Brain Volume Alterations and Cognitive Functions in Patients with Common Variable Immunodeficiency: Evaluating the Impact of Autoimmunity.

Etanercept treatment of cutaneous granulomas in common variable immunodeficiency

Simple SummaryPrimary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) weaken the immune system, making people prone to infections and possibly affecting cancer development. Epstein–Barr virus (EBV), a common virus, is linked to cancer, especially in those with weak immunity. This study compares immune factors like PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200, and EBV in chronic lymphocytic leukemia (CLL, a SID) and common variable immunodeficiency (CVID, a PID). We studied CLL, CVID, and healthy people, checking EBV activity and immune checkpoints. Both CLL and CVID patients showed more EBV activity, and their immune checkpoints were changed, possibly affecting EBV and immunity. This study shows how immune issues, EBV, and checkpoints might contribute to cancer in people with weakened immunity. It suggests ways to manage these risks. More research is needed to understand this fully and develop treatments.Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein–Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.

PurposeCommon variable immunodeficiency (CVID) is a primary antibody deficiency that commonly manifests as recurrent infections. Many CVID patients also suffer from immune dysregulation, an inflammatory condition characterized by polyclonal lymphocytic tissue infiltration and associated with increased morbidity and mortality. The genetic cause is unknown in most CVID patients and epigenetic alterations may contribute to the broad range of clinical manifestations. MicroRNAs are small non-coding RNAs that are involved in epigenetic modulation and may contribute to the clinical phenotype in CVID.MethodsHere, we determined the circulating microRNAome and plasma inflammatory proteins of a cohort of CVID patients with various levels of immune dysregulation and compared them to healthy controls. A set of deregulated microRNAs was validated by qPCR and correlated to inflammatory proteins and clinical findings.ResultsLevels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID.ConclusionCollectively, our data show that microRNAs correlate with the inflammatory response in CVID. Further investigations are needed to elucidate the role of miRNAs in the development of CVID-related immune dysregulation.

