Rheumatologic diseases in patients with inborn errors of immunity in the USIDNET registry.

There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatologic diseases. This study reports the frequency of rheumatologic conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatologic disease was reported. The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatologic disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%), and immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren's syndrome was the most common rheumatologic disease reported in ALPS patients (6.85%), and systemic lupus erythematosus was the most common rheumatologic disease in patients with chronic mucocutaneous candidiasis (CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (SAD) (3.66%), and ALPS (2.74%). This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatologic conditions was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications. Key Points • The rates of reported rheumatologic diseases in the USIDNET registry are different in individual IEIs. • Further studies are needed to guide clinicians for detecting rheumatologic conditions earlier in patients with IEI.

Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells.

The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell-dependent (TD) and T cell-independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast, SIgAs from the TI pathway bind a larger spectrum of bacteria, but the mechanism underpinning their production remains elusive. Here, we show that the intestinal TI pathway required CD40-independent B cell-activating signals from TACI, a receptor for the innate CD40 ligand-like factors BAFF and APRIL. TACI-induced SIgA responses targeted a fraction of the gut microbiota without shaping its overall composition. Of note, TACI was dispensable for TD induction of IgA in gut-associated lymphoid organs. Thus, BAFF/APRIL signals acting on TACI orchestrate commensal bacteria-specific SIgA responses through an intestinal TI program.

Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients.

B cells orchestrate pro-survival and pro-apoptotic inputs during unfolded protein response (UPR) to translate, fold, sort, secrete and recycle immunoglobulins. In common variable immunodeficiency (CVID) patients, activated B cells are predisposed to an overload of abnormally processed, misfolded immunoglobulins. Using highly accurate transcript measurements, we show that expression of UPR genes and immunoglobulin chains differs qualitatively and quantitatively during the first 4 h of chemically induced UPR in B cells from CVID patients and a healthy subject. We tested thapsigargin or tunicamycin as stressors and 4-phenylbutyrate, dimethyl sulfoxide and tauroursodeoxycholic acid as chemical chaperones. We found an early and robust decrease of the UPR upon endoplasmic reticulum (ER) stress in CVID patient cells compared to the healthy control consistent with the disease phenotype. The chemical chaperones increased the UPR in the CVID patient cells in response to the stressors, suggesting that misfolded immunoglobulins were stabilized. We suggest that the AMP-dependent transcription factor alpha branch of the UPR is disturbed in CVID patients, underlying the observed expression behavior.

Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Burden of copy number variation in common variable immunodeficiency.

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.

Autoimmunity in primary immune deficiency: taking lessons from our patients.

The elucidation of the genes leading to selected immune defects has accelerated our understanding of the molecular basis of tolerance in autoimmunity disorders. Mutations in genes of the immune system are known to lead to a catalogue of functional deficits, including loss of activation-induced Fas-mediated apoptosis, an inability to remove self-reactive T and/or B cells and insufficient numbers or functions of regulatory T cells. In most cases, microbial antigen stimulation occurs simultaneously, leading to further inflammatory responses. In each case, probing the molecular pathways involved in these primary immune defects has led to a better understanding of autoimmune diseases in general. While subjects with X-linked agammaglobulinaemia are almost devoid of autoimmune diseases, B cells which are present, but dysfunctional in other defects, lead to a significant incidence of autoimmune disease. Autoimmunity is also particularly common in the antibody deficiency states. Although organ-based autoimmunity also occurs, for unclear reasons the main conditions are immune thrombocytopenia purpura and autoimmune haemolytic anaemia. The common variable immune deficiency subjects most afflicted by these cytopenias are those with specific peripheral blood memory B cell phenotypes. B cells of these subjects have a retained autoimmune potential, lack of somatic hypermutation, profound loss of proliferative potential, accelerated apoptosis and loss of normal Toll-like receptor signalling. Treatment with high-dose immunoglobulin and/or steroids can be helpful, while rituximab provides benefits in the treatment of refractory cytopenias with apparently little risk, even with repeated use, due to ongoing immune globulin therapy.

Key aspects for successful immunoglobulin therapy of primary immunodeficiencies.

Immunoglobulin (Ig) therapy is the mainstay for treatment in the majority of primary immune deficiencies. While B cell defects are the predominant conditions in man, other diseases in which T cell dysfunction is severe also require antibody replacement. In many medical practices the phenotypic overlap between immune deficiency and symptoms of asthma leads to both missed opportunities for diagnosing immune defects and inappropriate Ig treatment of asthmatic patients with normal B cell function. As steroid therapy can lower serum IgG levels, this finding alone is an insufficient indicator for Ig replacement. In the past 3 decades, there has a gradual increase in recommended and commonly used doses of parenteral immune globulin, often based on both IgG trough levels and clinical responses. Special attention to Ig doses is needed for growing children, in cases of weight loss or gain, pregnancy and for subjects in whom more rapid consumption of Ig is likely, including febrile patients or those with gastrointestinal or lung disease. While acute bacterial infections are much less common in Ig-treated subjects, a number of reports note continued evidence of inflammatory complications. Monitoring patients over time includes, at minimum, physical examination, blood counts and chemistry screening tests and IgG trough levels, at 6-12-month intervals. Other monitoring tools include spirometry and at wider intervals with those with lung disease, carbon monoxide diffusion capacity and chest computed tomography scans. With careful selection of patients and adequate therapy, an improved quality of life is possible.

