Autosomal-dominant Roquin-1 immunodeficiency and hyperinflammation.

Here we review the rheumatologic and autoimmune features of primary immune deficiencies with a focus on recently recognized genetic diseases, the spectrum of autoimmunity in PID, and targeted therapies. Primary immune deficiencies (PIDs) were initially described as genetic diseases of the immune system leading to susceptibility to infection. It is now well recognized that immune dysfunction and dysregulation also cause noninfectious complications including autoimmunity. The increased application of molecular testing for PID has revealed the diversity of clinical disease. Recent discoveries of diseases with prominent autoimmunity include activated phosphoinositide 3-kinase δ syndrome and PIDs caused by gain-of-function in STAT1 and STAT3. Similarly, identification of larger cohorts of patients with molecular diagnoses in more common PIDs, such as common variable immune deficiency (CVID), has led to increased understanding of the range of autoimmunity in PIDs. Understanding the molecular basis of these PIDs has the potential to lead to targeted therapy to treat associated autoimmunity. Autoimmunity and rheumatologic disease can be presenting symptoms and/or complicating features of primary immunodeficiencies. Evaluation for PIDs in patients who have early-onset, multiple, and/or atypical autoimmunity can enhance diagnosis and therapeutic options.

Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis.

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Immunodeficiency-autoimmunity syndromes.

Gene therapy is often considered the ultimate treatment with its obvious potential advantage, the correction of genetic diseases at the molecular level, as opposed to merely treating the symptoms caused by genetic aberrations. This vision has spurred great interest in the development and clinical application of gene transfer-based therapeutic approaches. Moreover, recent progress in biotechnology and recombinant DNA techniques has greatly improved our understanding of the molecular basis of inherited diseases, providing the knowledge base necessary to attempt their treatment by gene transfer. In the last decade in particular, genetic defects underlying most of the primary immunodeficiency diseases (PIDD) have been identified (see Table 1), opening the way to the possibility of genetic correction. Theoretically, all PIDD that are curable by allogeneic bone marrow transplantation (BMT) are candidates for ex vivo gene therapy. However, because extensive knowledge of the function(s) and regulation of the involved gene is a clear prerequisite to the rational development of new gene-based therapies, diseases caused by mutations of genes whose function is still unclear (e.g. Xlinked agammaglobulinemia, Wiskott-Aldrich syndrome, and Chediak-Higashi syndrome) must await further studies before clinical gene transfer protocols for affected patients can be proposed. Gene transfer into the totipotent hematopoietic stem cell would seem to be the most logical strategy for treating most PIDD. Targeting the stem cell, however, has proven to be a very difficult task for a series of reasons. These include the lack of precise information about the phenotypic characteristics of the "true" self-renewing lymphohematopoietic stem cell capable of reconstituting the immune system and the very low gene transfer efficiency into such a functional unit that is achievable with current techniques. The results of the extensive clinical experience with BMT as treatment of severe combined immunodeficiencies (SCID) and other PIDD have indicated that the pres-

According to current understanding of the mechanisms underlying primary immunodeficiencies (PIDs) and their clinical course, there is a clear and clinically significant association between this group of disorders and autoimmune manifestations (AIMs).This article presents up-to-date information on AIMs in patients with PIDs, with a focus on the most common conditions and key clinical features that warrant consideration of PIDs in the differential diagnosis of patients with rheumatic diseases.

POS1435 CLINICAL CHARACTERIZATION AND PREDICTIVE FACTORS FOR PROGRESSION IN A COHORT OF ILD PATIENTS WITH FEATURES OF AUTOIMMUNITY: ARE IPAF CRITERIA SUFFICIENT?

Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran

The association of immunodeficiency and autoimmunity may represent a paradox, yet it has been described in an increasing number of conditions. Use of unbiased genomic approach to identify novel forms of primary immunodeficiencies (PIDs), along with in-depth functional studies in biological samples from affected individuals continue to unravel novel mechanisms underlying immune dysregulation in patients with altered ability of fighting pathogens. In particular, it has been clearly established that genetic defects that affect T and B cell development compromise not just the ability to generate a diversified repertoire of lymphocytes capable of recognizing multiple pathogens, but also impinge on mechanisms of central and peripheral tolerance, hence favoring autoimmune and inflammatory manifestations. Yet, the diagnosis of autoimmune symptoms in the context of PIDs is troublesome, the prognosis unclear, and the treatment challenging. In the present collection of manuscripts, several experts in the field provide an overview of the spectrum of different forms of monogenic defects of the immune system manifesting also with autoimmunity, and discuss established and novel mechanisms involved in immune dysregulation. Studies on patients with Immunedysregulation-Polyendocrinopathy Enteropathy-X-linked (IPEX) Syndrome, have paved the way to understand the phenotype arising from impaired peripheral tolerance due to dysfunctional regulatory T cells (Treg) expressing mutated FOXP3. However, this important T cell subpopulation can also be affected in other forms of PID, such as Wiskott–Aldrich syndrome (WAS) and adenosine deaminase (ADA) deficiency. In these disorders, the underlying genetic defect affects multiple cell types, resulting in impaired immune defense, but also poor Treg function. Similarly, STAT5B mutations disrupt an essential intracellular transcriptional activator for Treg cells, causing reduction of Treg number in affected individuals. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive condition due to mutation of the Autoimmune regulator (AIRE) gene. Patients with APECED present with predominant organ specific autoimmunity and autoantibodies with multiple specificities. AIRE has been shown to play a critical role in allowing expression of self-antigens in the thymus, thereby permitting deletion of self-reactive T lymphocytes or their diversion to Treg cells. Thus APECED stands as the prototypic monogenic disorder of central T cell tolerance. While it is still questionable whether deficiency of AIRE also affects peripheral tolerance, recent data indicate that the autoimmune-associated tissue damage may not be primarily due to autoantibodies, but rather to autoreactive CD8+ T cells. Moreover, recent studies in patients affected with Common Variable Immunodeficiency, a condition in which proper specific antibody production is deficient in favor of pathogenic autoantibody secretion, have highlighted the importance of mechanisms that control B cell development and receptor editing in maintaining immune homeostasis. Finally, two manuscripts call the attention to the dual role of certain cell types and their ability to acquire different immunological functions depending on the environment in which they differentiate, as described for Th17 cells and dendritic cells, at the end of the Topic. Possibly, the future of medicine should aim to implement physiological plasticity and to empower epigenetics modifications in order to recover from inborn errors of Nature.

