Stephen Jolles

Background: Primary immune regulatory disorders (PIRDs) represent a rapidly growing group of inborn errors of immunity (IEIs) characterized by infection susceptibility, autoimmunity, inflammation, and lymphoproliferation. However, the core features of the gene-disease relationships underlying these conditions are often obscured by limitations in available published data. The Clinical Genome Resource (ClinGen) is an international collaborative effort that seeks to address this challenge for PIRDs and other monogenic diseases through a standardized framework for classifying the strength of gene-disease relationships. Objective: We sought to systematically evaluate the evidence for proposed PIRD gene-disease relationships and identify conserved phenotypic features across this heterogeneous group of disorders. Methods: Using the standardized ClinGen framework, the ClinGen PIRD Gene Curation Expert Panel (GCEP) identified potential gene-disease relationships for monogenic conditions characterized predominantly by immune dysregulation. We subsequently curated evidence relevant to these relationships, classified the strength of evidence for these gene-disease relationships, and evaluated clinical patterns among these conditions through standardized phenotyping using the Human Phenotype Ontology (HPO). Results: As of April 2026, the PIRD-GCEP has curated a total of 46 genes corresponding to 49 gene-disease relationships characterized by immune dysregulation. Of these, 28 were categorized as definitive, 2 as strong, 9 as moderate, 7 as limited, and 3 as disputed. Analysis of HPO-based phenotyping revealed 3 major phenotypic clusters corresponding to lymphoproliferation and systemic inflammation, atopic and gastrointestinal inflammation, and combined immune deficiency with autoimmunity. Conclusion: The PIRD-GCEP framework provides validated gene-disease classifications and identifies three distinct phenotypic clusters, facilitating improved diagnosis while revealing genes requiring further investigation to confirm their role in immune regulatory disorders.

There is a need for pragmatic and cost-effective methodologies to facilitate earlier diagnosis of patients with primary and secondary immunodeficiencies, who often experience diagnostic delays that impact their quality of life, morbidity, and mortality. This review article will consider the utility of calculated globulin (CG) as a simple and unbiased screening tool for immunodeficiencies. We review literature indicating that CG can serve as an inexpensive and routinely performed proxy for immunoglobulin levels due to their established correlation. We also set out a workflow for the implementation of CG into clinical practice and discuss optimal approaches to embedding into laboratory reporting systems, and integration of AI approaches could expedite diagnoses. Finally, we discuss the challenges and pitfalls of CG screening, including the need for established CG cutoffs/action values across different patient age cohorts. Collaboration among biochemistry and immunology laboratories, clinicians, and patient organizations will be required to manage the logistics of effective broader implementation of CG screening into clinical practice.

Primary immunodeficiencies, also known as inborn errors of immunity (IEIs), and secondary immunodeficiencies (SIDs) present a multitude of challenges for clinicians due to their overlapping clinical features and diverse underlying aetiologies. IEIs mainly arise from inherited genetic defects, while SIDs are acquired conditions. IEIs are associated with an increased risk of cancer, particularly haematological malignancies, which have been linked to SID, highlighting an area of overlap. It is being increasingly recognised that in the context of cancer, immune deficiencies initially attributed to secondary causes were in fact due to an underlying IEI. This article aims to provide a comprehensive guide for recognising the subtle, yet pivotal clues that may help identify an underlying IEI in patients with haematological malignancies. Combinations of clinical features aligned to the manifestations of IEI, laboratory markers, functional studies, IEI experienced histological assessment, and genetic studies, alongside recognition of atypical responses to therapy for autoimmune and inflammatory features of IEI, and atypical features of the malignancy and its response to therapy and recurrence, can help unmask the IEI hidden within SID. This distinction is of critical importance for patients and their families, as it alters both the treatment of the underlying IEI as well as potentially the approach to the treatment of malignancy.

Due to limitations in current therapies (immunoglobulin replacement therapy), complications in X-linked agammaglobulinemia (XLA) such as bronchiectasis may continue to occur, with subsequent significant impacts on health-related quality of life (HRQoL). There were no significant differences in PedsQL 4.0 total scores against UK healthy norms (self 80.98, P = 0.277; parent 79.76, P = 0.465). There were no significant differences in the SF36v2 physical component score (PCS) against UK healthy norms (49.10, P = 0.712). However, XLA patients with bronchiectasis had significantly worse PCS than patients without (47.88 versus 55.14, P < 0.001) and significantly worse PCS than UK healthy norms (P = 0.004). In the absence of bronchiectasis, HRQoL is comparable to UK healthy norms. However, XLA patients with bronchiectasis have significantly worse HRQoL than patients without bronchiectasis and UK healthy norms. These data demonstrate that further work into novel therapies are needed to prevent bronchiectasis to enable XLA patients to have a normal quality of life.