Immunodeficiencies.

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

Lung disease, antibodies and other unresolved issues in immune globulin therapy for antibody deficiency.

Defects of antibody production are the most common of the primary immune defects of man. While these defects have been described in clinical terms for more than five decades, in most cases, the pathogenesis is still poorly understood. The most common clinically important of these is common variable immune deficiency. However there is no strict definition of this defect and the criteria for initiating immune globulin therapy are not standardized, leading to wide variation in treatment practices. In addition there has been no clear means to adequate assess progression of lung disease or elucidate the causes of progressive pulmonary inflammation found in some subjects. Moreover, there are still questions such as what are the best predictors of chronic lung disease and how can we prevent this disorder. Other complications such as autoimmunity, granulomatous disease, gastrointestinal inflation, are similarly poorly understood although treatment with various biological agents has been used with some success. A few bio-markers for assessing clinical and immunologic status have been proposed, and some have proved to be useful, but additional methods to gauge the benefits of therapy, predict outcomes, and harmonize treatment practices are needed. Aside from Ig replacement, additional means of prevention of lung disease may need consideration to reduce lung damage apart from prophylactic antibiotics. These might include using macrolides as anti-inflammatory agents, inhaled corticosteroids, bronchodilators, mucolytics or mechanical or rehabilitative respiratory methods.

Autoimmune manifestations in common variable immunodeficiency.

INTRODUCTION: About 20% of subjects with common variable immune deficiency (CVID) develop an autoimmune complication, most often immune thrombocytopenia or hemolytic anemia. While the pathogenesis of autoreactivity is unknown for CVID subjects in general, and to a greater extent in those with autoimmunity, there is a loss of switched memory B cells. DISCUSSION: About 7-8% of CVID subjects have mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), a significant association with this immune defect, although the same mutations may be found in normal relatives and rarely in healthy blood donors. In addition to generalized B cell dysfunction, defective elimination of autoimmune B cells has been demonstrated.

Frequent false positive beta human chorionic gonadotropin tests in immunoglobulin A deficiency.

A patient with IgA deficiency had a series of positive serum pregnancy tests which led to medical and surgical procedures for suspected molar pregnancy. These tests were found to be falsely positive due to heterophile antibody. The aim of this study was to determine the frequency of false positive betahCG assays in sera of IgA deficient patients. Sera from a panel of IgA deficient (IgA < 7 mg/dl) patients were tested for the presence of betaHCG using three different assays, and also for IgG anti-goat and anti-mouse antibodies. Patients were seen at Mount Sinai Medical Center and included 54 patients (ages 1-80 years, 32 females, 22 males) with IgA deficiency. Thirty percent of 54 IgA deficient patient sera yielded positive pregnancy tests by one or more of the three betahCG assays, however, none of the patients were pregnant. In comparison to sera of normal controls, 39% of the patient sera contained significant amounts of anti-goat antibody and 18% contained significant amounts of anti-mouse antibody. While heterophile antibodies are common in IgA deficient serum, false positive assays for betahCG in IgA deficient serum have not been previously reported. The possibility of false positive test results should be considered prior to invasive procedures in IgA deficient patients.

Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Lymphomas of mucosal-associated lymphoid tissue in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by low serum immunoglobulins IgG, IgA, and usually IgM. The central immune deficiency is impaired secretion of immunoglobulins and lack of antibody production; however, T cell dysfunction and a variety of inflammatory complications suggest global immune dysregulation. A number of reports have documented the association of primary immunodeficiency diseases with the development of non-Hodgkin's lymphoma (NHL). In CVID, the risk has been estimated to lie between 1.4% and 7%. As for NHL arising in other immunodeficiency states, the lymphomas in CVID are extranodal and are usually B cell in type. Of 22 B cell lymphomas that have appeared over a period of 25 years in a cohort of subjects with CVID, five lymphomas, appearing in more recently studied subjects, that arose in mucosal sites would be classified as mucosa-associated lymphoid tissue (MALT) lymphomas. MALT lymphomas are low-grade B cell lymphomas that result from a proliferation of neoplastic marginal-zone related cells of lymphoid tissue and tend to occur in organs that have acquired lymphoid tissue due to long-term infectious or autoimmune stimulation. Lymphomas of this kind have not been described in patients with congenital immunodeficiency, although chronic mucosal antigen stimulation is an integral part of these immune deficiency states.

