Cases Of Common Variable Immunodeficiency Research Articles

Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection

ObjectivesScreening for primary immunodeficiencies (PIDs) in adults is recommended after two severe bacterial infections. We aimed to evaluate if screening should be performed after the first invasive infection in young adults. MethodsEligible patients were retrospectively identified using hospital discharge and bacteriology databases in three centres during a 3-year period. Eighteen to 40-year-old patients were included if they had experienced an invasive infection with encapsulated bacteria commonly encountered in PIDs (Streptococcus pneumoniae (SP), Neisseria meningitidis (NM), Neisseria gonorrhoeae (NG), Haemophilus influenzae (HI), or group A Streptococcus (GAS)). They were excluded in case of general or local predisposing factors. Immunological explorations and PIDs diagnoses were retrieved from medical records. Serum complement and IgG/A/M testings were systematically proposed at the time of study to patients with previously incomplete PID screening. ResultsThe study population comprised 38 patients. Thirty-six had experienced a first invasive episode and a PID was diagnosed in seven (19%): two cases of common variable immunodeficiency revealed by SP bacteraemia, one case of idiopathic primary hypogammaglobulinaemia, and two cases of complement (C6 and C7) deficiency revealed by NM meningitis, one case of IgG2/IgG4 subclasses deficiency revealed by GAS bacteraemia, and one case of specific polysaccharide antibody deficiency revealed by HI meningitis. Two patients had previously experienced an invasive infection before the study period: in both cases, a complement deficiency was diagnosed after a second NM meningitis and a second NG bacteraemia, respectively. ConclusionPID screening should be considered after a first unexplained invasive encapsulated-bacterial infection in young adults.

P220 Severe hypogammaglobulinemia and poor antibody response in an asymptomatic patient with heterozygous taci mutation

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced serum immunoglobulin levels and increased risk of infections, autoimmunity, and cancer. Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations are found in 8-10% of CVID cases and sometimes in healthy non-hypogammaglobulinemic subjects. We present a 6 year-old boy with a heterozygous TACI mutation who had significant hypogammaglobulinemia and poor antibody responses but no infectious or autoimmune history.

Phenotypic and Functional Comparison of Class Switch Recombination Deficiencies with a Subgroup of Common Variable Immunodeficiencies.

Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications. Using a functional read-out, we previously identified a functional subgroup of CVID patients with plasmablasts (PBs) producing IgM only. We have now further characterized such CVID patients by a direct functional comparison with patients having genetically well-characterized CSR defects in CD40L, activation-induced cytidine deaminase (AID) and uracil N-glycosylase activity (UNG). The CSR-like CVID patients showed a failure in B cell activation patterns similar to the classical AID/UNG defects in three out of five CVID patients and distinct more individual defects in the two other CVID cases when tested for cellular activation and PB differentiation. Thus, functional categorization of B cell activation and differentiation pathways extends the expected variation in CVID to CSR-like defects of as yet unknown genetic etiology.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0321-2) contains supplementary material, which is available to authorized users.

Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries. Although in majority of cases it is sporadic, disease may be inherited in a autosomal recessive pattern and rarely, in autosomal dominant pattern. Patients, in addition to frequent sino-pulmonary infections, are also susceptible to various autoimmune diseases and malignancy, predominantly lymphoma and leukemia. Other characteristic lesions include lymphocytic and granulomatous interstitial lung disease, and nodular lymphoid hyperplasia of gut. Diagnosis requires reduced levels of at least two immunoglobulin isotypes: IgG with IgA and/or IgM and impaired specific antibody response to vaccines. A number of gene mutations have been described in CVID; however, these genetic alterations account for less than 20% of cases of CVID. Flow cytometry aptly demonstrates a disturbed B cell homeostasis with reduced or absent memory B cells and increased CD21(low) B cells and transitional B cell populations. Approximately one-third of patients with CVID also display T cell functional defects. Immunoglobulin therapy remains the mainstay of treatment. Immunologists and other clinicians in India and other South East Asian countries need to be aware of CVID so that early diagnosis can be made, as currently, majority of these patients still go undiagnosed.