Autosomal recessive mutations in TAP1, TAP2, TAPBP, or B2M , are associated with major histocompatibility complex (MHC) class I deficiency. Individuals may present with granulomatous skin ulceration, but the underlying antigenic triggers remain largely unknown. We identified TAP1 deficiency in a 32-year-old female referred with a 7-year history of localized skin ulceration. Histologic immunofluorescence revealed that rubella virus (RuV) infection was a likely driver of the associated inflammation, and modest clinical improvement was observed following topical calcineurin inhibition. To better define the natural history, clinical, and immunological manifestations of this condition, we also performed a scoping literature review. We identified 45 unique individuals from 36 reports with a combined follow-up duration of 1,184 patient years. Chronic necrotizing granulomatous skin lesions and childhood-onset bronchiectasis were common. Five deaths were reported (median age 36 years), typically linked to respiratory complications. Phenotypic heterogeneity was evident, with at least four individuals reaching adulthood without clinical symptoms. Diagnostic delay frequently exceeded a decade amongst symptomatic individuals, with misdiagnosis of granulomatous disease prompting systemic immunosuppression and infection-related morbidity. The presence of an abnormal CD8 ⁺ T-cell count or a history of consanguinity offered low sensitivity for MHC I deficiency (~ 50%), indicating a low threshold for further investigation is required for correct diagnosis. Graphical review of case reports identified morphologically similar lesions in other MHC I-deficient individuals. These findings suggest that the phenomenon of MHC I deficiency is underreported and that diagnosis should prompt testing for RuV.

Background: Anti-CD20 monoclonal antibodies are now a common first-line treatment for multiple sclerosis (MS). Rituximab, ocrelizumab and ofatumumab have all been associated with a dose-dependent risk of hypogammaglobulinaemia, but its relevance in clinical practice remains uncertain. Objectives: To study infection rates over time in a real-world cohort of people treated with ocrelizumab for MS, and their relationship to serum immunoglobulin. Design: Observational study of 152 people receiving ocrelizumab for MS followed for up to 5.6 years (mean 2.7 years). Results: Mean (SD) annualized changes in immunoglobulins during ocrelizumab treatment were IgM − 0.22 g/L/year (0.4), IgG − 0.38 g/L/year (0.9), IgA − 0.03 g/L/year. Rates of self-reported infection increased significantly during the first 4 years of treatment. Infection rates were not only associated with total immunoglobulin levels but also independently associated with age, comorbidity and female sex. We demonstrated for the first time that 29 out of 34 (87%) people on ocrelizumab with IgG in the lower normal range had sub-protective antibody responses to pneumococcus / haemophilus influenzae. Conclusions: Real-world observational studies complement open label extensions of clinical trials, often by having a more representative cohort and more complete follow-up. Our data suggest that while serious infections are rare in people on ocrelizumab, non-serious infections become increasingly burdensome. We offer practical suggestions on mitigating the risk of infection on ocrelizumab and other anti-CD20 medications.

Summary: This prospective study examines the immune response to SARS-CoV-2 vaccination in patients with psychotic disorders compared with healthy volunteers. Participants were recruited naturalistically as part of the UK's COVID-19 vaccination programme. Prior to receiving their first COVID-19 vaccine, blood samples were provided by participants to examine anti-SARS-CoV-2 immunoglobulins (IgG) at baseline, followed by a repeat assay 1 month after receiving their first vaccine to assess vaccine response. The increase of IgG levels from baseline to 1 month post-vaccination was significantly lower in patients compared with controls, supporting evidence of impaired vaccine response in people with psychotic disorders. When excluding patients treated with clozapine from the analysis, this difference was no longer significant, suggesting that effects may be particularly marked in people taking clozapine.

Background: The EVITE Immunity study investigated the effects of shielding Clinically Extremely Vulnerable (CEV) people during the COVID-19 pandemic on health outcomes and healthcare costs in Wales, United Kingdom, to help prepare for future pandemics. Shielding was intended to protect those at highest risk of serious harm from COVID-19. We report the cost of implementing shielding in Wales. Methods: The number of people shielding was extracted from the Secure Anonymised Information Linkage Databank. Resources supporting shielding between March and June 2020 were mapped using published reports, web pages, freedom of information requests to Welsh Government and personal communications (e.g. with the office of the Chief Medical Officer for Wales). Results: At the beginning of shielding, 117,415 people were on the shielding list. The total additional cost to support those advised to stay home during the initial 14 weeks of the pandemic was £13,307,654 (£113 per person shielded). This included the new resources required to compile the shielding list, inform CEV people of the shielding intervention and provide medicine and food deliveries. The list was adjusted weekly over the 3-month period (130,000 people identified by June 2020). Therefore the cost per person shielded lies between £102 and £113 per person. Conclusion: This is the first evaluation of the cost of the measures put in place to support those identified to shield in Wales. However, no data on opportunity cost was available. The true costs of shielding including its budget impact and opportunity costs need to be investigated to decide whether shielding is a worthwhile policy for future health emergencies.

Purpose Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome—related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency. Methods Literature review was performed using MEDLINE. Results Twenty cases have been described in the literature with significant heterogeneity. Conclusion The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.