Common variable immunodeficiency (CVID) is a clinically and molecularly heterogeneous disorder with a varied clinical presentation 1. The age of onset varies from early childhood to much later in life, and the disease is characterized by recurrent bacterial infections, hypogammaglobulinaemia and impaired antibody responses. In addition to recurrent infections, which can be mild or serious, CVID patients often develop inflammatory and autoimmune disorders, malignancies and systemic granuloma formation, as well as gastrointestinal (GI) problems 2. Most CVID cases are sporadic, but there are also families with more than one affected member. A small proportion of patients with CVID present in patterns resembling autosomal recessive or dominant inheritance, and mutations in several genes involved directly or indirectly in B cell differentiation, have been identified. This small subset of CVID patients have defects in inducible co-stimulator (ICOS), CD19, CD20, CD21, CD81, lipopolysaccharide-responsive beige-like anchor (LRBA), B cell-activating factor (BAFF) receptor and CXCR4 [the latter causing WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome] 3. Additionally, two autosomal dominant defects affecting the genes for NFκB2 and PIK3CD have been described recently. The NFκB2 mutation causes haploinsufficiency and results in a CVID-like phenotype with childhood onset, autoimmune features and adrenal insufficiency 4. Nuclear factor kappa B2 (NF-κB2) is the principal downstream effector in the non-canonical NF-κB pathway and is required for appropriate B cell development. Dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic P110δ and the p85α subunits of phosphoinositide 3-kinase (PI3 kinase) causes hyperactive PI3 kinase signalling, leading to early-onset autoimmunity, recurrent viral infections and bronchiectasis 5, 6. This suggests that clinical trials with PI3 kinase inhibitors are warranted. Most recently, a CVID-like syndrome, characterized by hypogammaglobulinaemia, a progressive loss of circulating B cells, immune dysregulation and lymphocytic infiltration of the brain, lung and gut was recognized to be caused by heterozygous mutations in the CTLA4 gene 7. CVID patients can be divided into those who exclusively experience infections (bacterial, viral or opportunistic) and, as a result, often develop chronic lung disease, and a second group who in addition develop an inflammatory condition. In the former subset, where recurrent infections are the primary symptom of concern, affected patients will have a near-normal life expectancy provided that they receive adequate treatment with intravenous immunoglobulin (IVIg) and/or antibiotics. Patients in the inflammatory subset are extremely prone to develop granulomas, autoimmune conditions and malignancies. Granulomas can develop in multiple locations, including the skin, lungs, liver and gut. Autoimmune conditions such as colitis, cytopaenia, hepatitis and malignancies, including leukaemia, lymphoma and colon cancer, are relatively frequent 1. This subset will generally have a reduced life expectancy and lower quality of life. Additionally, there is a third group encompassing conditions which are not considered 'classic' CVID: these are defects in T cell development, resulting in a 'CVID-like' condition with early-onset bronchiectasis, autoimmune disease and recurrent viral infections. These conditions (examples are LRBA deficiency 8 and gain-of-function mutations in the P110δ and the p85α subunits of PI3 kinase 5, 6) remain a diagnostic challenge, as it is unclear whether patients are suffering from 'true' CVID or a different type of hypogammaglobulinaemia with secondary B cell deficiency 9. Because both the genetics and clinical presentation of CVID are so variable, clinical diagnosis usually occurs by a lengthy process of eliminating other disorders. B cell phenotyping, T cell function assays, antigen (including neo-antigen) challenges, lymphokine studies, functional testing to measure processes such as phosphorylation of proteins, flow-based assays for surface and intracellular antigens, enzyme-linked immunosorbent assay (ELISA) and measurement of antibody production following vaccination with conjugate (Hib and Prevnar) and unconjugated (Pneumovax) vaccines are required to rule out other primary immunodeficiencies (PIDs). Because, in most cases, CVID may not be due to a single gene defect, molecular approaches thus far have been largely unrewarding, and successful in only a minority of CVID patients in identifying a genetic cause. Patients with a CVID-like phenotype and low numbers of circulating B cells may have mutations in the BTK gene, the cause of X-linked agammaglobulinaemia (XLA) or in genes causing autosomal recessive agammaglobulinaemia, including λ5, Igα, Igβ, B cell linker protein (BLINK) and γH 10. Recently, a homozygous mutation in the p85α subunit of PI3 kinase and a dominant negative mutation in E47 were found to cause agammaglobulinaemia 11, 12. The complexity of the molecular basis of CVID and the heterogeneity of the clinical phenotype requires a carefully designed treatment plan. The primary therapy is infusion of immunoglobulin, which can be either intravenous or subcutaneous, and is dosed based on the patient's immunoglobulin trough levels and clinical response, including frequency of infections. Prophylactic antibiotics help to prevent the development of chronic lung disease and immunosuppressive therapy of autoimmune complications are needed in some patients. Occasionally haematopoietic stem cell transplantation is required. As new causative genetic mutations are identified, new possibilities of gene defect-specific interventions become available. Promising results have been reported from recent studies using rituximab and azathioprine for the treatment of granulomatous lymphocytic interstitial lung disease associated with CVID 13. In terms of future directions for research into CVID, a key priority is to establish a more comprehensive set of diagnostic criteria for the differentiation of CVID and the less well-defined CVID-like conditions summarized here. Identification of novel CVID biomarkers will help to achieve this goal. Additional work in isolating causative genetic variants by whole exome/genome sequencing provides new opportunities to assist in genetic counselling and more specific therapies. Finally, research into better management of difficult-to-treat CVID symptoms such as subclinical infections, inflammatory complications and GI problems should be undertaken. The author would like to thank Meridian HealthComms Ltd for providing medical writing services. H. D. O. has received consultancy fees from CSL Behring.

Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p < 0.05) in CVIDid included Th1 and Th17-associated signaling, as well as IL10 and other immune regulatory markers (LAG3, TNFRSF9, CD83). Targeted serum proteomics provided an accurate and reproducible tool to discriminate between patients with CVIDid and CVIDio. Cytokine profiles provided insight into activation of Th1 and Th17 pathways and indicate a possible role for chronic inflammation and exhaustion in immune dysregulation. These findings serve as a first step towards the development of biomarkers for immune dysregulation in CVID.

Evaluation of cytokine genetic polymorphisms in adult patients with common variable immunodeficiency: A single-center study

Exhausted phenotype of follicular CD8 T cells in CVID

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia

INTRODUCTION: Common variable immune deficiency (CVID) is considered primarily a B cell disorder characterized by low immunoglobulin levels, defective specific antibody production and susceptibility to sinopulmonary infections. Recent studies have implicated T cells in the pathogenesis of CVID. OBJECTIVES: To compare T cell maturation in children and adults with CVID. METHODS: Through PRIMES (Canadian Primary IMmunodeficiency Evaluation Study) registry, we recruited eight children and ten adults with CVID. T cell phenotype was assessed by flow cytometry. Patients were compared to healthy controls (thirteen children and ten adults). Wilcoxon Rank Sum test was used to assess differences in T cell subsets. RESULTS: Total lymphocyte count, CD3, CD4 and CD8 lymphocytes were decreased in children with CVID compared to controls (p=0.0006, p=0.0003, p=0.0003, p=0.03). Percentage and absolute numbers of naïve (p=0.012, p=0.002) and absolute numbers of memory cells (p=0.001) were decreased in children with CVID. However, there were no statistical differences between adults with CVID and healthy controls. DISCUSSION: Our data shows decreased T cell subsets in childhood CVID while levels in adults were normal. Studies assessing temporal trends in T cell subsets are required to determine if these differences in children are due to age-related compensatory mechanisms or if different mechanisms play a role in the pathogenesis of childhood versus adult onset CVID.

