Metabolomics distinguishes DOCK8 deficiency from atopic dermatitis: towards a biomarker discovery

Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenyalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria

Introduction: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. Aim: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. Materials and Methods: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. Results: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. Conclusions: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation

Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency

Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date

A novel mutation in the POLE2 gene causing combined immunodeficiency

16sinonenoneFrugoni, Francesco; Dobbs, Kerry; Felgentreff, Kerstin; Aldhekri, Hasan; Al Saud, Bandar K.; Arnaout, Rand; Ali, Afshan Ashraf; Abhyankar, Avinash; Alroqi, Fayhan; Giliani, Silvia; Ojeda, Mayra Martinez; Tsitsikov, Erdyni; Pai, Sung-Yun; Casanova, Jean Laurent; Notarangelo, Luigi D.; Manis, John P.Frugoni, Francesco; Dobbs, Kerry; Felgentreff, Kerstin; Aldhekri, Hasan; Al Saud, Bandar K.; Arnaout, Rand; Ali, Afshan Ashraf; Abhyankar, Avinash; Alroqi, Fayhan; Giliani, Silvia Clara; Ojeda, Mayra Martinez; Tsitsikov, Erdyni; Pai, Sung Yun; Casanova, Jean Laurent; Notarangelo, Luigi D.; Manis, John P