Common Primary Immunodeficiency Research Articles

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.

Patients with common variable immunodeficiency paradoxically have increased rates of autoimmune disorders

Common variable immunodeficiency (CVID), characterised by disordered B cell function, is one of the most common primary immunodeficiency disorders. Patients with CVID are at lifelong risk of recurrent infections, particularly...

Is it Celiac Disease or CVID-Associated “Celiac-Like Disease”?

Common Variable Immunodeficiency (CVID) is the most common primary immunodeficiency in adults. Gastrointestinal (GI) symptoms are common in CVID patients, and up to 50% of patients have chronic diarrhea with malabsorption. CVID is commonly associated with intestinal villous atrophy mimicking Celiac Disease (CD). The prevalence of true CD in CVID remains unknown. We present a case of gluten-free diet (GFD) responsive CD in a patient with CVID. A 67 year old Caucasian female with long standing history of CVID on IgG replacement therapy, chronic kidney disease, and severe iron deficiency presented for evaluation of persistent nausea, anorexia, weight loss and non-healing chronic leg ulcer. She underwent EGD after initial anti tissue transglutaminase (anti-TTG) was found to be 17 U/mL, which showed marked villous blunting and mild lymphocytic infiltration with inflammatory pathology. Enteral access was obtained for nutritional supplementation in a setting of ongoing weight loss. An EGD 1 month after high fidelity enteral GFD showed resolution of inflammatory changes and improvement in villous blunting. (Table 1) The ensuing 3 months of strict diet adherence resulted in removal of the feeding tube with resolution of anorexia and nausea, as well as a 35 pound weight gain with return to healthy baseline weight. A dramatic improvement in her chronic leg wound was observed that had previously been resistant to all therapies. Anti-TTG levels at 4 month mark improved to 8 U/mL. Common variable immunodeficiency (CVID) with an estimated prevalence of 1/100,000 to 1/50,000 is the most common symptomatic primary antibody deficient syndrome. Up to 50% of CVID patients have chronic diarrhea with malabsorption. CVID is commonly associated with intestinal villous atrophy mimicking Celiac Disease (CD). Due to unreliable antibody testing and inconsistent response to GFD making a diagnosis of CD in CVID remains a challenge. Based on a few recent studies, the only criterion to confirm CD in CVID population is histological response to GFD. Our patient had significant improvement in symptoms and showed a histological response with GFD. CVID and CD can co-exist, hence a high level of clinical suspicion is warranted to diagnose CD in the CVID population.Table: Table. Sequential Duodenal Bulb Biopsies

Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. Prevalence varies greatly between countries and studies. Most diagnostic criteria include hypogammaglobulinemia and impaired vaccine response. To evaluate the minimum prevalence as well as the clinical and immunological phenotypes of CVID in Southern Finland. We performed a cross-sectional study to assess all adult CVID patients followed up in three hospital districts in Southern and South-Eastern Finland between April 2007 and August 2015. CVID diagnosis was based, with a minor modification, on the ESID/PAGID criteria for primary CVID. Antipolysaccharide responses to Pneumovax® were defined as impaired only if 50% or more of the serotypes did not reach a level of 0.35 µg/mL after vaccination. We further characterized the patients' B cell phenotypes and complications associated with CVID. In total, 9 patients were excluded due to potential secondary causes before diagnosis. ESID/PAGID criteria were met by 132 patients (males 52%), of whom, 106 had "probable" and 26 "possible CVID." Based on the population statistics in the three hospital districts, the minimum adult prevalence per 100,000 inhabitants in Finland for all CVID ("probable CVID," respectively) patients was 6.9 (5.5). In the highest prevalence district (Helsinki and Uusimaa), the prevalence was 7.7 (6.1). CVID patients suffer from frequent complications. Ten patients died during follow-up. Of probable CVID patients, 73% had more than one clinical phenotype. Intriguingly, gradual B cell loss from peripheral blood during follow-up was seen in as many as 16% of "probable CVID" patients. Patients with possible CVID displayed somewhat milder clinical and laboratory phenotypes than probable CVID patients. We also confirm that large granular lymphocyte lymphoproliferation is a CVID-associated complication. The prevalence of CVID in Finland appears the highest recorded, likely reflecting the genetic isolation and potential founder effects in the Finnish population. Studies to discover potential gene variants responsible for the high prevalence in Finland thus seem warranted. Increased awareness of CVID among physicians would likely lead to earlier diagnosis and improved quality of care.

