Common Variable Immunodeficiency Phenotype Research Articles

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

Genomic crossroads between non-Hodgkin's lymphoma and common variable immunodeficiency.

Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin’s lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an in-silico approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management.

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient’s CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient’s complex clinical phenotype.

Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency.

Common Variable Immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is frequently associated with severe inflammatory complications that determine its morbidity and mortality. We hypothesize that Helicobacter pylori (HP), a very common worldwide infection, may contribute to the clinical and immune phenotype of CVID. We stratified 41 CVID patients into HP+ (n=26) and HPneg (n=15) groups, according to previous urease breath test and/or gastric biopsies, and compared their clinical manifestations and immune profile evaluated by flow cytometry. No genetic variants with known potential impact in HP infection were found upon WES/WGS. Gastric complications were significantly more frequent in HP+ patients. Importantly, the six CVID patients with gastric cancer were infected with HP. In contrast, a significantly higher frequency of cytopenias was observed in the HPneg. Moreover, HP+ did not feature higher prevalence of organ auto-immunity, as well as of lung, liver or intestinal inflammatory manifestations. We observed the same B-cell profiles in HP+ and HPneg groups, accompanied by marked CD4 and CD8 T-cell activation, increased IFNγ production, and contraction of naïve compartments. Notably, HP+ patients featured low CD25 despite preserved Foxp3 levels in CD4 T cells. Overall, HP impact in CVID inflammatory complications was mainly restricted to the gastric mucosa, contributing to increased incidence of early onset gastric cancer. Thus, early HP screening and eradication should be performed in all CVID patients irrespective of symptoms.

Evaluation of Humoral and Cellular Immune Responses to the SARS-CoV-2 Vaccine in Patients With Common Variable Immunodeficiency Phenotype and Patient Receiving B-Cell Depletion Therapy.

IntroductionSARS-CoV-2 vaccines’ effectiveness is not yet clearly known in immunocompromised patients. This study aims to assess the humoral and cellular specific immune response to SARS-CoV-2 vaccines and the predictors of poor response in patients with common variable immunodeficiency (CVID) phenotype and in patients treated with B-cell depletion therapies (BCDT), as well as the safety of these vaccines.MethodsFrom March to September 2021, we performed a prospective study of all adult patients who would receive the SARS-CoV-2 vaccination and were previously diagnosed with (i) a CVID syndrome (CVID phenotype group; n=28) or (ii) multiple sclerosis (MS) treated with B-cell depleting therapies three to six months before vaccination (BCD group; n=24). Participants with prior SARS-CoV-2 infection; or prior SARS-CoV-2 vaccine administration; or use of any immunosuppressant (except BCDT in MS group) were excluded. A group of subjects without any medical condition that confers immunosuppression and who met all study criteria was also assessed (control group; n=14). A chemiluminescence immunoassay was used to determine pre- and post-SARS-CoV-2 vaccine anti-S IgG antibodies. T-cell specific response was assessed by analysis of pre- and post-SARS-CoV-2 vaccination blood samples with an interferon-gamma release assay. The baseline blood sample also included several biochemical, haematological and immunological analyses.ResultsSARS-CoV-2 vaccines are safe in immunocompromised patients, although their effectiveness was lower than in healthy individuals. CVID phenotype patients showed impaired humoral (29%) and cellular (29%) response, while BCD patients fundamentally presented humoral failure (54%). Low IgA values, low CD19+ peripheral B cells, low switched memory B cells, and a low CD4+/CD8+ ratio were predictors of inadequate specific antibody response in CVID phenotype patients. No factor was found to predict poor cellular response in CVID phenotype patients, nor a defective humoral or cellular response in BCD patients.ConclusionThe effectiveness of SARS-CoV-2 vaccines in CVID phenotype and BCD patients is lower than in healthy individuals. Knowledge of predictive factors of humoral and cellular response failure in immunocompromised patients could be very useful in clinical practice, and thus, studies in this regard are clearly needed.

