CCR5 promoter region polymorphisms in systemic lupus erythematosus.

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected  = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected  = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.

Androgen Receptor Signaling Positively Regulates Monocytic Development.

Myeloid cells are critical cells involved in the orchestration of innate and adaptive immune responses. Most myeloid cells derive from the adult bone marrow in a process called myelopoiesis, a tightly controlled process that ensures constant production of myeloid cells. Sex differences in myeloid cell development have been observed; males exhibit greater monocytic differentiation in the bone marrow, and men have increased blood monocyte numbers when compared to women. Here we use a genetic mouse model of myeloid androgen receptor (AR) knockout (MARKO) and pharmacological inhibition of AR to investigate the role of androgen signaling in monocytic differentiation. We observe that although myeloid AR signaling does not influence total bone marrow cell numbers, it does affect the composition of the bone marrow myeloid population in both homeostatic and emergency settings. Genetic deletion of AR in myeloid cells led to reduced monocytic development in vivo. Similarly, pharmacologic inhibition of AR signaling in vitro reduced monocytic development. However, alteration in monocytic differentiation in the absence of AR signaling did not lead to reduced numbers of circulating myeloid cells, although MARKO male mice display reduced ratio of classical to non-classical monocytes in the blood, implying that blood monocyte subsets are skewed upon myeloid AR deletion. Our results suggest that the sex differences observed in monocytic differentiation are partly attributed to the positive role of the androgen-AR axis in regulating monocytic development directly at the myeloid cell level. Furthermore, we have identified a novel role for AR in regulating blood mature monocyte subset turnover. Investigating how androgen signaling affects monocytic development and monocyte subset heterogeneity will advance our understanding of sex differences in monocytic function at homeostasis and disease and can ultimately impact future therapeutic design targeting monocytes in the clinic.

The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

Systems-Level Immunomonitoring from Acute to Recovery Phase of Severe COVID-19.

Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

Stressful Beginnings with Long-Term Consequences.

Early-life stress can have long-term health consequences, but the mechanisms of this are unknown. In this issue of Cell, Hong et al. demonstrate one such mechanism linking perinatal corticosteroid exposure to reduced CD8+ T cell function later in life and impaired anti-cancer and anti-bacterial immune responses.

Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection.

Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.

SIRT1 promoter polymorphisms as clinical modifiers on systemic lupus erythematosus.

Silent mating type Information Regulator 2 homolog 1 (SIRT1) is a deacetylase protein that participates in several physiological processes with importance in transcriptional silencing, apoptosis, immune system regulation and inflammation. Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease in which upregulated expression of SIRT1 on CD4+ T lymphocytes of active patients has been reported. Also, global hypoacetylation of histones H3 and H4, with H3 hypoacetylation was correlated with a higher disease activity index. SIRT1 promoter rs12778366 and rs3758391 may account for differential expression of this molecule and the role of these variants was investigated in SLE susceptibility and morbidity. Genomic DNA was extracted from peripheral blood of 367 SLE patients and 290 healthy controls of a Southern Brazilian population. SIRT1 rs12778366 and rs3758391 were amplified through PCR and genotyped through sequencing. No statistically significant differences were observed between patients and controls for allelic, genotypic or haplotypic frequencies. Nevertheless, SIRT1 rs3758391 was not in Hardy-Weinberg equilibrium, presenting a paucity of CT heterozygous both in patients and controls. SLE patients with TT and CT genotypes displayed a higher chance of developing lupus nephritis (Pc = 0.012, OR = 2.04 95 % CI 1.32-3.14) and presented a higher disease activity index (Mean rank 170.95 vs 137.26, Pc = 0.006) when compared with CC homozygous patients. Our results suggest that SIRT1 rs3758391 modifies SLE morbidity, with rs3758391 T allele being a risk factor for nephritis and a higher SLEDAI. Nevertheless, it remains to be elucidated how SIRT1 rs3758391 functionally influences SLE severity.