Background and Aims Granulomatous interstitial nephritis (GIN) is a rare form of tubulointerstitial nephritis being generally associated to infection, drugs or immune mediated disease. Sarcoidosis is the most frequent disease responsible for GIN, but conversely granulomatous inflammation can also be associated with immunodeficiency. Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by impaired B cell differentiation with defective immunoglobulin production. It is the most prevalent form of significant antibody deficiency affecting both children and adults and can present later in life. Besides recurrent infections, immune dysregulation seen in CVID can lead to autoimmunity, presenting with cytopenia and granulomatous infiltrations of several organs, namely the lungs, liver and lymphoid organs. Kidney involvement is rare in CVID and GIN has been reported in less than 5 cases worldwide to our knowledge. Case report We report the case of a 58-year-old man with a past medical history of type 2 diabetes mellitus, hypertension and of two major skin infections (arm infection with compartment syndrome in childhood and Fournier gangrene at adult age). He presented with anorexia, asthenia, nausea and weight loss (12 Kg in the previous 3 months). Physical examination was unremarkable. Laboratory workup identified leucopenia, lymphopenia, rapidly progressive renal insufficiency (Scr 0.98 mg/dL to 3.5 mg/dL in 2 months), with bland urinary sediment, and urinary protein-to-creatinine ratio of 512.4 mg/g. Additionally, we identified hypercalcemia 11 mg/dL (normal PTH), normal erythrocyte sedimentation rate and increased angiotensin converting enzyme level (ACE 282 U/L). Auto-antibodies screening and complement were normal. Virology (including viral load of EBV and CMV) and tuberculosis quantiferon were also negative. Protein electrophoresis revealed hypoproteinemia with normal albumin and hypogammaglobulinemia and monoclonal gammopathy was excluded. IgG (374 mg/dL) and IgM (17 mg/dL) were below normal range, with normal IgA level. IgG 1 and IgG 2 sub-classes were also markedly decreased as also specific antibodies titters for pneumococcus. Vaccine response was not tested because of the urgent need to begin immunosuppressive treatment. Peripheral blood lymphocyte immunophenotyping showed a slight decrease in B cell proportion (CD19: 4.2%), and analysis of other B and T cell subpopulations in the peripheral blood was not possible due to the urgent need of treatment. Imagiology workup with CT scan revealed multiple adenopathies, lung parenchyma with septal diffuse and irregular thickening and hepatosplenomegaly. Renal biopsy was performed and revealed tubulointerstitial nephritis with noncaseous granulomas. Lung function was normal and broncofibroscopy with biopsy revealed also noncaseous granulomas and excluded infection or neoplasm. There was absence of B cells in the in the bronchoalveolar lavage. Following multidisciplinary discussion with immunoallergology and pneumology, CVID was considered and presented with related complications as granulomatous–lymphocytic infiltration, in the lungs and kidneys, cytopenias, hepatosplenomegaly and persistent diffuse adenopathies, making sarcoidosis diagnosis less probable. Considering immunodeficiency, intravenous immunoglobulin (IVIg) was added to glucocorticoid (GC) therapy (prednisolone 1 mg/kg) with significant pulmonary improvement, decrease in adenopathy size, renal function recovery (Scr 1.2 mg/dL without proteinuria 1 month later) and normalization of ACE and calcium. Conclusion Although GIN is usually associated with sarcoidosis, finding primary hypogammaglobulinemia with defective specific antibody production should raise the suspicion of an underlining immunodeficiency. Although GC are used as first line treatment for both, IVIg replacement treatment is essential to avoid potential severe infections. As such and as our case underlines, evaluation of immunoglobulin serum levels is of paramount importance before considering immunosuppressive treatment, especially in granulomatous disease.