Dysregulatory processes of the cellular link of the immune system in the dynamics of common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a variant of primary immunodeficiency in which inhibition of antibody production is formed due to disorders of intercellular interaction affecting cellular elements of both innate and adaptive immune responses. A feature of CVID is the late start and variability of clinical minifestation. These arguments determine the purpose of the study: to identify the dynamics of changes in the cellular parameters of the adaptive and innate immune response depending on the duration and severity of the infectious manifestation of CVID. In this regard, a retrospective analysis of medical histories and dynamic observation of fifteen patients with CVID were carried out. Selection of specific parameters of cellular indices of factors of innate resistance and adaptive immunity was carried out on the basis of systemic-functional approach of immunodiagnostics. It is shown that in patients with CVID -mediated hypogammaglobulinemia and infectious phenotype of clinical manifestation, enhancement of quantitative and functional potentials of T-link effector cells of adaptive immunity is recorded against the background of reduction of number of regulatory T-helpers. With a more severe clinical course of the disease, the number of CD3+HLA DR + limphocytes is lower than with a more favorable version, there is a tendency to decrease the number of these cells, as well as the number of peripheral Treg with an increase in the length of the disease. Cellular components of innate immunity are characterized by a decrease in neutrophil activity, inhibition of antigen-presenting monocyte activity, the number and cytotoxicity of natural killers. At the same time, the tendency to decrease the cytolytic potential of NK with an increase in the length of illness and statistically significant differences depending on the severity of the manifestation of the infectious phenotype of CVID was recorded. The obtained results determine the importance of evaluating the cellular link of the immune system in patients with CVID, including as a prognostic criterion for the severity of the course.

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children’s Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

Novel heterozygous NFKB1 mutation—variable penetrance in a family cohort

Background: Common variable immunodeficiency (CVID) is a term used to define a heterogeneous group of patients who commonly have hypogammaglobulinemia and variable degrees of modest T cell dysfunction. Recent advances made in next generation sequencing technologies have accelerated the identification of CVID disease-causing genes, including NFKB1, a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Objective: We sought to identify the genetic defect in a 3-generation family of patients with CVID who presented with cytopenias, eczema, and recurrent sinopulmonary infections. Methods: Whole exome sequencing and Sanger confirmation was performed, and a combination of molecular and cellular techniques used to assess the variant impact on B and T cell function. Results: A novel heterozygous frameshift mutation in NFKB1, encoding the transcriptional regulator protein p50/p105, was identified. This resulted in c.1584dupG (p.M528fs). We demonstrate that c.1584dupG is a loss-of-function variant, responsible for reduced p105/p50 protein expression in affected individuals as well as variable increased CD21low B cell numbers. Conclusion: This novel mutation affecting NFKB1 causes a CVID phenotype with variable clinical manifestations. Given the wide spectrum of age in this kindred, this may reflect diversity of phenotype expression, or more probably, age-related expression of typical features. Statement of novelty: We report here a novel loss-of-function frameshift mutation in NFKB1.

A CASE WITH YEARS IN THE MAKING

Introduction The immune system dysregulation that occurs in some cases of immunodeficiency manifests itself by autoimmunity and malignancy. These complications may be more likely to occur in patients with specific genetic defects that lead to common variable immunodeficiency (CVID). Case Description A 48-year-old woman with a history of frequent respiratory tract infections and CVID on immunoglobulin replacement has been followed in our immunology clinic for 11 years. In the 18 years since diagnosis of CVID, she has also been diagnosed with type 1 diabetes mellitus, hypothyroidism, rheumatoid arthritis, Non-Hodgkin's Lymphoma, and enteropathy. An immunoglobulin G level obtained at the age of 30 revealed an IgG of 672 mg/dL (low). At age 38, she had the following findings: IgG Discussion CTLA4 plays an active role in self-tolerance, as it is an inhibitory molecule located on T cells to help regulate T cell responses. Mutations in this protein can lead to improper regulation, and therefore, autoimmunity and organ infiltration by T cells. CTLA4 haploinsufficiency has been identified as one of the mutations which may lead to a CVID phenotype.

Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations

Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

Campylobacter infection in adult patients with primary antibody deficiency

Campylobacter infection in adult patients with primary antibody deficiency

Primary Antibody Deficiencies: Scientific Discoveries Leading to Challenging Paradigms in a Complex Disease Landscape

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies in humans that affect both children and adults. The patients display a decrease in IgG and/or IgA serum levels associated with lower, normal or higher IgM levels, which cause an increased susceptibility to bacterial but also viral infections. Main other complications are auto-immunity, lymphoproliferation and increased susceptibility to various types of cancers. PADs can be caused by B intrinsic and/or extrinsic defects leading to impaired early B cell development, B cell migration, B cell survival, B cell activation or defects in Immunoglobulin class switch recombination (CSR). Among the latter (B cell activation- and CSR-deficiencies), some PADs are linked to unbalanced signaling pathways, in which both gain of function and loss of function variations lead to different immune defects, pinpointing the requirement of a tightly controlled activity for proper immune response.1) Activated PI3K-d Syndromes (APDS) are due to dominant mutations in either the PIK3CD gene encoding the p110d protein, the catalytic subunit of phosphoinositide 3 kinase d (PI3Kd) or the PIK3R1 gene encoding the regulatory subunit of phosphoinositide 3 kinase p85a. Both gene defects lead to hyperactivation of PI3K through an increased p110δ function. A frequent hyper-IgM phenotype is observed, likely due to both a T and a B cell defect. Of note, impaired or loss of function of p110δ or p85α subunit of PI3K leads to a completely different phenotype characterized by an autosomal recessive agammaglobulinemia. The main life-threatening complication of APDS is B lymphoma occurrence. Targeted therapy aiming to decrease PI3K activation is currently on trial.2) The importance of the canonical NF-kB signaling for B cell function was firstly highlighted by the description that missense hemizygous mutations in the IKBKG gene, encoding NEMO, the NF-kB essential modulator, cause an X-linked CSR-deficiency associated with hyphohydrotic ectodermal dysplasia. Recently, heterozygous mutations in either the NFKB1 or the NFKB2 genes (encoding respectively for p105 processed to p50 and p100 processed to p52), have been reported to be causative for common variable immunodeficiency (CVID) due to haploinsufficiency of NF-êkB1 (p52) or NF-kB2 (p50), with less nuclear NF-kB accumulation and less transcriptional regulation. Some carriers are asymptomatic, pinpointing to incomplete penetrance, that suggests the role of gene modifyers or environmental factors. Although NF-κB1-deficiency affects mostly B cells, NF-kB2- deficiency combines a T, B and NK cell defect and is frequently associated to pituitary hormone deficiency.CARD11 (caspase recruitment domain containing protein 11)-deficiency (caused by loss of function bi-allelic mutations) also indicated the importance of CARD11 mediated canonical NF-kB1 signaling for B and T cell function since CARD11-deficient patients have a CVID phenotype. Interestingly, heterozygous gain of function mutations in CARD 11 lead to a different phenotype, the so-called BENTA syndrome (“B cell expansion with NF-kB and T cell anergy”) characterized by B cell lymphocytosis, lymphoproliferation and immunodeficiency.These examples of PADs show that gain of function, haploinsufficiencies and loss of function mutations can be deleterious by disturbing the delicate balance required for adequate signaling pathways during the immune response. DisclosuresNo relevant conflicts of interest to declare.

Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes

Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.

