed to Albert C Shaw.

5 recordsLinked to original sources

PubMed2025

High-affinity CD16A polymorphism associated with reduced risk ofsevere COVID-19.

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.

Humans↗

PubMed2007

Age-associated defect in human TLR-1/2 function.

The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.

Adult↗

PubMed2005

Triggering TLR signaling in vaccination.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors that are an important link between innate and adaptive immunity. Many established, as well as experimental, vaccines incorporate ligands for TLRs, not only to protect against infectious diseases but also in therapeutic immunization against noninfectious diseases, such as cancer. We review the underlying mechanisms by which engagement of TLR signaling pathways might trigger an adaptive immune response after immunization. Although the engagement of TLR signaling pathways is a promising mechanism for boosting vaccine responses, questions of efficacy, feasibility and safety remain the subject of active investigation.

Animals↗

PubMed2004

Discs large (Dlg1) complexes in lymphocyte activation.

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex.

Actins↗

PubMed2002

Truncated immunoglobulin Dmu causes incomplete developmental progression of RAG-deficient pro-B cells.

Early stages of B cell development are dependent on the expression of a pre-B cell receptor (BCR), composed of a mu heavy chain (HC) in association with surrogate light chain (SLC) proteins and the signaling molecules, Igalpha and Igbeta. During the formation of the variable region of the mu chain by somatic gene rearrangement, a truncated form of the mu protein (called Dmu) is sometimes produced by the rearrangement of a D(H) segment to a J(H) segment using one of three reading frames (designated rf2). When a Dmu protein is formed, subsequent B cell development is blocked by down-regulation of further HC rearrangements, so that a full-length muHC cannot be formed. In this study, we demonstrate that in recombinase activating gene (RAG)-2-deficient B220(+) CD43(+) pro-B cells in which B lymphopoiesis has been arrested at fraction C, transgenic expression of Dmu promoted partial developmental progression to fraction C', but was unable to mediate the pro-B to pre-B cell transition to fraction D effected by full-length muHC protein. These data suggest that the intracellular signaling pathways engaged by the Dmu pre-BCR are insufficient to facilitate the expansion and/or survival of pre-B cells, and are distinct from those engaged by the pre-BCR-containing full-length muHC.

Animals↗