Clinical Heterogeneity of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common, clinically relevant, primary immunodeficiency (PID). In the western world the incidence of this disease is about 1:50000. CVID is characterized by hypogammaglobulinemia which involves in all cases immunoglobulin G (IgG), in about 70-80% of cases immunoglobulin A (IgA) and in about 50% of cases immunoglobulin M (IgM). Additionally, patients with CVID develop weak or no immunization responses against polysaccharide (mainly) and protein antigens. Clinical manifestations of CVID may present either early in childhood or late in adulthood, usually between the third and fourth decade of life. The range of CVID clinical manifestations is broad. Underlying CVID should be considered mainly in cases of patients who present with recurrent or persistent bacterial infections of the upper or lower respiratory tract. The possibility of underlying CVID has also to be examined during laboratory investigation of various clinical syndromes, such as lymphadenopathy, hepatosplenomegaly, chronic diarrhea, or malabsorption, and also of autoimmune cytopenias such as idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia. It is noteworthy, that autoimmune diseases and malignancies in the form of lymphoma and neoplasm of the gastrointestinal tract occur with increased incidence in CVID patients in comparison to the general population. Treatment strategy of CVID patients should not be limited to immunoglobulin substitution therapy (administered either intravenously or subcutaneously), but it also has to target effective management of infections and early diagnosis of occurring malignancies (lymphomas and gastrointestinal tumors) through systematic patient monitoring. With regard to life expectancy of CVID patients, two recently published large retrospective studies showed that CVID patients suffering only from infections had prolonged overall survival compared to those who presented with other CVID clinical manifestations. Exclusion of all potential causes of secondary hypogammaglobulinemia is mandatory for establishing the diagnosis of CVID. Also, in some CVID cases, differential diagnosis from other PID may be required, such as X-linked agammaglobulinemia (XLA), antibody deficiency with increased IgM (Hyper-IgM syndrome), and X-linked lymphoproliferative syndrome (XLP).

Common variable immunodeficiency associated with microdeletion of chromosome 1q42.1-q42.3 and inositol 1,4,5-trisphosphate kinase B (ITPKB) deficiency.

Common variable immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia and impaired specific antibody response and increased susceptibility to infections, autoimmunity and malignancies. A number of gene mutations, including ICOS, TACI and BAFF-R, and CD19, CD20, CD21, CD81, MSH5 and LRBA have been described; however, they account for approximately 20–25% of total cases of CVID. In this study, we report a patient with CVID with an intrinsic microdeletion of chromosome 1q42.1-42.3, where gene for inositol 1,3,4, trisphosphate kinase β (ITPKB) is localized. ITPKB has an important role in the development, survival and function of B cells. In this subject, the expression of ITPKB mRNA as well as ITKPB protein was significantly reduced. The sequencing of ITPKB gene revealed three variants, two of them were missense variants and third was a synonymous variant; the significance of each of them in relation to CVID is discussed. This case suggests that a deficiency of ITPKB may have a role in CVID.

CD4+CD25+Foxp3+ T regulatory cells, Th1 (CCR5, IL-2, IFN-γ) and Th2 (CCR4, IL-4, Il-13) type chemokine receptors and intracellular cytokines in children with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines - IL-2, IL-4, IL-13, IFN- γ-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-γ in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID. In addition, Th1 cells seem to be more involved in the disease pathogenesis than Th2 cells.

The Incidence and Prevalence of Common Variable Immunodeficiency Disease in Taiwan, A Population-Based Study.

Common variable immunodeficiency (CVID) is one of the primary immunodeficiency diseases that occur in both children and adults. We present here a nationwide, population-based epidemiological study of CVID across all ages in Taiwan during 2002–2011. Using the International Classification of Diseases, Ninth Revision code 279.06, cases of CVID were identified from Taiwan's National Health Insurance Research Database from January 2002 to December 2011. Age- and sex-specific incidence and prevalence rates were calculated. A total of 47 new cases of CVID during 2002–2011 were identified. Total prevalence rose from 0.13 per 100,000 in 2002 to 0.28 per 100,000 in 2011. The annual incidence rate during 2002–2011 was 0.019 per 100,000. Cases were equally distributed between males and females and males mostly occurred in younger patients. This nationwide population-based study showed that the incidence and prevalence of CVID in Taiwan were lower than that in Western countries.