Health-related quality of life in patients with common variable immunodeficiency switching from intravenous to subcutaneous immunoglobulin therapy

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency disease (PID) among adults. CVID consists of two phenotypes—one in which infections are the characteristic and another in which impressive inflammatory and/or hematological complications also develop, including lymphadenopathy, splenomegaly, autoimmune cytopenias, enteropathy, and granulomatous disease. These phenotypes appear to be stable, are related to immunological and inflammatory markers, and are predictive of outcomes. Both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) are equally effective for replacement therapy. No data are available about specific factors affecting the quality of life related to switching from IVIG to SCIG in the Arabian Gulf area. We present the case reports of three adult CVID patients, who were shifted from IVIG to SCIG by the US conversion method (1 : 1.5). We followed-up patients for clinical outcomes, side-effects, immunoglobulin G (IgG) trough levels, annual infection rate, and quality of life using questionnaires (RAND-36) over a 3-year period. Three patients (two females and one male), with a mean age of 26 years, had received IVIG [Gamunex-C (Grifols Therapeutics Inc., NC, 27709 USA) 10%; Grifols] treatment for an average duration of 4 years and had average IgG trough levels of 7.7±2.9 g/dl. Patients were shifted to SCIG [Subcuvia (Baxalta Innovation GmbH, Vienna, Austria) 10%; Baxter] for different reasons. SCIG was administered, using an infusion pump, under medical supervision at the hospital, on a weekly basis. The average IgG trough level on SCIG was 10.4±1.5 g/dl. The annual infection rate of pneumonias, sinusitis, otitis media, and others significantly declined after switching to SCIG in all three patients. However, while on IVIG treatment, some patients reported headache and malaise, but when on the SCIG treatment the reactions were mild and infusion site-related such as erythema, swelling, and itching. Remarkably, all patients were successfully switched to SCIG with significant decrease in the annual rate of infections and a favorable steady-state of serum trough levels of IgG. The use of SCIG was generally associated with notable improvement in physical, emotional, and social health.

Clinical symptoms in IgA deficiency

IgA deficiency is the most common primary immunodeficiency. Early diagnosis and clinical follow-up may improve the quality of life of patients with IgA deficiency. To this end, IgA deficiency should be further studied and better understood on its clinical manifestations. To determine IgA deficiency clinical manifestations. Cross-sectional, retrospective, exploratory study, where the medical records of 39 patients with IgA deficiency were analyzed. Among the analyzed cases, 10 patients were diagnosed with total IgA deficiency and 29 patients with partial IgA deficiency. Partial and total IgA deficiency main clinical manifestations were allergic rhinoconjunctivitis and allergic asthma. In total IgA deficiency, in addition to allergic diseases, a statistically significant number (p < 0.05) of cases of infection-related rhinosinusitis, tonsillitis and conjunctivitis were also observed. This study showed that the main clinical manifestations in IgA deficiency were allergic rhinoconjunctivitis and allergic asthma. In addition, patients with total IgA deficiency showed a significant increase in infection-related rhinosinusitis, tonsillitis and conjunctivitis, when compared with patients with partial IgA deficiency.

Allergic and autoimmune disorders in families with selective IgA deficiency.

