Humoral Primary Immunodeficiencies Research Articles

Proof-of-concept study evaluating humoral primary immunodeficiencies via CJ:KREC ratio and serum BAFF level

Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children’s hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.

Low total gamma globulin level discovery at diffuse large B-cell lymphoma diagnosis predicts high risk of infection-related death: data from a monocentric retrospective study.

Diffuse large B-cell lymphoma can complicate the course of B-cell primary immunodeficiencies or induce lowering of total gamma globulin levels, whose clinical status as an effective secondary immunodeficiency remains unspecified. This study aimed to assess the frequency, and clinical and prognostic relevance of the low total gamma-globulin levels discovered at diagnosis of diffuse large B-cell lymphoma. In a 2-year monocentric retrospective study, 96 patients diagnosed with diffuse large B-cell lymphoma who had a serum electrophoresis were included. Patients were divided into those with lower (L-TGL and higher (H-TGL) total gamma-globulin levels (total gamma-globulin levels ≤5.5 g/l and >5.5 g/l) and compared for outcomes, including fatal infectious events. Twelve (12.5%; 8 males; age median 68 years, range 55-82 years) exhibited L-TGL. There was no difference between the both groups regarding demographics, Ann Arbor lymphoma stage, inflammatory parameters or chemotherapy regimen. However, overall death rates (10/12, 83.3% versus 22/96, 26.2%; p = 0.03) and infection-related death rates (10/12, 83% versus 6/96, 6.2%; p <0.001) were significantly higher in the L-TGL group. We demonstrate for the first time the strong negative impact of L-TGL on overall and infection-related mortality in diffuse large B-cell lymphoma. Prospective studies should distinguish immunodeficiencies secondary to the lymphoma from pre-existing humoral primary immunodeficiencies, using biomolecular testing and post-treatment total gamma-globulin level monitoring, to determine the best management strategy for infectious risk during diffuse large B-cell lymphoma treatment in the context of L-TGL.

Pulmonary Radiological Manifestations of Humoral and Combined Immunodeficiencies in a Tertiary Pediatric Center.

Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The "combined" group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The "humoral" group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant findingin patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, andthoracic lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.

Challenges and insights raised by comorbidity with FMF and selective IgA deficiency

: Familial Mediterranean Fever (FMF) is the most common form of genetic autoinflammatory disease worldwide. In turn, selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency, yet most patients remain asymptomatic. Case Presentation: A Jewish Brazilian female came to our attention due to recurrent inflammatory febrile episodes since very early in life, initially attributed to unexplained infections linked to SIgAD. At the age of 15 years, disabling buttock pain prompted a sacroiliac MRI, which demonstrated sacroiliitis. Direct genetic sequencing of the MEFV gene confirmed the diagnosis of FMF. After severe gastrointestinal intolerance to colchicine was observed, canakinumab achieved clinical and radiological control, enabling the reinstatement of colchicine. Conclusion: Here we report the first case of concomitant FMF and SIgAD in a Brazilian patient, highlighting the relevance of these comorbidities in the patient's diagnosis and follow-up. This coincidental association also provides insight into interactions between serum and mucosal IgA and the pyrin inflammasome in the control of inflammation and gut dysbiosis.

Chronic kidney disease in adults with primary immunodeficiency diseases in treatment with intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is the treatment of choice for humoral primary immunodeficiency diseases (PIDs). A third of the patients who receive intravenous immunoglobulin have adverse reactions, such as osmotic nephrosis. To assess the presence of kidney disease in adults with humoral PIDs, in treatment with intravenous immunoglobulin. A cross-sectional, descriptive, and observational study of patients who belong to the PID Clinic of the Specialties Hospital of the National Medical Center "Siglo XXI", Mexico City, who receive treatment with intravenous immunoglobulin. A questionnaire with demographic information, 24h urine creatinine clearance, serum creatinine, urea, and BUN (Blood Urea Nitrogen) was applied. 35 patients were surveyed; 65.7 % were women; the average age was 34 years; 51.4 % of the patients presented kidney damage. Those with > 5 years of treatment with intravenous immunoglobulin presented chronic kidney disease (CKD) with more frequency (55.6 %) according to the KDOQI scale. Chronic kidney disease occurs in 51 % of adult patients with PID who have been treated with intravenous immunoglobulin for more than 5 years; which is why these patients require periodic evaluations of their kidney function, and the use of sugar-free immunoglobulin in order to reduce the risk.

