Sex Differences in Immunity to Viral Infections

Jacobsen, Henning; Klein, Sabra L.

doi:10.3389/fimmu.2021.720952

Cited by 161 publications

(137 citation statements)

References 174 publications

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“…Noteworthily, CD8+ T cells originated from females expressed a higher level of exhausted molecules (Supplementary Figure 2B), which was hardly reported before. CD4+T cells are at the core of initiating and modulating the adaptive immune responses, male-derived CD4+T cells exhibited increased immune-suppressive genes than females, like FOXP3 and IL2RA (Supplementary Figures 2C, D), in another word, more Treg cells may exist in the TME of male NSCLC patients, which is supported by several studies (37). In comparison, except for plasmacytoid dendritic cells (pDCs) showed relatively obvious sexual dimorphism (38,39), researches about the differences of myeloid cells between sexes were less characterized.…”

Section: Myeloid Cells In the Tumor Immune Microenvironment And Their Compositional Differences Between Sexessupporting

confidence: 67%

Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes

et al. 2021

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Non-Small Cell Lung Cancer (NSCLC) is a disease with high morbidity and mortality, which has sex-related differences in prognosis and immunotherapy efficacy. However, the difference in the mechanisms remains unclear. Macrophages, characterized by high plasticity and heterogeneity, act as one of the key cells that exert anti-tumor effects in the tumor microenvironment (TME) and play a complicated role in the process of tumor progression. To elucidate the subtype composition and functional heterogeneity of tumor-associated macrophages (TAMs) in NSCLC and further compare the sex-mediated differences, we conducted a single-cell level analysis in early-stage smoking NSCLC patients, combined with ssGSEA analysis, pseudotime ordering, and SCENIC analysis. We found two universally presented immune-suppressive TAMs with different functional and metabolic characteristics in the TME of NSCLC. Specifically, CCL18+ macrophages exerted immune-suppressive effects by inhibiting the production of inflammatory factors and manifested high levels of fatty acid oxidative phosphorylation metabolism. Conversely, the main metabolism pathway for SPP1+ macrophage was glycolysis which contributed to tumor metastasis by promoting angiogenesis and matrix remodeling. In terms of the differentially expressed genes, the complement gene C1QC and the matrix remodeling relevant genes FN1 and SPP1 were differentially expressed in the TAMs between sexes, of which the male upregulated SPP1 showed the potential as an ideal target for adjuvant immunotherapy and improving the efficacy of immunotherapy. According to the early-stage TCGA-NSCLC cohort, high expression of the above three genes in immune cells were associated with poor prognosis and acted as independent prognostic factors. Moreover, through verification at the transcription factor, transcriptome, and protein levels, we found that TAMs from women showed stronger immunogenicity with higher interferon-producing and antigen-presenting ability, while men-derived TAMs upregulated the PPARs and matrix remodeling related pathways, thus were more inclined to be immunosuppressive. Deconstruction of the TAMs at the single-cell level deepens our understanding of the mechanism for tumor occurrence and progress, which could be helpful to achieve the precise sex-specific tumor treatment sooner.

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Section: Myeloid Cells In the Tumor Immune Microenvironment And Their Compositional Differences Between Sexessupporting

confidence: 67%

Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes

et al. 2021

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“…While several studies reported a sex-related association of specific immunoproteasome SNPs to be associated with autoimmune-related diseases such as psoriasis or multiple sclerosis [ 60 , 61 ], the uniform reduction of all immunoproteasome and the standard β1 activity in women has not been observed before. It is feasible that this diminished proteasome function in females contributes to the well-established differences in immune responses between men and women: the generally more pronounced innate and adaptive immune responses in females contribute to faster clearing of pathogens and greater vaccination efficiency in women while—as a drawback—leading to an increased susceptibility to inflammatory and autoimmune diseases [ 62 , 63 ]. Sex-related immune regulation has been partly attributed to the differential effects of sex hormones, such as estrogen and progesterone as female, and testosterone and androgens as male sex hormones.…”

Section: Discussionmentioning

confidence: 99%

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

Kammerl

Flexeder

Karrasch

et al. 2021

Cells

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Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

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“…Takahashi et al [14] conducted a study of patients with moderately severe COVID-19 and found that IL-8 and IL-18 levels were higher in males than in females, and that T-cell activation was stronger in females than in males. It is speculated that the decreased levels of testosterone in older males is associated with immune dysfunction, as well as the other complications of COVID-19 [15,16], whereas females have a stronger immune response based on genetic factors, such as Toll-like receptor 7 encoded in X chromosome, which might not be affected by aging or hormonal changes [17].…”

Section: Discussionmentioning

confidence: 99%

Waning of Anti-SARS-CoV-2 Spike Antibody Levels 100 to 200 Days after the Second Dose of the BNT162b2 Vaccine

et al. 2022

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Anti-SARS-CoV-2 antibodies of 444 vaccinated hospital employees in Japan were measured 94–109 days and 199–212 days after receiving the second BNT162b2 vaccine dose to evaluate the intensity and duration of antibody response in our own cohort. Among uninfected participants, anti-S antibody levels were greatly decreased 199–212 days after the second vaccination compared to the levels measured 94–109 days after the second vaccination (median levels: 830 AU/mL and 2425 AU/mL, respectively; p < 0.001). The rate of decrease between the two testing periods was lower in infected participants than in uninfected participants (median: 47.7% and 33.9%, respectively; p < 0.001). Anti-S antibody levels were significantly higher in females (median: females, 2546 AU/mL; males, 2041 AU/mL; p = 0.002 during the first test period). The peak body temperature after vaccination was higher in females than in males (median: females, 37.4 °C; males: 37.1 °C; p = 0.044). Older males tended to have lower antibody levels. In conclusion, the duration of the anti-S antibody response to the BNT162b2 vaccine was short-lived, particularly in males. Anti-S antibody levels of 1000 AU/mL or lower according to SARS-CoV-2 IgG II Quant (Abbott) might indicate insufficient prevention against the delta variant, and the majority of participants appeared to have lost their protection 200 days after vaccination.

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Sex Differences in Immunity to Viral Infections

Cited by 161 publications

References 174 publications

Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes

Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

Waning of Anti-SARS-CoV-2 Spike Antibody Levels 100 to 200 Days after the Second Dose of the BNT162b2 Vaccine

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