Infections and infectious complications are hallmarks of common variable immunodeficiency (CVID) and the leading cause of morbidity and mortality in affected patients at any age. However, the pediatric CVID is no longer perceived as a primary immunodeficiency associated solely with infectious manifestations; autoimmune, allergic, lymphoproliferative, and malignant disorders and organ-specific immunopathology also characterize the spectrum of non-infectious complications. In this study, we sought to determine the role of immune dysregulation and frequency of non-infectious sequelae in children affected with CVID. We also aimed at providing an insight into the pathogenesis of non-infectious complications and at delineating the diagnostic approach to pediatric CVID with immune dysregulation. An in-depth retrospective analysis of clinical manifestations and their correlations with selected immune parameters was performed in a group of 39 CVID children, followed by our pediatric immunology department. Whereas recurrent sinopulmonary infections were present in all (100%) of the children studied, an unexpectedly high rate of non-infectious disorders and immune dysregulation phenotypes were observed in as many as 32 (82.05%) patients, compared with infection-only phenotypes limited to 7 (17.95%) male patients. The most common inflammatory comorbidity was asthma, diagnosed in 21 (53.85%) patients. The second most frequent immune dysregulation group was autoimmune disorders, present in 18 (46.15%) of the children studied with a high rate of autoimmune thyroiditis in as many as 10 (25.64%) of the CVID-affected children. Lymphoproliferation was seen in 14 children (35.90%), and, among them, lymphadenopathy occurred in nine (23.08%) cases and granulomatous lymphocytic interstitial lung disease in seven (17.95%) cases. Finally, malignancies occurred in two female patients (5.13%), papillary thyroid cancer in the first one and T-cell lymphoblastic leukemia in the other one. The most prominent abnormalities in the B- and T-cell compartment contributing to complex immune deficiency and immune dysregulation phenotypes were seen in the autoimmunity group, showing significant reductions in the switched memory B cell, naive T helper cell, and regulatory T-cell subsets. Herein, we document the previously unreported high rate of immune dysregulation in pediatric CVID as a clinical and diagnostic challenge with the variability of defects in the humoral and cellular immune responses.

Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 are associated with modulation of inflammatory responses. CVID patients have decreased proportions of CCR7(+) T cells in peripheral blood and we hypothesized a further dysregulation of CCL19/CCL21/CCR7 in CVID. Serum levels of CCL19 and CCL21 were compared in CVID patients and controls. T cell expression of CCR7 was related to clinical characteristics in CVID patients. Spleens extirpated from CVID patients were analysed for expression of CCL19, CCL21 and CCR7. Peripheral blood mononuclear cells (PBMC) from CVID patients and controls were analysed for cytokine response on stimulation with CCL19 and CCL21. The main findings were: (i) CVID patients have raised serum levels of CCL19 and CCL21 independently of features of chronic inflammation; (ii) CCL19 and CCR7 have similar expression in spleens from CVID patients and controls, while CCL21 is variably down-regulated in spleens from patients; (iii) T cell expression of CCR7 is particularly low in patients characterized by chronic inflammation in vivo; and (iv) PBMC from CVID patients had attenuated cytokine response to stimulation with CCL19 and CCL21. CVID patients have raised circulatory levels of CCL19 and CCL21, and an attenuated cytokine response to stimulation with these chemokines. Because CCR7, CCL19 and CCL21 are key mediators balancing immunity and tolerance in the immune system, the abnormalities of these mediators might contribute to the profound immune dysregulation seen in CVID.

Background/objectives: Common variable immunodeficiency (CVID) is a heterogeneous syndrome described by defective antibody production and occurrence of multiple clinical manifestations including autoimmune, lymphoproliferative, and granulomatous diseases. Genes within the major histocompatibility complex (MHC) region have previously been reported to be involved in the pathogenesis of the disease. Methods: To elucidate the human leukocyte antigen (HLA) association, PCR was performed to clarify type HLA B, DR, and DQ alleles in a large sample of Iranian and Swedish CVID patients. Results: No HLA association was observed between Iranian patients with “sporadic” CVID (n=50) and controls. A slight HLA association (B8, DR3, DQ2) was found in Swedish CVID patients (n=95). However, the latter was entirely due to an association in the familial form of the disease. Using 13 informative multiplex families with patients affected by CVID and IgA deficiency (IgAD), shared haplotypes such as HLA-B8-DR3-DQ2; HLA-DR1-DQ5; HLA- DR4- DQ3, and HLA-DR7-DQ2 were observed. Conclusions: Based on our results, we hypothesize that only the familial form of CVID/IgAD may have a common HLA-associated genetic background, whereas “sporadic” cases show no HLA association.

CLINICAL ANALYSIS OF THE COMMON VARIABLE IMMUNODEFICIENCY IN PATIENTS WITH LUNG DISEASES: EXPERIENCE IN JAPAN