Trying to Understand NK Cell Function in vivo Points towards a Severity Score for CVID Patients

Natural Killer (NK) cells were described 40 years ago as lymphoid cells exerting cytolytic activity against tumor cell lines in vitro (Herberman et al., 1975) and are accounted to the group of innate lymphoid cells. Functionally, they have been associated with anti-viral immunity (esp. herpesviridae) and tumor surveillance. However, NK cells have been less in the research focus compared to other components of the immune system (citations in Pubmed in 2015: ~ 2600 for NK cells compared to ~ 7100, ~ 14,600 and ~ 12,100 for B, T cells and macrophages, respectively). An isolated reduction of NK cells in humans has been suggested to be asymptomatic. Whether this notion somewhat reflects the inattentiveness towards NK cells or if NK cells in humans have only redundant functions in the immune system is still a matter of debate. Eric Vivier and colleagues hypothesized that the function of NK cells in humans might be revealed in immunocompromised subjects and report on a large cohort of patients with common variable immunodeficiency (CVID) registered in the French Registry (DEFI) (Ebbo et al., 2016). They stratified 457 CVID patients according to their NK cell numbers at study inclusion: roughly half of the patients had normal NK cell counts (> 100/μl), one quarter of the patients had slightly reduced NK cell counts (50–99/μl) and almost one quarter had severely reduced NK cell numbers (< 50/μl). CVID patients with severe NK cell lymphopenia exhibited a statistically significant increased rate of invasive bacterial infections defined as septicemia, pneumonia or meningitis: the frequency of invasive infections was 68.7% in severe NK lymphopenia, 60.2% in mild NK lymphopenia and 48.8% in patients with normal NK cell counts. However, there was no correlation of NK cell number and viral infections or malignancies. These results rely on prospectively collected registry data that might be skewed by reporting bias and correlations do not necessarily prove causality. Nonetheless, this observation fits well into the increasingly recognized role of NK cells in adaptive immunity. Apart from insights into NK cell biology the paper by Ebbo et al. reveals interesting aspects of NK cells in CVID. On a clinical basis CVID patients can be separated into patients who suffer from infectious complications as only complaint (“infection-only group”) and those who additionally suffer from non-infectious complications/immune dysregulation with e.g. lymphoproliferation, lung disease, enteropathy and malignancies. Whilst the infection-only group has a close to normal life expectancy when treated with immunoglobulin replacement, patients with immune dysregulation have an elevated mortality (Resnick et al., 2012). It is therefore of crucial interest to identify these patients early in the course of the disease and multiple groups have attempted to identify biomarkers in CVID by different approaches targeting B and/or T cells in the majority of cases (Piqueras et al., 2003, Giovannetti et al., 2007, Moratto et al., 2006, Driessen et al., 2011, Kamae et al., 2013, Wehr et al., 2008, Chapel et al., 2012). Ebbo and co-workers now add NK cells as a potential biomarker to the list as they showed that CVID patients with non-infectious complications are overrepresented amongst the patients with severe NK lymphopenia. This was significant for patients with granulomatous complications (NK cells severely reduced vs mildly reduced vs normal: 25.3% vs 13.6% vs 8.8%, p < 0.001) but there was also a trend towards higher frequencies of lymphoid hyperplasia (35.4% vs 24.6% and 19.2%), enteropathies (41.4% vs 28% vs 24.2%) and autoimmune cytopenia (25.3% vs 12.7% vs 14.6%). The authors also report that severely reduced NK cell counts in CVID are associated with lymphopenia i.e. CD4 + lymphopenia (median 415/μl vs 568 and 691/μl, p = 0.003), reduction of naive CD4 + cells (median 63/μl vs 135 and 183/μl, p = 0.003), CD8 lymphopenia (310/μl vs 431/μl vs 479/μl, p = 0.003) and B lymphopenia (median: 59/μl vs 99/μl and 122/μl, p = 0.003). CVID patients with severe NK lymphopenia also had lower levels of IgG, A and M at initial diagnosis compared to the two other groups. Mortality was higher in CVID with low T cell numbers (T cells < 200/μl) but not in patients with isolated low NK lymphopenia. Whilst other groups have associated low naive CD4 cell counts and expansion of CD21low B cells with a more severe CVID phenotype, Ebbo et al. show a weak, positive correlation between NK cell counts and CD21low B cells (r = 0.13, p = 0.05). Considering the large CVID cohort investigated by Ebbo et al., NK cells will have to be considered in future attempts to stratify CVID patients. Ideally the topic will be approached by a multinational team to unify the multiple attempts and dissect predictive biomarkers in CVID helping to early identify patients at risk from severe manifestations.