IgA deficiency is the most common human primary immunodeficiency. The prevalence of allergic disorders and autoimmunity is thought to be increased in selective IgA deficiency (sIgAD). However, it is currently unclear if these disorders coincide within these families. We aimed to evaluate the frequency of allergic and autoimmune disorders in children with sIgAD and their first-degree relatives (FDRs). The study included 81 children diagnosed with sIgAD and 274 of their FDRs. The presence of allergic and autoimmune disorders was evaluated and serum antithyroglobulin and antithyroid peroxidase levels were measured in both patients and their first-degree relatives. The mean age of the patients was 9.9 ± 3.9 years. Among the patients with sIgAD, 45.7% of them had at least one allergic disorder and 17.3% of them had at least one autoimmune disorder. The frequencies of asthma, allergic rhinitis, and eczema in the FDRs of sIgAD patients were 10.9%, 9.1%, and 7.7%, respectively. Among their FDRs, 14.6% had autoimmunity, compared to an estimate of 5% in the general population. Increased frequency of allergic and autoimmune disorders in patients with sIgAD and their FDRs suggests a possible common predisposing genetic component for sIgAD and autoimmunity in these families.

Successful Outcome Following Allogeneic Haematopoietic Stem Cell Transplantation in Adults with Inherited Primary Immunodeficiency (PID)

The primary immunodeficiencies (PID) are rare inherited diseases characterised by severe dysfunction of adaptive and/or innate immunity. Over 200 distinct PIDs have been described, with 20 of them accounting for > 90% cases. The 3 most common PIDs are severe combined immunodeficiency (SCID), Wiskott Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Many have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT), however, almost all published series to date have focussed on paediatric patients. In the largest published series, the median age at transplant is < 1 year for SCID, 12.7 years for CGD, and 3 years for WAS.Early Allo-HSCT is preferred for PID patients, but not always possible. Delayed diagnosis and 'milder' clinical phenotypes may delay treatment with curative intent. With improved supportive care PID patients are more likely to survive to early adulthood without Allo-HSCT, despite serious co-morbidities. Furthermore, for several PIDs, controversy surrounding optimal timing of Allo-HSCT remains due to rarity of disease and lack of experience. Furthermore, Allo-HSCT for older adolescents and adults with PID has previously been avoided due to severe TRM and poor outcomes.Here we report the largest group of consecutive adult PID patients described to date (n=27) who underwent Allo-HSCT in the adult HSCT programme of University College London. The mean age was 24 years (range 17-50) at transplant. Of these, 11 patients had X-linked or autosomal recessive CGD and 16 had other inherited PID, including CVID (1 with T-NHL, 1 with HLH, 1 with GLILD) (n=3), autoimmune LPD (1 Fas mutation) (n=2), X-linked LPD (n=1), DCML +/- Gata2 mutation (n=2), Gata2 Defic (n=1), Cg-SCID (n=1), CID with CD27 Defic (1 with HL and DLBCL, 1 with HL) (n=2), NK Defic (n=1), AR IL12 Recb Defic (n=1), XIAP with Crohn's and HLH (n=1) and Rag2 compound heterozygote with red cell aplasia (n=1). Stem cell donors were matched unrelated (MUD) (n=14), mismatched unrelated (MMUD) (n=5, all 1 Ag mismatch) or matched related donors (MRD) (n=8). Stem cell source was PBSC (n=20) and BM (n=7).Reduced intensity conditioning was used in 26 patients including Flu/Mel/Alemtuzumab (n=17), Flu/Bu/Alemtuzumab (n=8) and Flu/Bu/ATG (n=1). One patient underwent myeloablative conditioning with Flu/Cy/TBI. Additional GVHD prophylaxis with cyclosporine was used in all patients. Reverse isolation, antimicrobial and antifungal prophylaxis were used to reduce the risk of infectious complications. Acute and chronic GVHD incidence and severity and time to engraftment, lineage specific chimerism, immune reconstitution and discontinuation of immunoglobulin replacement therapy were recorded.Overall survival (OS) at 2 years for all patients was 85.6%, and by donor was 75% for MRDs (n=8) and 89.5% for MMUD/MUD (n=19) with a mean follow up of 35 months (range: 7 to 11 years 1 month). Analysis of outcome by diagnosis demonstrated OS at 2 years of 81.8% for CGD patients (n=11) and 87.5% for other PIDs (n=16).TRM was low with only four deaths observed at a median follow-up of 22 months (n=27). 2 patients died of multi organ failure and sepsis prior to engraftment, one at 7 months post-HSCT of granulomatous meningitis and grade III aGVHD and one at 28 months post-HSCT of sepsis in the context of chronic extensive GVHD.8 patients developed grades I-II aGVHD (6 skin only, 1 involving the gut and 1 progressing to chronic lung GVHD). GVHD had resolved in all but one patient at last follow up. For all patients, neutrophil and platelet engraftment occurred after a median of 12 and 14 days respectively.Peripheral blood chimerism was available for 22 of the 23 surviving patients at last follow up. Multilineage full donor chimerism was observed in 8 (36%) with mixed chimerism observed in at least one cell lineage tested for the remainder. At 1-year post transplant, 80% of those tested had achieved a normal lymphocyte count (1.0-2.8 x 109/L), 47% had normalization of absolute CD3+ count (0.7-2.1 x 109/L), 40% had a normal CD4+ count (0.3-1.4 x109/L) and 87% had normalisation of their CD8+ cell count (0.2-0.9 x109/L).Allo-HSCT is well tolerated in this patient group and should be considered as an alternative therapeutic option in PID patients not transplanted in childhood where an appropriate donor is available. Triggers for referral should include life threatening infections, malignancy, severe autoimmunity and refractory disease. DisclosuresFielding:Baxalta: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency.