Clinical and Laboratory Features of 184 Italian Pediatric Patients Affected with Selective IgA Deficiency (SIgAD): a Longitudinal Single-Center Study.

Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

High-resolution computed tomography findings in humoral primary immunodeficiencies and correlation with pulmonary function tests.

AIMTo compare high-resolution computed tomography (HRCT) findings between humoral primary immunodeficiencies (hPIDs) subtypes; to correlate these findings to pulmonary function tests (PFTs).METHODSWe retrospectively identified 52 consecutive adult patients with hPIDs who underwent 64-row HRCT and PFTs at the time of diagnosis. On a per-patient basis, an experienced radiologist recorded airway abnormalities (bronchiectasis, airway wall thickening, mucus plugging, tree-in-bud, and air-trapping) and parenchymal-interstitial abnormalities (consolidations, ground-glass opacities, linear and/or irregular opacities, nodules, and bullae/cysts) found on HRCT. The chi-square test was performed to compare the prevalence of each abnormality among patients with different subtypes of hPIDs. Overall logistic regression analysis was performed to assess whether HRCT findings predicted obstructive and/or restrictive PFTs results (absent-to-mild vs moderate-to-severe).RESULTSThirty-eight of the 52 patients with hPIDs showed common variable immunodeficiency disorders (CVID), while the remaining 14 had CVID-like conditions (i.e., 11 had isolated IgG subclass deficiencies and 3 had selective IgA deficiencies). The prevalence of most HRCT abnormalities was not significantly different between CVID and CVID-like patients (P > 0.05), except for linear and/or irregular opacities (prevalence of 31.6% in the CVID group and 0 in the CVID-like group; P = 0.0427). Airway wall thickening was the most frequent HRCT abnormality found in both CVID and CVID-like patients (71% of cases in both groups). The presence of tree-in-bud abnormalities was an independent predictor of moderate-to-severe obstructive defects at PFTs (Odds Ratio, OR, of 18.75, P < 0.05), while the presence of linear and/or irregular opacities was an independent predictor of restrictive defects at PFTs (OR = 13.00; P < 0.05).CONCLUSIONCVID and CVID-like patients showed similar HRCT findings. Tree-in-bud and linear and/or irregular opacities predicted higher risks of, respectively, obstructive and restrictive defects at PFTs.

Clinic of humoral primary immunodeficiencies in adults. Experience in a tertiary hospital

Primary immunodeficiencies (PID) are characterized by alteration of the components of the immune system. Humoral deficiencies represent 50%. The most common are selective IgA deficiency, Bruton agammaglobulinemia, and common variable immunodeficiency (CVID). To describe the epidemiological and clinical characteristics of adults with humoral PID, cared for in a Primary Humoral Immunodeficiencies Clinic. A descriptive cross-sectional study that included a year of analysis, including 35 patients with humoral PID, 31 with CVID, and 4 with Bruton agammaglobulinemia. Data were analyzed with descriptive statistics. Of 35 patients studied, 31 had CVID (88.5%) and 4 (11.5%) Bruton agammaglobulinemia; 21 were men and 14 women. The age at onset of symptoms was 22.7 years, and the delay in diagnosis was 7.2 years. 11.4% of CVID patients died during the study; 4 had malignancies, 22.8% autoimmune diseases, and 48.5% gastrointestinal disorders. Patients with Bruton agammaglobulinemia presented no comorbidities. Unlike reports in the literature, in the study group, CVID was the most common cause of humoral PID, predominantly in men; the most common gastrointestinal disorder was intestinal functional disorder.

Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).

X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene.The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis.One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset.This report constitutes the largest group of patients with BTK mutations in China. A genotype–phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene.

Prevalence of Atopic Diseases in Patients with Humoral Primary Immunodeficiency: A Comparison of a Single Center and the US Immunodeficiency Network (USIDNET)

Prevalence of Atopic Diseases in Patients with Humoral Primary Immunodeficiency: A Comparison of a Single Center and the US Immunodeficiency Network (USIDNET)

Features of the cytokine profile in humoral primary immunodeficiency patients

The results of cytokines serum levels in patients with infectious and autoimmune phenotypes of X-linked agammaglobulinemia (X-AGG) and common variable immunodeficiency (CVID) are presented. In patients with varying nature of the primary agammaglobulinemia similar cytokine changes were estimated.