Hematologic complications of primary immune deficiencies.

Primary immune deficiencies have an estimated overall incidence of 1 in 10,000 individuals. These disorders are diverse, depending on the specific immune functions involved, and lead to chronic or recurrent infections, inflammatory conditions, and a variety of autoimmune diseases. The most common autoimmune disorder is immune thrombocytopenic purpura (ITP), followed by autoimmune hemolytic anemia (AHA). While cytopenias are common in all the congenital immune diseases, they are particularly common in the antibody defects, common variable immunodeficiency and selective immunoglobulin A deficiency. In common variable immunodeficiency, ITP occurred in 7.6% of the patients and AHA in 4.8%. Treatment options include corticosteroids, intravenous immunoglobulin (i.v.Ig), anti-D, and splenectomy. Although the association between cytopenias and congenital immune deficiency is unclear, defects in T-cell regulation, cytokine defects, abnormal apoptosis, and abnormal production of immunoglobulins with autoimmune features are potential mechanisms.

Analysis of SWAP-70 as a candidate gene for non-X-linked hyper IgM syndrome and common variable immunodeficiency.

SWAP-70 is a recently identified protein that functions as the only B cell-specific component of an isotype switch recombination complex called SWAP. The SWAP complex has specificity for the switch regions upstream of the constant region immunoglobulin genes and it facilitates the transfer of DNA between switch regions. These features suggested that mutations in the gene encoding SWAP-70 might result in humoral immunodeficiency. To test this hypothesis we determined the genomic structure of this gene and used single-stranded conformational polymorphism (SSCP) analysis to screen DNA from 38 patients with either non-X-linked hyper IgM syndrome or common variable immunodeficiency. The results demonstrated that SWAP-70 consists of 12 exons spread over 89 kb at chromosome 11p15.2. SSCP analysis of the patient population revealed five polymorphic variants in the gene, one of which (Q505E) is an amino acid substitution in the putative nuclear export signal of SWAP-70. However, none of the alterations appeared to be associated with disease in the patients screened.

Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency.

Physicians in the United States who treat patients with primary immunodeficiency were contacted to identify subjects who had been infected with hepatitis C due to exposure to contaminated intravenous immunoglobulin (IVIg) in 1993-1994. From this survey we gathered information on 58 PCR-positive hepatitis C-infected patients; 37 had CVID, 9 had XLA, 5 were IgG subclass deficient, 4 were antibody deficient with normal immunoglobulin levels, 2 had SCID after BMT, and 1 had B cell linker deficiency. Of the 58 subjects, 30 had been treated with IFN-alpha in combination with ribavirin in 5 cases, and 26 other subjects were not treated. Of those who were treated, 11 (37%) resolved the infection and became PCR-negative; of the 26 who were not treated, 5 (19%) have resolved the infection, outcomes not significantly different. Patients 20 years of age or younger had a significantly better outcome compared to those older than age 20 (P = 0.02). Five subjects of the 58 have had a liver transplantation, a sixth has had two transplants, and 10 (17%) of the group have died. This survey demonstrates the heterogeneity of the clinical outcome in subjects with primary immunodeficiency who contracted hepatitis C due to viral contamination of IVIg.

Physiology of IgA and IgA deficiency.

Although secretory immunoglobulin A (IgA) is important in mucosal immunity. selective IgA deficiency is the most common primary immunodeficiency of humans. In most cases this defect is not associated with any illness. The reasons for this are unknown, but other immunological compensations might provide sufficient or complete restitution. Alternatively, it is possible that IgA deficiency alone may not predispose to disease, but additional immunological abnormalities might be present in symptomatic individuals. Some IgA-deficient individuals have a reduced antibody response to immunizations (even with normal IgG and IgM levels) and others have deficient responses to bacterial polysaccharides when IgG subclass levels are normal. The physiological role of IgA, the frequency and causes of IgA deficiency, the diseases associated with its absence, and current limited understanding of the pathogenesis of selective IgA deficiency will be reviewed.

Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency.

Combined immunodeficiency disorders are characterized by abnormalities in cellular and humoral immunity. This classification includes common variable immunodeficiency (CVI), a primary immunodeficiency disorder characterized by hypogammaglobulinemia, recurrent bacterial infections, and significant T-cell abnormalities. Associated autoimmune diseases include rheumatoid arthritis, pernicious anemia, idiopathic thrombocytopenic purpura, and systemic lupus erythematous. Granulomatous lesions in lymphoid tissues, solid organs, and skin have been reported. We describe a patient with CVI who developed cutaneous granulomas with perineural invasion; to our knowledge, this is a previously undescribed feature.