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Although it may seem paradoxical, Primary Immunodeficiency Disorders (PID) are frequently complicated by autoimmune and inflammatory conditions. These conditions pose significant diagnostic and therapeutic challenges for clinicians caring for these patients. There have been a number of new insights into how Rheumatologists should understand the basis for and manifestations of autoimmunity in PID to more effectively care for these patients.
A number of mechanisms have recently been proposed to link primary immunodeficiencies and autoimmunity, including increased homeostatic proliferation and defects in regulatory T cells.
The realization that Primary Immunodeficiencies can also impair negative regulation of immune responses has provided a new framework for the understanding of autoimmunity associated with these conditions, and may lead to new, more targeted therapies for these clinically challenging patients.
The primary immunodeficiency disorders (PID) are a heterogeneous group of diseases resulting from inherited defectsin the development and maturation of immune cells. PID can involve defects in adaptive immunity, with involvement of either or both B and T cells, and PID can also affect the innate immune system  PID are inevitably associated with increased susceptibility to infections, with the type of infection determined by which immune cells are affected by each disorder. Although it may at first seem paradoxical, autoimmunity and abnormal inflammation in the apparent absence of infection has often been observed clinically in association with PID. In a PID patient presenting with symptoms consistent with autoimmune or autoinflammatory disease, subclinical and clinical infections must always be considered. However, autoimmune complications of PID are often independent of any known infection, and persuasive evidence has come from animal models showing that the underlying immunodeficiency can directly predispose to autoimmune or autoinflammatory disease by disrupting mechanisms that normally negatively regulate immune responses. Just as specific PID are often linked to characteristic opportunistic infections, different forms of PID have been linked to specific autoimmune complications at various frequencies (Table 1). We will review autoimmune complications of primary immunodeficiencies and discuss recent findings that have uncovered cellular and molecular mechanisms linking PID to autoimmune disease.
A number of PID affect lymphocyte development, resulting in severely decreased numbers of peripheral T and/or B cells. These disorders are part of the spectrum of Severe Combined Immunodeficiecies (SCID). Although these are among the most clinically severe immunodeficiencies, autoimmune complications have been noted . Omenn Syndrome (MIM #603554) is SCID subtype associated with a number of specific autoimmune complications. This syndrome is characterized by severely decreased circulating T and B cells, some cases of which are caused by mutations in recombination-activating genes (RAG) 1 and 2, proteins that are critical in catalyzing the DNA recombination that generates the T and B cell repertoire. In addition to increased susceptibility to infections from birth, patents with Omenn syndrome can develop autoimmune complications including lymphadenopathy, splenomegaly, erythroderma, and autoimmune hepatic dysfunction. These complications are associated with eosinophilia and elevated IgE, suggesting involvement of the Th2 subset of T cells that produces IL-4, IL-6 and other cytokines that drive plasma cell differentiation and IgE production by B cells. Patients with these complications have been treated with high-dose steroids, antithymocyte globulin, and cyclosporin A. Bone marrow transplantation remains the only definitive treatment.
Immunodeficiencies resulting in severe lymphopenia may result in autoimmunity through an immunological process termed homeostatic proliferation. While normal naïve T and B cells turn over very slowly, much more rapid T and B cell proliferation is seen in the setting of severe lymphopenia. In animal models, it has been found that T cells in a lymphopenic environment can divide as rapidly as every two days without any external stimulus [4,5]. Homeostatic proliferation can be seen after therapies that deplete lymphocytes, bone marrow transplantation, transfer of cells into a lymphopenic environment, and during the physiological lymphopenia of the neonatal period . Homeostatic proliferation is thought to be driven by the functional excess of cytokines such as Interleukin-7 that normally are limiting in a replete lymphocyte compartment due to binding and uptake by specific receptors  Originally thought to be a benign process that simply reconstitutes a damaged immune system, T cells that proliferate through this mechanism have been more recently shown to acquire properties of memory cells including effector cytokine production and cytotoxicity. Because homeostatically proliferating lymphocytes are presumably reactive against self-antigens, potent autoreactive effector cells may be produced . In the NOD mouse model of type I diabetes, homeostatic proliferation secondary to lymphopenia was found to be integral to the development of anti-islet autoimmunity . Less is known about the autoreactive potential of B cells expanded through homeostatic proliferation, but some of the same principals may apply. Notably, mice engineered to have RAG1 mutations similar to those in Omenn syndrome developed the eosinophila, hypergammaglobulinemia and T cell infiltration seen in humans with this disease, and homeostatically proliferating memory–phenotype T cells producing effector cytokines were isolated from these animals. [10,11]. Homeostatic proliferation may predispose to autoimmunity in any PID involving severe lymphopenia. Conceivably, therapies that could increase lymphocyte numbers in these patients may ameliorate autoimmune manifestations as well as treat the underlying immunodeficiency.