Clinical and immunological features of common variable immunodeficiency in China.

Background:Common variable immunodeficiency (CVID) is one of the most common symptomatic primary immunodeficiency syndromes. The purpose of this article was to broaden our knowledge about CVID for better diagnosis and treatment.Methods:Clinical and immunological features of 40 Chinese patients with CVID were analyzed retrospectively.Results:The median age at onset was 11-year-old (range 4–51 years). The median age at diagnosis was 14.5-year-old (range 5–66 years). The average time of delay in diagnosis was 5.3 years (range 1–41 years). The most common main complaint was fever due to infections (35 cases, 87.5%). Pneumonia (28 cases, 70%) was the most common type of infections. Bronchiectasis was present in 6 patients (15%). Autoimmune disease was detected in 6 cases of CVID, and malignancy in 2 cases. The median total serum levels of IgG, IgA, and IgM at diagnosis were 1.07 g/L, 0.07 g/L, and 0.28 g/L, respectively. The percentages of CD3−/CD10+ B-cells were 1%–3.14%.Conclusions:Infection is the most frequent presentation of CVID. Patients with unexplainable infections should receive further examination including serum immunoglobulin (Ig) and lymphocyte subset analysis. Regular and sufficient substitution with Ig is recommended.

Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá

Event Abstract Back to Event Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá CARLOS E. OLMOS1* and CATALINA GOMEZ PARADA1 1 Cayre IPS y Fundacion, Colombia Introduction: Common variable immunodeficiency (CVID) is the primary immunodeficiency most frequently identified in the clinical practice. Clinically, it is defined as the presence of recurrent infections, reduction in IgG serum (at least 2 standard deviations before the reference values for the subject’s age), at least another one of the Ig (IgA or IgM), and a reduction or absence of the production of antibody. The clinical spectrum include multiple recurrent respiratory infections, systemic bacterial infections, gastrointestinal complications, and autoimmunity. We report two cases of CVID occurring in siblings with infectious and autoimmunity manifestations early in school age. Case report: Male adolescents from Tolima, Colombia, diagnosed with CVID after 6 years of the onset of symptoms. The first brother was diagnosed at the 12 years of age with a history of severe insulin-depend diabetes mellitus since the age of two years associated to severe respiratory infections with multiple hospital admissions including sinusitis, otitis media, and complicated pneumonias with bronchiectasis, chronic conjunctivitis, gastroenteropathy, and lymphadenopathies with hypogammaglobulinemia G and M and specific antibody deficiency. The second patient was diagnosed at the 14 years of age after a history of recurrent moderate respiratory infections and frequent diarrheal illness since the age of 6 with development of pernicious anemia, hyperparathyroidism with clinical rickets, detection of hypogammaglobulinemia G and M, and specific antibody deficiency. Both patients are being treated with monthly intravenous immunoglobulin G [IVIG] replacement, vitamin B12 and D, additional nutritional support and multidisciplinary management. Discussion: The CVID is usually a sporadic and non-monogenic condition. The presentation in two brothers with recurrent bacterial and viral infections, autoimmunity and gastroenteropathy point us to a Mendelian susceptibility. This report also demonstrates the difficulty of diagnosing early CVID based only on the traditional alert signs such as recurrent infections. Autoimmunity manifestations should alert on additional signs suggesting CVID. References • Javier Chinen, MD, PhD,a Luigi D. Notarangelo, MD,b and William T. Shearer, MD, PhDa. Advances in basic and clinical immunology in 2014 J Allergy Clin Immunol 2015;135:1132-41. • Karakoc-Aydiner E, AO Ozen, Baris S, Ercan H, Ozdemir C, Barlan IB. Alteration in Humoral Immunity Is Common Among Family Members of Patients With Common Variable Immunodeficiency. J Investig Allergol Clin Immunol 2014; Vol. 24(5): 346-351. • Xiao X, et al, Common variable immunodeficiency and autoimmunity – an inconvenient truth, Autoimmun Rev (2014). • Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract 2013; 1:545–56. • Ochs HD. Common variable immunodeficiency (CVID): new genetic insight and unanswered questions. British Society for Immunology, Clinical and Experimental Immunology, 178: 5–6. Keywords: Common variable immunodeficiency (CVID), hypogammaglobulinemia, Autoimmunity, recurrent respiratory infections, Pernicious anemia Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Immunodeficiencies Citation: OLMOS CE and GOMEZ PARADA C (2015). Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 Jun 2015; Published Online: 14 Sep 2015. * Correspondence: Dr. CARLOS E OLMOS, Cayre IPS y Fundacion, Bogota, Colombia, colmos.8600@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers CARLOS E OLMOS CATALINA GOMEZ PARADA Google CARLOS E OLMOS CATALINA GOMEZ PARADA Google Scholar CARLOS E OLMOS CATALINA GOMEZ PARADA PubMed CARLOS E OLMOS CATALINA GOMEZ PARADA Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