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our GWAS meta-analysis of 1,635 IgAD patients and 4,852 controls identified four new significant (P < 5x10−8) loci and association with a rare IFIH1 variant (Ile923Val). Peak novel variants (PVT1 P = 4.3x10−11, ATG13–AMBRA1 P = 6.7x10−10, AHI1 P = 8.4x10−10 and CLEC16A P = 1.4x10−9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including eQTLs for AHI1 and DEXI and DNase hypersensitivity in FOXP3+ T regulatory cells. A pathway analysis of the meta-analysis results showed a striking association with the KEGG pathway for IgA production (pathway P < 0.0001): where 22 of 30 annotated pathway genes contained at least one variant with a P-value ≤0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contribute to IgAD.

T-Cell Abnormalities in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common clinical primary immunodeficiency. It is characterized by a defect in B-cell differentiation to plasma and memory B cells. Moreover, numerous T-cell abnormalities have been reported and include decreased T-cell count and proliferative response, increased T-cell activation and apoptosis, and abnormalities in cytokine production. The aims of this review are to describe phenotypic and functional defects in T cells in CVID patients and to review the literature with respect to the effects of immunoglobulin replacement on the T-cell component in CVID patients.

Reduced serum BCMA levels distinguish patients with primary antibody deficiency

Abstract B-cell maturation antigen (BCMA) is a TNF family receptor that binds a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF). BCMA is expressed by immunoglobulin secreting cells, but not other B cells, and supports their survival. Primary antibody deficiency (PAD) is the most common primary immunodeficiency and may lead to infection and complications including autoimmunity, enteropathy, lung disease, and malignancy. PAD patients with these complications have reduced survival, yet there are no validated tests to predict those at risk. We previously demonstrated that BCMA is present in the serum and its levels are elevated in patients with multiple myeloma. As BCMA is expressed by both normal and malignant antibody-producing cells, we examined serum levels of BCMA in PAD. Patients with PAD (n=68) had markedly reduced BCMA levels (median, 7.30) compared with healthy donors (n=119; median, 35.20; P &amp;lt; 0.0001). When subgrouped based upon PAD diagnosis, serum BCMA was reduced compared to controls among those with common variable immunodeficiency (CVID) (n=48; median, 7.16; P &amp;lt;0.0001) and X-linked agammaglobulinemia (n=8; median, 2.30; P &amp;lt;0.0001), but not among those with selective IgA deficiency or hyper IgM syndrome. CVID patients with any inflammatory complication, or enteropathy specifically, had significantly lower serum BCMA than CVID patients without complications (P &amp;lt; 0.01 for both). Serum BCMA moderately correlated with isotype-switched memory B cells (r = 0.473), but poorly correlated with IgA, IgG, or IgM levels or total B cell levels. These results demonstrate that reduced serum BCMA levels are found in PAD patients, distinguish types of PAD, and are associated with the development of complications in CVID.