At present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations. We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families. In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance. We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.

Congenital neutropenia and primary immunodeficiency diseases.

Primary immunodeficiencies (PIDs) include more than 130 different disorders affecting the development and function of the immune system [1, 2]. PIDs are generally monogenic disorders with a Mendelian inheritance, although a more complex polygenic origin has been described in some cases. PIDs are characterized by a variable clinical spectrum. As for other genetic diseases, phenotypic diversity is often caused by disease penetrance and interactions between genetic and environmental factors. PIDs are rare and have an overall prevalence of approximately 1:10,000 live births, with the exception of IgA deficiency (IgAD). However, a much higher rate is observed among populations with high consanguinity rates or genetically isolated. PIDs are classified according to the component of the immune system that is mostly engaged. Defects in adaptive immune responses include antibody deficiency syndromes and combined immunodeficiencies (CIDs). Conversely, impairment of innate immunity comprises disorders of several cells and molecules involved in the first defense against pathogen (i.e., phagocytes, Toll-like receptors, complement, NK cell). All of these forms are characterized by increased susceptibility to recurrent infections, severe infections, and sometime distinctive susceptibility to various types of pathogens depending on the nature of the immune defect. In addition, there are some forms of PIDs presenting mainly with a phenotype of immune dysregulation rather than immunodeficiency, and there are also syndromes with complex phenotype in which immunodeficiency is only one of multiple components of the disease spectrum. PIDs affecting the B and T cell compartment are traditionally the ‘‘classic’’ forms of inherited immune deficit widely described and usually recognized also by general practitioners. Defective antibody production causes increased susceptibility, primarily to bacterial infections with involvement of the upper and lower respiratory tract (otitis, sinusitis, and pneumonia), although recurrent viral infections are also common as well as infections caused by parasites (i.e., Giardia species) [2, 3, 4]. Primary antibody deficiencies (PAD) are the largest group of inherited disorders of the immune system [5] and comprise a variety of defects that interfere with B cell development, maturation, and/or function. They are mainly characterized by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation. X-linked agammaglobulinemia (XLA) is a well-described condition affecting males and characterized by mutation of the X-linked Bruton’s tyrosine kinase (BTK) gene [6, 7], named after Dr. Bruton, who described the first agammaglobulinemia patient in 1952 [8]. BTK, a transduction molecule of both pre-B cell-receptor (pre-BCR) and BCR, is essential for B cell differentiation in bone marrow. Besides XLA, many other gene defects were found as responsible of PAD and most of them have only been identified over the past 6 years. Moreover, the discovery of new PAD has contributed also to improve the clinical care of affected patients. The review by van der Burg et al. E. Gambineri (&) Department of Sciences for Woman and Child’s Health, ‘‘Anna Meyer’’ Children’s Hospital, Haematology-Oncology Department, BMT Unit, University of Florence, Viale Gaetano Pieraccini, 24, 50139 Florence, Italy e-mail: eleonora.gambineri@unifi.it Cell. Mol. Life Sci. (2012) 69:1–5 DOI 10.1007/s00018-011-0833-0 Cellular and Molecular Life Sciences

Hematologic complications of primary immune deficiencies

Large Granular Lymphocyte Infiltration in the Bone Marrow in Children and Young Adults May Suggest Primary Immune Deficiency

ObjectivesMany patients with interstitial lung disease (ILD) have autoimmune manifestations but do not meet criteria for a systemic rheumatic disease. A subset meets criteria for interstitial pneumonia with autoimmune features (IPAF) and have ILD requiring therapy. We conducted a multicentre observational study to examine the use of rituximab (RTX) in IPAF.MethodsPatients from Mass General Brigham (MGB) and University of Chicago Medicine (UCM) were included if they were ≥18 years old, met the 2015 classification criteria for IPAF and were treated with RTX. Clinical improvement was defined as improvement in four out of four domains at 1 year after RTX initiation: documented clinician global assessment; oxygen requirement; need for respiratory-related hospitalization; and survival.ResultsAt MGB, 36 IPAF patients (mean age 61 years, 44% female) were treated with RTX. At 1 year, 18 (50%) were clinically improved, 12 (33%) were stable, and 6 (17%) died from progressive respiratory failure. At UCM, 14 IPAF patients (mean age 53 years, 71% female) were treated with RTX. At 1 year, eight (57%) were improved, two (14%) were stable, three (21%) died from progressive respiratory failure, and one (7%) was lost to follow-up. Two patients experienced minor infusion reactions, and two patients discontinued therapy owing to adverse events (infections).ConclusionIn patients with IPAF treated with RTX at two medical centres, the majority (40 [80%]) demonstrated improvement/stability at 1 year. These findings call for prospective studies, including randomized clinical trials, to determine the risks, benefits and cost effectiveness of RTX in IPAF.