Biology subjects

Peckham, H.

Publications and source records attributed to Peckham, H..

4 recordsLinked to original sources

bioRxiv2024

Site-specific quantification of the in vivo UFMylome reveals myosin modification in ALS

UFMylation is a ubiquitin-like protein post-translational modification of Ubiquitin Fold Modifier 1 (UFM1) applied to substrate proteins. The UFMylation system is important for normal development and plays a critical role in a variety of cellular processes including regulating telomere length, stress responses and protein quality control. Here, we describe the development of an antibody-based enrichment approach to immunoprecipitate in vivo remnant UFMylated peptides and identification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). We used this approach to identify >200 UFMylation sites from various mouse tissues revealing extensive modification in skeletal muscle. Furthermore, we show that UFMylation is increased in skeletal muscle biopsies from people living with Amyotrophic Lateral Sclerosis (plwALS). Quantification of UFMylation sites in these participant biopsies with multiplexed isotopic labeling and LC-MS/MS reveal prominent increases in myosin UFMylation. Finally, in silico modelling suggest UFMylation of myosin directly adjacent to the ATP-binding site may regulate stability and/or function. Our data suggest that although UFMylation is not as widespread as ubiquitylation, its in vivo status is more complex than previously thought.

biochemistry↗

bioRxiv2024

Oestrogen influences B cell class-switching in individuals with an XX sex chromosome complement

Sex differences in humoral immunity are well-documented, though the mechanisms underpinning these differences remain ill-defined. Here, we demonstrate that post-pubertal cisgender females have higher levels of class-switched B cells compared to age-matched cisgender males. However, whilst sex chromosome-encoded genes characterise most of the differences in total B cell transcriptomes between cisgender-females and -males, sex differences in class-switched B cells are only observed post-pubertally. Accordingly, B cells express high levels of oestrogen receptor 2 (ESR2) and genes known to regulate B cell class-switching are enriched for ESR2-binding sites. Using a gender-diverse cohort of young people, we show that in transgender males (XX chromosomal background), blockade of natal oestrogen reduced the frequency of class-switched B cells, whilst gender-affirming oestradiol treatment in transgender females (XY chromosomal background), did not increase the frequency of class-switched B cells. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen only supporting B cell class-switching on an XX chromosomal background. eTOC summarySex hormones and chromosomes work in tandem to impact immune responses, with oestrogen influencing B cell class-switching exclusively on an XX chromosomal background.

immunology↗

bioRxiv2021

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

immunology↗

bioRxiv2019

Sex differences in autoimmunity could be associated with altered regulatory T cell phenotype and lipoprotein metabolism

Male and female immune responses are known to differ resulting in an increased prevalence of autoimmunity in women. Here sex differences in T-cell subset frequency and function during adolescence were examined in healthy donors and patients with the autoimmune disease juvenile (J)SLE; onset of JSLE commonly occurs during puberty suggesting a strong hormonal influence. Healthy adolescent males had increased regulatory T-cell (Treg) frequency, and increased Treg suppressive capacity and IL-4 production compared to healthy adolescent females. The T-helper 2-like profile in male Tregs was associated with increased expression of GATA3 which correlated significantly with elevated Treg plasma membrane glycosphingolipid expression. Differential Treg phenotype was associated with unique serum metabolomic profiles in males compared to female adolescents. Notably, very low density lipoprotein (VLDL) metabolomic signatures correlated positively with activated Tregs in males but with resting Tregs in females. Consistently, only VLDL isolated from male serum was able to induce increased Treg IL-4 production and glycosphingolipid expression following in cultured cells. Remarkably, gender differences in Treg frequency, phenotype and function and serum metabolomic profiles were lost in adolescents with JSLE. This work provides evidence that a combination of pubertal development, immune cell defects and dyslipidemia may contribute to JSLE pathogenesis.

immunology↗