SLAM-SAP signaling promotes differentiation of IL-17-producing T cells and progression of experimental autoimmune encephalomyelitis.

IL-17 plays critical roles in host defenses, combating bacterial and fungal infections, as well as the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). The signaling adaptor SAP is essential for normal immune homeostasis and mutations within SH2D1A, the locus encoding this protein, result in serious and sometimes fatal syndromes, including X-linked lymphoproliferative disease and severe cases of common variable immunodeficiency. However, the precise cellular basis of how SAP deficiency contributes to immune dysfunction remains incompletely understood. In this study, we found that CD4 and CD8 T cells lacking SAP had a diminished capacity to differentiate into IL-17-producing Th17 and T cytotoxic (Tc17) cells relative to wild-type lymphocytes. The use of costimulating SLAM Abs was found to augment the differentiation of IL-17-secreting effectors in wild-type but not Sh2d1a(-/-) splenic T cells under IL-17-polarizing conditions. In addition, SAP's regulation of IL-17-secreting T cells was shown to be a T cell-intrinsic role, as purified naive Sh2d1a(-/-) CD4 and CD8 T cells were inherently defective at converting into Th17 and Tc17 cells in vitro and in vivo. Furthermore, Sh2d1a(-/-) mice were protected from EAE and exhibited greatly decreased numbers of CNS-infiltrating Th17 and Tc17 effector T cells and reduced disease severity. Collectively, these results suggest that SLAM-SAP signaling drives the differentiation and function of Th17 and Tc17 cells in vitro and in vivo and contributes to the pathogenesis of autoimmunity in EAE.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

The European Society for Immunodeficiencies (ESID) registry 2014.

The current European Society for Immunodeficiencies (ESID) registry was established 10 years ago in 2004, when the system was moved from a paper-based to an online system. The purpose of the registry is to collect data on European patients with primary immunodeficiencies (PIDs) and their treatment, with the aim of building an easily accessible database for use by physicians and researchers.

Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project.

Median diagnostic delay of five to six years seen in primary hypogammaglobulinaemia results in morbidity including bronchiectasis. Patients typically have multiple health care encounters and blood tests before the diagnosis is considered. We report outcomes from using the difference between total protein and albumin (globulin fraction) to reduce diagnostic delay in unsuspected hypogammaglobulinaemia. A prospective >5 year programme in the setting of a National Health Services Hospital Blood Sciences pathology service processing serum samples from primary and secondary care. Patients with globulin fraction below the first percentile were reviewed in the context of supplied clinical details. Immunoglobulin measurements were performed in selected patients. Of 2,910,850 globulin fractions 27,304 (0.9%) were below the 1st percentile globulin fraction (<18 g/L). After exclusions, 933 (3% of these) had immunoglobulins measured. Of these, 292 had IgG < 5 g/L, 186 < 4 g/L and 80 < 3 g/L, giving respective positive predictive values of 31%, 20% and 8.6%. Positive predictive value for common variable immunodeficiency was 1.3%. We identified 12 new cases of common variable immunodeficiency, 10 new haematological disorders and 20 hypogammaglobulinaemias secondary to medication. Locally derived cut-offs are required as small differences between analysers have a significant effect on screen-positive rates. Use of a 1st percentile globulin fraction improved early detection of hypogammaglobulinaemia. This is a useful adjunct to alert clinicians to unsuspected hypogammaglobulinaemia but should not replace immunoglobulin measurement. Patients with globulin fraction below the first percentile should be reviewed for possible hypogammaglobulinaemia.

