Paul Gray's research while affiliated with Western Sydney University and other places

... Two independent papers in this issue of JEM now provide comprehensive evidence for an autosomal dominant OTULIN deficiency by means of negative dominance (Davidson et al., 2024;Takeda et al., 2024). The three reported patients manifested an ORAS-like disease but carried mono-allelic instead of bi-allelic disease-causing mutations in OTULIN (see Table 1). ...

... In TRAF3-deficient cells, the increase of NIK, a crucial enzyme regulating noncanonical NF-κB activation, leads to deregulation of the canonical NF-κB pathway. A genetic study in human inborn errors of the alternative NF-κB pathway (autosomaldominant p52LOF/IκBδGOF NF-κB2 disorders, autosomalrecessive NIK, or autosomal-recessive RELB) has shown that these disorders are associated with a higher risk of developing life-threatening COVID-19 pneumonia as well as the development of neutralizing autoantibodies against IFN-I [68]. This suggests that the alternative NF-κB pathway p52-RELB activation is necessary to prevent central T cell tolerance toward IFN-I in human. ...

... The present study provides a prospective clinical, immunological, and genetic characterisation of paediatric patients referred for autoimmune lymphoproliferative syndrome evaluation, with the aims: (1) to describe the genetic landscape of autoimmune lymphoproliferative syndrome and autoimmune lymphoproliferative syndrome-like diseases in a defined patient cohort; (2) to evaluate novel and existing biomarkers to delineate autoimmune lymphoproliferative syndrome from autoimmune lymphoproliferative syndrome-like diseases; (3) to analyse how patients with defined diagnoses differ from patients remaining undiagnosed despite genetic testing; and (4) to evaluate if classifications such as autoimmune lymphoproliferative syndrome-like, lympho proliferative common variable immunodeficiency, or Evans syndrome help to achieve a molecular diagnosis. ...

... OTULIN has emerged as a key ubiquitin E3 ligase in the process of linear ubiquitination, a post-translational modification with essential regulatory roles in canonical NF-kB signaling and inflammatory responses (1)(2)(3)(4). In 2016, the first description of otulipenic patients, caused by recessive loss-of-function (LOF) mutations in OTULIN, was published (5,6), while more recently, a dominant negative mutation with a monoallelic heterozygous mutation has been reported (7). All patients presented with neonatal-onset life-threatening autoinflammation accompanied by fever, neutrophilic dermatitis, panniculitis, arthralgia/arthritis, lymphadenopathy, hepatosplenomegaly, gastrointestinal inflammation, and failure to thrive. ...

... This makes up the bulk of cases. [6][7][8][9] ...

... Similarly, our work has shown that the corneal DC density remains elevated during the asymptomatic phase of AC, but that the conjunctival DC density decreases compared to the active phase. However, these corneal DCs had smaller cell bodies with fewer dendrites during the asymptomatic phase of AC [16]. ...

... However, autoantibodies against type I IFNs were subsequently considered to be clinically silent. Since 2020, autoantibodies neutralizing IFNα and/or IFNω have been detected in ~15% of cases of life-threatening COVID-19 pneumonia 62 , 20% of the fatal COVID-19 cases tested 63,64 and 20% of individuals with 'breakthrough' hypoxemic COVID-19 pneumonia despite an appropriate antibody response to mRNA vaccine 65,66 . The risk of critical disease increases with the number and concentration of type I IFNs neutralized. ...

... There is a CD21−/ low memory B cell (MBC) population in PB that constitutes approximately 5% of the B cell pool, comprising both CD27+ and CD27− as well as switched and unswitched cells [61]. In humans, the generation/maintenance of CD21−/ low B cells is dependent on T cells, IL21R, and Tbet [62,63]. The CD21−/ low cells are antigen-experienced MBCs in a majority of conditions, as the cells are isotype-switched and express BCRs that have undergone somatic hypermutation. ...

... Strains MANB/NachJ, MANF/NachJ, TUCA/NachJ, and TUCB/NachJ carry a predicted loss-of-function splice-donor variant in Ifnar1 (chr16:91302893). Humans with mutations in this gene have immunodeficiency-106 and exhibit hyperinflammatory responses to some vaccines [48]. ...

... [3][4][5] Most have found that different PID subtypes, with a few exceptions, were not independent risk factors for infection severity. 6,7 Rather, this is generally underpinned by advanced age and the presence of comorbidities, particularly cardiomyopathy and respiratory disease. 6 Few reports have outlined the experience and outcomes of Australian individuals with PID during the COVID-19 pandemic. ...