Helicobacter pylori infection in patients with selective immunoglobulin a deficiency.

Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori-infected dyspeptic patients with IgAD. Case samples were drawn from all subjects ≥12 years of age (n=104729) who had undergone serum total IgA measurements during 2004-14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA <0·07 g/l. The control group was comprised of a random sample of remaining patients with a case-control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD-9-CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24·2%) versus 821 (23·6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori-positive subjects [59 (17·1%) versus 524 (15·1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61·9%) versus 38 (21·6%), P < 0·001), duodenal ulcers [seven (33·3%) versus 19 (10·8%); P=0·01] and nodular lymphoid hyperplasia (NLH) [two (9·5%) versus none; P=0·011]. IgAD is not associated with increased prevalence of H. pylori-associated dyspepsia; nevertheless, H. pylori-infected dyspeptic IgAD subjects experience more EGD-proved gastritis, duodenal ulcers and NLH.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

X-linked Agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is one of the commonest primary immune deficiencies encountered in pediatric clinical practice. In adults, common variable immunodeficiency (CVID) is the most common primary immunodeficiency disease (PID). It is an X-linked disorder characterized by increased susceptibility to encapsulated bacteria, severe hypergammaglobulinemia and absent circulating B cells in the peripheral blood. Replacement immunoglobulin therapy is the main cornerstone of treatment. Aggressive management of intercurrent infections and prophylactic antimicrobials are needed. This review attempts to highlight varied clinical manifestations and management of XLA, especially in the context of developing country.

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.

Is familial screening useful in selective immunoglobulin A deficiency?

Abstract Introduction Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown. Objectives To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening. Patients and methods Descriptive, cross-sectional study (October 2010–September 2011) of all patients with SIgAD followed up in our centre. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least 1 affected FDR. Results Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and 14 (16%) affected FDRs. Six family members had to be studied in order to detect 1 affected member. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p = 0.001, OR = 9.57, 95% CI 2.59–35.3), hospitalisations (p = 0.045, OR = 4.01; 95% CI 1.10–14.67], and need for chronic treatment (p = 0.006, OR = 5.5; 95% CI 1.57–19.54) were higher in affected FDRs than in unaffected ones. Conclusions The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency

Common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD) are the most common primary immunodeficiencies in human. Both diseases share clinical manifestation and molecular defects. Increased apoptosis may be one of the mechanisms involved in the pathogenesis of CVID and SIgAD. Elevated apoptosis in this disorder leads to defective long-term survival of B-cells, reduced antibody production, decreased lymphocyte proliferation and defective cytokine secretion. For the first time, we reviewed the role of apoptosis in CVID and SIgAD.

Immunoglobulin G Subclass Deficiencies in Adult Patients with Chronic Airway Diseases.

Immunoglobulin G subclass deficiency (IgGSCD) is a relatively common primary immunodeficiency disease (PI) in adults. The biological significance of IgGSCD in patients with chronic airway diseases is controversial. We conducted a retrospective study to characterize the clinical features of IgGSCD in this population. This study examined the medical charts from 59 adult patients with IgGSCD who had bronchial asthma or chronic obstructive pulmonary disease (COPD) from January 2007 to December 2012. Subjects were classified according to the 10 warning signs developed by the Jeffrey Modell Foundation (JMF) and divided into two patient groups: group I (n = 17) met ≥ two JMF criteria, whereas group II (n = 42) met none. IgG3 deficiency was the most common subclass deficiency (88.1%), followed by IgG4 (15.3%). The most common infectious complication was pneumonia, followed by recurrent bronchitis, and rhinosinusitis. The numbers of infections, hospitalizations, and exacerbations of asthma or COPD per year were significantly higher in group I than in group II (P < 0.001, P = 0.012, and P < 0.001, respectively). The follow-up mean forced expiratory volume (FEV1) level in group I was significantly lower than it was at baseline despite treatment of asthma or COPD (P = 0.036). In conclusion, IgGSCD is an important PI in the subset of patients with chronic airway diseases who had recurrent upper and lower respiratory infections as they presented with exacerbation-prone phenotypes, decline in lung function, and subsequently poor prognosis.

