Deconstructing common variable immunodeficiency by genetic analysis Alejandro A Scha¨ffer1, Ulrich Salzer2, Lennart Hammarstro¨m3 and Bodo Grimbacher4 Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Patients have recurrent bacterial infections and an increased risk of developing autoimmune diseases, lung damage, and selected cancers. Since 2003, four genes have been shown to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19. Heterozygous mutations in TNFRSF13B are also associated with CVID, whereas the other three genes are purely recessive. Recent genetic linkage studies have also identified possible loci for dominant CVID genes on chromosomes 4q, 5p and 16q. These findings markedly improved the genetic diagnosis of CVID and point towards new strategies for future genetic studies. In addition, some CVID genes might be relevant to more common diseases such as asthma and stroke. Addresses 1 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Department of Heath and Human Services, 8600 Rockvile Pike, Bethesda, MD 20894, USA 2 Division of Rheumatology and Clinical Immunology, Medical Center, University of Freiburg, Hugstetterstraße 55, 79106 Freiburg, Germany 3 Division of Clinical Immunology, Karoliska Institutet at Karolisnka University Hospital Huddinge, SE-141 86 Stockholm, Sweden 4 Department of Immunology and Molecular Pathology, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG, UK Corresponding author: Grimbacher, Bodo (
[email protected])
Current Opinion in Genetics & Development 2007, 17:201–212 This review comes from a themed issue on Genetics of disease Edited by Robert Nussbaum and Leena Peltonen Available online 27th April 2007 0959-437X/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2007.04.002
Introduction The major achievement in the evolution of the adaptive immune system is its capability to generate specific antibodies directed against invading pathogens, and to memorize this immune response. These antibodies, generated as various immunoglobulin (Ig) isotypes (i.e. IgM, IgG, IgA and IgE), represent an important component of the humoral immune system and are thus kept at a constant concentration in blood. Disorders affecting www.sciencedirect.com
immunoglobulin production or turnover frequently lead to hypogammaglobulinemia, rendering patients susceptible to recurrent infection, especially by encapsulated bacteria. The severity of this hypogammaglobulinemic state can range from IgG subclass deficiencies in combination with IgA deficiency to complete absence of all three major Ig isotypes (IgA, IgG and IgM), which is termed ‘agammaglobulinemia’. The diagnosis of common variable immunodeficiency (CVID) is typically made in patients with a history of recurrent bacterial infections and substantially lowered serum levels of immunoglobulins. In particular, CVID patients almost always have low IgG and IgA serum levels, and about 85% also show a reduction of IgM in serum [1]. The clinical course in CVID patients includes an elevated risk of autoimmune diseases, lung complications and several types of cancer. CVID is the most common primary immunodeficiency that necessitates clinical attention, with an incidence estimated at 1:10 000 to 1:50 000 [2]. Isolated IgA deficiency is much more common in Caucasians, with an incidence estimated at 1:700, but the vast majority of cases are clinically unapparent. Several individuals have been shown to gradually progress from IgA deficiency to full-blown CVID [3–6]. How often this deterioration occurs and over what time frame is hard to estimate, because isolated IgA deficiency is often asymptomatic and thus underdiagnosed. In a large CVID patient cohort, Cunningham-Rundles and Bodian [1] estimated that the difference between the median age at the onset of initial symptoms and the median age at diagnosis is five to six years. In the current European database for CVID, this diagnostic delay was shown to be four years [7]. Once patients are diagnosed with CVID, immunoglobulin substitution is an effective treatment in the majority of patients [8]. Immunoglobulin administration is not a curative treatment, but a lifelong replacement therapy that has to be applied either on a monthly basis if given by the intravenous route or weekly if subcutaneous immunoglobulin replacement therapy is chosen. The safety and reliability of Ig replacement therapy are overshadowed by various factors: possible deleterious effects over decades of treatment [8,9]; economic constraints, because Ig therapy is expensive; and the resources for the production of Ig for clinical application are limited by the availability of eligible Current Opinion in Genetics & Development 2007, 17:201–212
