Background Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. Aim To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. Methods This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. Results In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. Conclusions In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7 MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.
Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4 + T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4 + T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19 + B-cells, switched memory B-cells, naïve CD8 + T-cells, and a higher frequency of EM CD8 + T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.
Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.
BackgroundNeuroinflammation has been linked with the pathologic progression of Alzheimer’s disease (AD). Previous studies focused primarily on the innate immune system; however, there are few human studies evaluating the potential relationships between adaptive immune cells and the development of AD pathology. Alterations in the immune system occur with aging, likely contributing to increased infection, malignancy and inflammation in older adults. One of the most prominent immune changes with age includes the expansion of memory CD8+ T cells in peripheral blood. Notably, cytotoxic IL‐7 receptor alpha low (IL‐7Rα or CD127low) CD45RA+ effector memory (EM) CD8+ T cells (TEMRA) have been associated with dementia and mild cognitive impairment (MCI) due to AD. In addition, our lab recently discovered an age‐associated gene expression signature of IL‐7Rα low EM CD8+ T cells. Thus, we hypothesized that individuals with AD have altered levels of IL‐7Rα low EM CD8+ T cell aging gene expression.MethodsA total of 40 genes which include 9 IL‐7Rαlow aging genes and 31 genes previously reported to be associated with AD and/or memory were analyzed in peripheral blood of 82 participants with AD and 40 cognitively normal age‐balanced participants by quantitative polymerase chain reaction (qPCR). Gene expression data was analyzed utilizing one‐way ANOVA, principal component analysis (PCA), and unbiased hierarchical clustering analysis.ResultsEight genes were differentially expressed (P < 0.05) between cognitively normal participants and participants with MCI or dementia due to AD. These genes included 5 IL‐7Ralow aging genes (GZMH, NUAK1, TGFBR3, PRSS23, OSBPL5), 2 genes related to AD and/or memory (CD163, CYP4F3) and a gene related to both aging and AD (PADI4). The expression levels of IL‐7Ralow aging genes moderately correlated with those of AD and memory genes. PCA and clustering analysis suggest IL‐7Ralow aging genes may be associated with disease status in a subset of AD subjects.ConclusionsAn altered CD8+ T cell age‐associated gene signature is present in AD patients, warranting further studies investigating biological implications of CD8+ T cells, especially highly cytotoxic and inflammatory IL‐7Rαlow EM CD8+ T cells, in AD.
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