Clinical Characteristics and Molecular Analysis of 21 Chinese Children with Congenital Agammaglobulinemia

Congenital agammaglobulinemia is a humoral primary immunodeficiency and affected patients have extremely low levels of peripheral B cells and profound deficiency of all immunoglobulin isotypes. Mutations of the Bruton's tyrosine kinase (BTK) gene are responsible for most of the congenital agammaglobulinemia. In this study, the phenotypes of congenital agammaglobulinemia were investigated in 21 male children from 21 unrelated Chinese families. Sixteen different mutations of BTK gene were identified in 18 patients, and three patients did not have BTK gene mutations. Nine mutations had been reported previously including one gross deletion (c.722_2041del), one missense mutation (c.1764G>T), three non-sense mutations (c.194C>A, c.895C>T and c.1821G>A) and four invariant splice-site mutations (c.971+2T>C, c.1481+2T>A, c.1482-2A>G, c.1699-2A>G). Seven novel mutations were identified (c.373_441del, c. 504delG, c.537delC, c.851delA, c.1637G>A, c.1879T>C and c. 1482_1882 del). Ten of the eighteen mutations of BTK gene were located in the TK domain, four in the PH domain, three in the SH3 domain and one spanned the TH, SH3, SH2 and TK domain. Candidate genes of autosomal-recessive agammaglobulinemia, including IGHM, CD79a, CD79b and IGLL1, were screened in three patients without mutations in the BTK gene. A compound heterozygosity mutation in the IGHM gene (c.1956G>A, c.175_176insC) was identified in one patient. The results of our study further support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.

Patients with humoral primary immunodeficiency do not develop protective anti-influenza antibody titers after vaccination with trivalent subunit influenza vaccine

Yearly influenza vaccination is recommended for patients with humoral primary immunodeficiency (hPID). However, humoral responses following vaccination can be expected to be reduced in these patients. The efficacy of influenza vaccination in patients with hPID, anti-influenza antibody responses was assessed in 26 patients with hPID and 26 matched healthy controls (HC) using hemagglutination inhibition assay. Following vaccination, geometric mean titers (GMT) significantly increased for all influenza strains in the HC group, but only for A/H1N1 in the patient group. Fold increase in anti-influenza titer and seroprotection rates were lower for patients than for HC for A/H3N2 and A/H1N1, leading to postvaccination titer > or =40 in only 29% and 83% vs. 77% and 100%, respectively. Previous vaccination in patients and treatment with IVIg did not result in a higher rate of postvaccination titer > or =40. In conclusion, patients with hPID show hardly any humoral response following influenza vaccination.

Characterization of Bruton's tyrosine kinase mutations in Mexican patients with X-linked agammaglobulinemia

X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency in which affected patients have very low levels of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Mutations in the gene encoding for Bruton's tyrosine kinase (Btk) are responsible for most of the agammaglobulinemia. In this work, 14 Btk mutations responsible of causing XLA are described; eight of which are novel and six are mutations previously reported. Seven of the mutations were due to deletions and insertions of exons and introns, respectively, which suggest splicing defects. The others were missense mutations, five of which affect arginine residues and have been described, and two new which affect leucine and glutamine residues (L111P and E605G). Most of these mutations were located at the kinase domain of Btk and, less frequently, they were found in PH and SH2 domains. Protein expression was also affected since most of the patients did not express or express very low Btk.

Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features

CD40 is a member of the tumor necrosis factor receptor family, which is expressed by a variety of cells including B cells, macrophages, dendritic cells, and other nonimmune cell types. CD40 activation is critical for B-cell proliferation, immunoglobulin (Ig)-isotype switching, and germinal center formation. In physiological conditions, the activation of CD40 occurs by binding to its natural ligand, CD154, which is expressed on activated T cells. The in vivo critical role of CD40-CD154 interaction on B-cell differentiation and isotype switching is provided by the discovery that mutations in either CD40 or CD154 gene cause the hyper IgM syndrome, termed HIGM3 or HIGM1, respectively, characterized by very low levels of serum IgG, IgA, and IgE, with normal or elevated IgM, associated with a defective germinal center formation. Originally considered humoral primary immunodeficiencies, the clinical features and the defect of T-cell priming, resulting from a defective T-B cell or dendritic cell interaction, is now considered as combined immunodeficiencies. In this article, we present a comprehensive overview of the clinical, genetic, and immunological features of patients with hyper IgM syndrome due to CD40 mutations.