Biology subjects

McKinnon, J. E.

Publications and source records attributed to McKinnon, J. E..

4 recordsLinked to original sources

bioRxiv2026

Preserved Barrier Integrity and Altered Immune Profiles in Chronic Cannabis Users: Potential Roles of Δ9-Tetrahydrocannabinol

Although cannabinoids such as delta-9-tetrahydrocannabinol (THC) are generally immunosuppressive in preclinical models, chronic cannabis use in humans is paradoxically associated with increased infection risk and systemic inflammation. In this study, we demonstrate that THC directly strengthens intestinal epithelial barrier function in vitro by increasing trans-epithelial electrical resistance in a concentration-dependent manner in Caco-2 monolayers. In a cross-sectional study of chronic cannabis users via smoking or snorting compared with non-using controls, plasma lipopolysaccharide (LPS), and microbial translocation-driven inflammatory cytokines (IL-23, MCP-1, IL-8) were significantly reduced, while some cytokines (IL-6, IL-1{beta}, TNF-, IL-10) remained unchanged. Concurrently, users exhibited elevated macrophage-derived chemokine (MDC) and homeostatic cytokines IL-15 and IL-21, markedly suppressed IL-7 and IL-4. Plasma IL-15 and MDC levels correlated with consumption intensity, and IL-23, IL-7, and IP-10 correlated with age of first use or during heaviest use. These findings suggest that habitual cannabis use may protect gut barrier integrity and reduce microbial translocation and associated inflammation, while simultaneously disrupting systemic immune homeostasis through selective cytokine dysregulation. This dual, dose-dependent immunomodulatory profile highlights the complex balance between potential benefits and risks in both recreational and therapeutic cannabis use.

immunology↗

bioRxiv2025

Female-predominant anti-CD4 IgG autoantibody production and its correlations with plasma levels of progesterone, microbial translocation, and blunted immune reconstitution in HIV-infected patients on suppressive ART

Autoimmunity contributes to HIV immunopathogenesis even in the absence of overt autoimmune disease. We previously showed that anti-CD4 autoantibodies from people with HIV (PWH) on suppressive antiretroviral therapy (ART) can mediate cytotoxicity against CD4+ T cells, implicating a role in impaired immune reconstitution. Despite viral suppression, many PWH with poor CD4 recovery exhibit chronic immune activation, microbial translocation, and dysregulated humoral immunity. Here, we identify a female-predominant elevation of plasma anti-CD4 IgG autoantibodies in aviremic PWH receiving ART. Across two independent cohorts, HIV-positive females, but not males, displayed significantly higher anti-CD4 IgG, predominantly IgG1, compared with HIV-negative controls, without parallel increases in anti-CD4 IgA or IgM. This sex-specific pattern was unique to anti-CD4 IgG and was not observed for anti-CD8 IgG, anti-double-stranded DNA IgG, or anti-nuclear antigen IgG; these control autoantibodies correlated with one another but not with anti-CD4 IgG. Elevated anti-CD4 IgG levels were associated with lower plasma progesterone levels and reduced absolute CD4+ T-cell counts. Markers of microbial translocation, soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), and lipopolysaccharide (LPS), were also selectively increased in HIV-positive females, with sCD14 and LBP showing significant or borderline associations with anti-CD4 IgG. Together, these findings identify anti-CD4 IgG as a sex-dimorphic autoimmune signature in treated HIV infection, linked to progesterone levels, persistent microbial translocation, and incomplete immune recovery. This work highlights an under-recognized intersection of sex, mucosal barrier dysfunction, and autoimmunity in HIV pathogenesis and suggests potential therapeutic targets to improve immune reconstitution in women.

pathology↗

bioRxiv2025

Characterize Oral-to-Blood Microbial DNA Translocation in Individuals with Cocaine Use Disorder

BackgroundCocaine disrupts gut barriers in animal models, potentially enabling microbial translocation and inflammation in the periphery and central nervous system (CNS), but its direct role in inducing inflammation remains controversial. This study aimed to determine if the oral cavity is a source of circulating microbial DNA translocation in individuals with current cocaine use disorder (CUD). ResultsA cross-sectional case-control study was conducted, comparing CUD and demographically matched non-drug controls. Ten CUD (via smoking or vaping) and 24 controls provided paired saliva and blood samples. Microbial 16S rRNA V4 region was sequenced in isolated microbial DNA from saliva and plasma. Single-cell RNA sequencing (scRNAseq) was analyzed in human peripheral blood mononuclear cells. Saliva from CUD, but not plasma, exhibited reduced alpha diversity and altered beta diversity, characterized by enriched Streptococcus and depleted Fusobacterium, Neisseria, and other taxa relative to controls. Controls exhibited low to undetectable microbial translocation in plasma. By contrast, plasma displayed CUD-specific oral enrichment of several Streptococcal species and evidence of translocation into the bloodstream. S. parasanguinis, but not cocaine alone, induced IL-1{beta} and TNF- production in human primary monocytes in vitro. scRNAseq further revealed innate immune activation, impaired T cell function, and heightened susceptibility to infection in CUD. ConclusionsThis pilot study demonstrating that CUD via smoking or snorting exhibited oral microbial dysbiosis and selective oral-to-blood microbial translocation in vivo. These findings suggest that a compromised oral-to-blood barrier, rather than cocaine itself, promotes immune perturbations in CUD.

microbiology↗

bioRxiv2025

Systemic translocation of S. aureus Drives Anti-CD4 Autoimmunity in Treated HIV Infection

BackgroundIn 2017, our group first demonstrated that autoimmunity contributes to HIV pathogenesis, even without autoimmune disease. This concept is now broadly recognized, exemplified by the role of autoimmunity in severe COVID-19. In people with HIV (PWH) on suppressive ART, anti-CD4 autoantibodies may impair CD4+ T cell recovery, though the mechanisms driving their production remain unclear. Building on evidence from our group and others that Staphylococcus aureus and its peptidoglycan (PGN) promote autoimmunity, we investigated their contribution to anti-CD4 IgG in HIV. MethodsPlasma from 32 ART-naive PWH, 53 ART-treated PWH, and 32 HIV-negative controls was analyzed for IgG autoantibodies and markers of S. aureus translocation using protein array, ELISA, and microarray. EcoHIV mice were injected intraperitoneally with saline, S. aureus PGN, or Bacillus subtilis PGN. PGN structures were compared by mass spectrometry. ResultsAmong 87 autoantibodies, 40% were elevated in ART-naive PWH and largely normalized by ART; however, anti-CD4 IgGs remained elevated in PWH on ART. Anti-CD4 IgG levels inversely correlated with CD4+ T cell counts in ART-treated PWH and positively with S. aureus translocation. In mice, S. aureus PGN induced anti-CD4 IgGs, reduced gut CD4+ T cells, and promoted surface IgG binding and apoptosis in CD4+ T cells. ConclusionS. aureus and its PGN translocation may drive anti-CD4 autoimmunity and hinder immune recovery in PWH on suppressive ART, highlighting S. aureus colonization as a therapeutic target and supporting the development of competitive probiotic interventions such as Bacillus subtilis.

immunology↗