202 Genetics of disease
plasma donors. Therefore, the identification of genetic factors that are involved in the etiology of CVID will enable not only new diagnostics but also new leads for possibly curative, therapeutic interventions. It was recognized decades ago that CVID has a genetic component [10]. The progression from IgA deficiency to CVID mentioned above is most frequently observed in families in which at least one immunodeficient individual is diagnosed with CVID and in which the immunoglobulin levels of available relatives are measured. Both by this strategy and by strategies of ascertaining IgAdeficient probands, Vorˇechovsky´ et al. [11] estimated that approximately 20% of cases of IgA deficiency are familial, whereby IgAD and CVID can cluster within single families. For CVID alone we, and others, estimate the frequency of familial occurrence to be about 10% [1]. There have been surprisingly few genetic studies of CVID until the past few years. Early studies using genetic linkage and association established that there is at least one susceptibility locus in the HLA region on chromosome arm 6p. However, as with so many other HLAlinked immune related diseases [12], pinning down the CVID susceptibility genes and mutations on 6p has been a quixotic challenge. Both dominant and recessive inheritance have been documented in CVID–IgAD families, with dominant inheritance being far more common [11]. For recessive inheritance, numerous CVID candidate genes have been suggested on the basis of studies of single-gene knockout mice that have low immunoglobulin levels and are susceptible to infections. Within the past five years, studies of such candidate genes outside 6p, and genome-wide linkage studies of CVID have identified several causative or associated genetic factors: three genes mutated in a small number of recessive cases; one gene that is mutated in as many as 10% of CVID cases; and some possible regions of genetic linkage between polymorphic markers and the CVID–IgAD phenotype. In the central sections of this article, we review these recent genetic findings. To put these findings into a broader genetic context, we first describe some examples of genetically defined differential diagnoses of CVID, several of which have been made possible by the identification of other genes mutated in immunodeficiencies that can mimic the clinical picture of CVID. In the later sections, we speculate on the prospects for future genetic studies of CVID and we discuss the possible relevance of CVID-causing genes to two more common diseases, asthma and stroke.
CVID is a diagnosis of exclusion Many conditions can manifest with the symptoms of hypogammaglobulinemia and subsequent recurrent bacCurrent Opinion in Genetics & Development 2007, 17:201–212
terial infections. Still today, the diagnosis of CVID is usually made when a variety of tests for other conditions are negative. Only the discovery of some CVID-causing genes, as described below, enabled us to make a definite, genetically based diagnosis of CVID (i.e. by identification of a mutation) in a small percentage of patients. In Table 1, we highlight some monogenic immune diseases that can mimic the clinical phenotype of CVID and as such constitute important differential diagnoses. Incomplete or abortive clinical courses of some multisystem monogenic disorders such as ataxia telangiectasia and myotonic dystrophy can also manifest with a CVIDlike phenotype. Additionally, exposure to non-genetic factors such as drugs (e.g. gold salts) and viral infections (e.g. Epstein-Barr virus [EBV]) can also result in states of hypogammaglobulinemia. In male CVID patients, especially when there is a family history compatible with X-linked inheritance, two wellknown other immunodeficiency disorders need to be excluded: in X-linked agammaglobulinemia (XLA), B-cell development is blocked at the pre-B-cell stage, resulting in severe peripheral B-cell lymphopenia and usually very low immunoglobulin levels; in X-linked lymphoproliferative syndrome (XLP) the clinical picture contains the triad of an often fatal infection with EBV associated with the development of lymphoma and hypogammaglobulinemia [13]. A crucial distinction between XLA and XLP and CVID is that the onset of XLA and XLP is usually shortly after birth, whereas the diagnosis of CVID is usually reserved for patients whose onset is above age 2. However, several papers cited in Table 1 document XLA and XLP cases with hypomorphic mutations that led to later age of onset and misdiagnosis as CVID. XLA can be distinguished from CVID by the nearly complete lack of B cells (