Two genetic immunodeficiency/dysregulation syndromes specifically affecting mechanisms of T cell tolerance illustrate how PID can affect checkpoints that govern both positive and negative regulation of immunity. Autoimmune polyendocrinopathy-candidasis-ectodermal dystrophy(APECED) (autoimmune polyglandular syndrome type 1) is an autosomal recessive disorder with a genetic mutation of the AIRE gene whose product is expressed in the thymus, lymph nodes, pancreas, adrenal cortex and fetal liver. Primary manifestations include hypoparathyroidism (89%), chronic mucocutaneous candidiasis (75%), adrenal insufficiency (60%), primary hypogonadism (45%), and malabsorption (25%). Other non-endocrine and autoimmune manifestations include alopecia, pernicious anemia, chronic hepatitis, and vitiligo . The gene mutated in APECED, termed the autoimmune regulator (AIRE) gene, is a nuclear transcription factor that functions in the thymus to upregulate expression of tissue-specific genes in thymic epithelial cells. Developing thymocytes with a TCR that recognize these antigens undergo apoptosis during development, creating central immune tolerance to these antigens. Central tolerance fails in AIRE deficient mice, which recapitulate many features of APECED [13–15]. Defective AIRE expression in the thymus has also been seen in two patients with Omenn’s syndrome , suggesting that feedback from normal T cell development may be necessary in some cases for proper expression of AIRE and central tolerance.
Genetic deficiency in the FoxP3 transcription factor that is essential for the development of CD25+ regulatory T cells produces the syndrome of Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX), providing dramatic proof that regulatory T cells are necessary for immunological self-tolerance in humans. Clinical features include early onset type 1 diabetes mellitus, severe enteropathy, autoimmune hepatitis, eczema, anemia, thrombocytopenia, and hypothyroidism . Mutations in the FoxP3 gene that encodes the protein scurfin has been identified in most IPEX patients . FoxP3 deficient mice recapitulate many of the symptoms of IPEX patients. Immunosuppressive therapy including tacroliums, cyclosporine, methotrexate, infliximab, and rituximab has been used to treat this syndrome, but bone-marrow transplanation remains the only curative therapy . Interestingly, lymphoproliferation during the neonatal period has recently been identified as another possible contributor to autoimmunity in FoxP3 deficient mice 
In some cases, autoimmunity itself may contribute to immunodeficiency. Although not strictly a primary immunodeficiency disorder, idiopathic CD4 Lymphopenia (ICL) shares some features with SCID and in some cases appears to be linked to autoimmunity. ICL is diagnosed in patients who develop CD4 T-lymphocytopenia with CD4 counts <300 cell/uL without HIV infection or other known viral cause. Increased susceptibility to infections, particularly Cryptococci, has been noted in these patients. The lymphopenia associated with Sjogren’s syndrome can become severe enough in some cases for patients to be classified as having ICL; in a study of 214 Sjögren’s patients, (3.7%) were found to have ICL , with lymphocytopenia associated with antibodies directed against CD4 lymphocytes. Decreased numbers of CD4 lymphoctyes and a low CD4:CD8 ratio were associated with severe renal disease or thrombocytopenia [22,23]. Lymphopenia in SLE patients may have a related pathogenesis. These observations suggest the interesting possibility that autoantibodies against immune cells may play a role in functional immunodeficiency and susceptibility to infections seen clinically in patients with systemic autoimmune conditions.