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.

Common variable immunodeficiency at the end of a prospering decade: towards novel gene defects and beyond

Patients with a primary antibody deficiency of unknown cause are usually allotted the diagnosis of common variable immunodeficiency (CVID), thus creating a genetically, immunologically, and clinically highly heterogeneous study population, that focuses the attention of many clinicians and researchers worldwide. The purpose of this review is to highlight the most important publications of the past year with an emphasis on novel findings in genetics and the immunophenotype of CVID. New gene defects associated with a CVID phenotype have been described in BAFF-R, CD81, and CD20 in single consanguineous families. The CD21 B-cell subpopulation in CVID has been intensively characterized by us and other groups and is now better understood leaving their true nature and origin however still obscure. Further immunophenotypic analysis of T and B cells in large CVID patient cohorts revealed subgroups with signs of severely disturbed cellular immunity. Several studies investigated the status of regulatory T cells in CVID and found them to be reduced in numbers and impaired in function. Previous findings of impaired TLR function in CVID were confirmed and further extended. Within the past decade, basic and clinical research on CVID has been boosted up by the discovery of the first gene defects and the systematic immunological classification by phenotypic and functional studies. The challenge for the next 10 years is not only the continuation of this ongoing work but also the translation of this acquired knowledge into the clinic and new therapeutic strategies.

Autoimmune Hemolytic Anemia and Common Variable Immunodeficiency

To describe the main characteristics and treatment of autoimmune hemolytic anemia (AHA) in patients with common variable immunodeficiency (CVID), we analyzed data from 18 patients, 4 from an earlier study and 14 from the French DEF-I cohort on adult patients with primary hypogammaglobulinemia. To be included, patients had to have CVID and a previous history of AHA with a hemoglobin level < or =90 g/L at onset. To determine whether AHA is associated with a particular clinical phenotype of CVID, we conducted a case-control study from the DEF-I cohort. The estimated frequency of AHA in CVID patients from the DEF-I cohort was 5.5% (14/252). Median age at AHA diagnosis was 26 years (range, 1-57 yr), and 27.5 years (range, 5-61 yr) at CVID diagnosis. CVID was diagnosed before the onset of AHA in only 2 patients (11%). CVID was diagnosed more than 6 months after AHA in 10 cases (55.5%), and the 2 conditions were diagnosed concomitantly in 6 cases. The 14 patients included in the DEF-I cohort were compared with 238 control patients with CVID but without AHA. Corticosteroids were used as initial treatment for all patients in the current study. An initial response was obtained in 15 of 18 (83%) patients. Overall, 9 of these (60%) achieved a lasting response with steroids alone (7 patients) or in combination with intravenous immunoglobulin (2 patients). Seven patients underwent splenectomy, and 5 additional splenectomies were performed for associated autoimmune thrombocytopenic purpura. After splenectomy, a lasting response was obtained in 3 of the 7 patients with AHA. However, 5 of the 12 splenectomized patients experienced life-threatening infection. Severe infection occurred in 2 of 4 patients receiving immunosuppressive drugs. At the end of follow-up, 13 of 18 (72%) patients were in treatment-free remission (13 complete responses), and 4 of 18 (22%) were in remission while on prednisone < or =20 mg/d. One patient had died, of cancer.

Common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency that is characterized by low level of serum immunoglobulins and an increased susceptibility to infections. The patients show a variety of clinical, cellular, and immunological defects, may develop autoimmune disease, and are susceptible to malignancy. The recent identification of four genetic defects that result in the CVID phenotype demonstrates that the genetic basis of CVID is highly variable. The responsible gene products include, ICOS, TACI, BAFF-R, CD19. Insufficiency of each molecule disrupts B cell maturation, function and differentiation at a different stage. Despite the elucidation of responsible genes, the molecular mechanisms leading to the immune defects are still yet to be understood. In this paper, we overview the molecular basis of CVID, and will provide some data on how the defect leads to autoimmunity.