Autoimmunity and Immunodeficiency.

The references provided include data from evidence A and B studies based on the relevant populations. Because many primary immunodeficiencies associated with autoimmune diseases are rare, illustrative cases (evidence D) also are referenced. On the basis of level A evidence, immunoglobulin A deficiency is the most common primary immunodeficiency and is associated with defective mucosal immunity and autoimmune disease. On the basis of strong evidence (level A), Wiskott Aldrich syndrome presents early in life and is associated with autoimmune arthritis and anemia. On the basis of strong evidence in the literature, a number of primary immunodeficiencies are associated with defects in T regulatory cell number and development, cytokine aberrancies, and, as a consequence, production of autoantibodies. On the basis of strong evidence (level A) and case reports (level D), complement deficiency can be associated with autoimmune disease, most notably systemic lupus erythematosus.

Common Variable Immunodeficiency or Celiac Disease? Or Both in the Same Patient?

Introdution: Common variable immunodeficiency (CVID) is the most common life-threating primary immunodeficiency disease. There are few reports concerning CVID and celiac disease (CD) in the same patient. In this study, we describe clinical picture and histological alterations on duodenal mucosa of two patients with the initial diagnosis of CVID and posterior CD diagnosis. In addition, we evaluate of the role of a gluten-free diet (GFD) in the follow-up of the patients. Methods: Case 1. A 52-year-old woman, diagnosed with CIVD, receiving intravenous gamaglobulin (i.v.IgG). Three years ago symptoms of intestinal malabsorption, weight loss (15kg). At the first consultation, severe malnutrition, anasarca, anemia, hypoalbuminemia, indetectable IgA and very low levels of IgG and IgM; HLA DQ2 positive / DQ8 negative. Histology revealed villous atrophy, crypt hyperplasia and increased number of IEL and few plasmocytes in the lamina propria. Final diagnosis were CVDI and CD. Treatment, i.v.IgG and GFD. Follow-up: After 6 months, without GI symptoms, gained weight. After 10 months presented dermatitis herpetiformis. She was followed in another service and return after 4 years with weight loss and gastric complaints. Upper endoscopy revealed gastric tumor and abdominal ultrasonography liver metastasis. She died after one month after gastric surgery. Case 2: A 50-years-old man diagnosed with CVID, receiving i.v.IgG for 10 years. For the last 9 months, diarrhea, weight loss (13 kg). Two years ago, chronic hepatopathy, suggesting portal hypertension. At first consultation, severe malnutrition, anasarca, increased levels of transaminases and gama GT, anemia, hypoalbuminemia, indetectable IgA and low levels of IgG and IgM; HLA DQ2 negative / DQ8 positive. Histology revealed gastritis, Hp-; villous atrophy and increased number of IEL. Few plasmocytes in the lamina propria. Final diagnosis were CVDI and CD. Treatment: i.v.IgG and GFD. Follow-up: After 3 months, gained weight, duodenal biopsy showed slight improvement lesions. Prednisone was introduced. After 9 months, great clinical and histological improvement in duodenal mucosa. Currently treated with low dose of steroids, GFD and i.v.IgG. Discussion: The association between CD and CVID should not be considered as fortuitous. We recommend screen to CD in patients with CVID with GI complaints. Clinicians should be aware of the low sensitivity of serologic testing in this setting.