Gastric adenocarcinoma in common variable immunodeficiency: features of cancer and associated gastritis may be characteristic of the condition.

Common variable immunodeficiency (CVID) is associated with an increased risk of gastric cancer. The aim of the study was to determine the morphological features of CVID-associated gastric adenocarcinoma (CAGA) and of the background gastritis. The population of gastric cancer patients with CVID of Mayo Clinic in the period 2000-2010 was studied; 6 cases of CVID (2 males, 4 females, average age 47 years, age range 26-71 years) were found in 5793 patients with gastric cancer in the study period. Each patient underwent gastric resection for which histology slides were reviewed. Chronic gastritis variables, CVID-related findings, and features of the adenocarcinoma were recorded. CAGA was of intestinal type, with high number of intratumoral lymphocytes (ITLs). Cancer was diagnosed in younger patients than in the overall population of gastric cancer. Severe atrophic metaplastic pangastritis with extensive dysplasia was present in the background in 4 cases, with features of lymphocytic gastritis in 2 cases. Features of CVID (plasma cells paucity in 4 of 6 cases, lymphoid nodules prominent in four cases) could be detected. In summary, gastric adenocarcinoma at young age with ITLs, accompanied by atrophic metaplastic pangastritis, should alert the pathologist of the possibility of CAGA. It follows that, in presence of those characteristics, the search of CVID-associated abnormalities should be undertaken in the nonneoplastic tissues.

A review on guidelines for management and treatment of common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. As symptoms of CVID are usually heterogeneous and unspecific, diagnosis and follow-up of CVID can be challenging. In light of this, a broad review of advances in management and treatment of CVID is performed here in order to reach a distinct protocol. However, it should be noted that owing to the nature of the disease, it can only be treated symptomatically but not cured. There is little evidence to guide appropriate or universal guidelines to improve the current status of management of the disease. The most satisfactory treatments of CVID could be achieved by the use of immunoglobulin replacement, antibiotics, immunosuppressants and hematopoietic stem cell transplantation. This review is written based on the importance of clinical surveillance of asymptomatic CVID cases and early recognition of different clinical complications. Moreover, for each complication, appropriate interventions for improving outcomes are mentioned.

Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients

We have studied the effect of intravenous immunoglobulins (IVIG) on monocyte subpopulations and cytokine production in patients with CVID. The absolute number of CD14(+)CD16(++) monocytes decreased on average 2.5-fold 4h after IVIG and after 20h returned to the baseline. The cytokine level in the supernatants of peripheral blood mononuclear cells (PBMC) after ex vivo LPS stimulation demonstrated the >2-fold decrease in TNF production 4h after IVIG. The TNF expression, which is higher in the CD14(+)CD16(++) monocytes, was decreased in these cells by IVIG in 4/7 CVID cases. In vitro exposure of the healthy individuals' monocytes to the IVIG preparation resulted in reduced TNF production, which was overcome by blockade of the FcγRIIB in the CD14(+)CD16(++) CD32B(high) monocytes. Our data suggest that reduction in the number of CD14(+)CD16(++) monocytes and the blockade of their cytokine production via triggering CD32B can contribute to the anti-inflammatory action of IVIG.

Do ribosomopathies explain some cases of common variable immunodeficiency?

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone-marrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms

The association of common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients. In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed bronchiectasis and had low levels of circulating MBL. These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.

Déficits immunitaires communs variables (DICV). Signes d’alerte chez l’enfant

Common variable immunodeficiency (CVID) occurs less frequently in children than in adults. It is important to be able to make the diagnosis as early as possible in order to reduce the sequelae. In children, clinical manifestations at presentation are similar to those of adults. When bacterial infections are recurrent and resistant to treatment, determination of serum immunoglobulin levels should be done. The onset of an autoimmune disease or unexplained lymphoid infiltrations usually leads to a full immunological evaluation. Other complications such as lymphoma or failure to thrive are rarely revealing at presentation in children. The existence of a positive family history may allow an early diagnosis. Molecular screening is often impossible because genetic defects have not yet been identified for most cases of CVID.