Patients with defects in humoral immunity can also suffer from autoimmune complications. Since autoantibody production is limited by the B cell defects in these patients, other mechanisms likely contribute. X-linked agammaglobulinemia (XLA or Bruton’s agammaglobulenemia) is due to mutations in Bruton’s tyrosine kinase, a signal transduction molecule essential for B cell maturation. Btk-deficient B cells do not differentiate into antibody-producing plasma cells, and patients have pan-hypogammaglobulinema. Clinical manifestations include recurrent bacterial sinopulmonary infections, eczema, and diarrhea. Interestingly, XLA patients have an elevated incidence of juvenile rheumatoid arthritis, aspetic polyarthritis, cytopenias, IBD, and dermatomyositis . Hyper-IgM (HIGM) is a primary immunodeficiency from a genetic defect in the CD40 ligand pathway (X-linked HIGM) or in other proteins required for immunoglobulin class switch recombination. (MIM #308230). Consequently, HIGM patients have selective IgG deficiency with normal or elevated IgM levels, and are prone to recurrent sinopulmonary and gastrointestinal infections. Autoimmunity has often been described in HIGM patient series. In a cohort of 56 X-linked HIGM patients, IBD was seen in 6%, seronegative arthritis in 11%, chronic neutropenia in 45% . In another study of 79 patients, 60% were found to have neutropenia, with anemia and thrombocytopenia in 15% and 4%, respectively . Parvovirus B19 infection was only detected in 4% of the patients raising the suspicion of an autoimmune etiology independent of known infections.
Primary immunodeficiencies affecting CD8 and Natural killer (NK) cell cytotoxicity such as perforin deficiency (MIM #603553) and Griscelli Syndrome (MIM #607624) are associated with development of the hemophagocytic syndrome HLH (Hemophagocytic lymphocytic histiocytosis). In HLH, abnormal activation of both lymphocytes and innate cells, especially macrophages, can lead to immune cell infiltration into a number of organs, including the bone marrow, which leads to the complication of aplastic anemia and other features . Another immunodeficiency associated with HLH is X-linked Immunoproliferative Syndrome (XLP1, MIM #308240), a disorder characterized by fulminant mononucleosis, lymphomas and other lymphoproliferative syndromes and dysgammaglobulinemias. XLP1 results from mutations in the gene encoding SAP, an adapter protein that transduces signals from SLAM family receptors  . This family of cell surface molecules is important in mediating homotypic lymphocyte interactions that are necessary for CD8 T and NK cell-mediated killing of EBV-infected targets, for development of the NKT cell lineage, as well as for T:B cell interactions required for germinal center formation and long-term humoral immunity. Abnormal cytolytic activity towards EBV infected B cells is a hallmark of this disorder, and like other disorders with abnormal cytolytic activity, HLH-type complications, including development of aplastic anemia, can develop in a small percentage of patients. Other rare complications include lymphocytic vasculitis and other lymphocytic tissue infiltration, which have on occasion been treated successfully with steroids. Whether these features result from inappropriate lymphocyte interactions, a lack of NKT cells or other alterations in lymphocyte homeostasis (including abnormal cell death that is observed in this syndrome) is unknown. The only definitive treatment for XLP is bone marrow transplantation.
Common variable immunodeficiency (CVID) is a heterogeneous group of diseases characterized by defective antibody production and underlying T cell defects. About 10% of CVID cases have been linked to autosomal dominant mutations in the TNF-receptor family member TACI [30,31]. Clinical manifestations include recurrent sinopulmonary and gastrointestinal infections, with chronic bronchiectasis. Autoimmune diseases, particularly chronic inflammatory bowel disease, autoimmune cytopenias such as thrombocytopenia and hemolytic anemia, and rheumatoid arthritis are common in patients with CVID [32,33]. Interestingly, mice engineered to lack TACI have a partial deficiency in B cell class-switching, but also develop splenomegaly and accumulate B cells that hyper-produce immunoglobulins, reproducing some features of CVID. [34,35]
Wiskott - Aldrich syndrome (WAS) is a single gene PID that affects many aspects of immune cell function and is associated with a remarkably high prevalence of autoimmunity, as high as 70% in retrospective cohorts [36,37] with some patients developing multiple autoimmune manifestations. The mutated gene in WAS encodes a multidomain protein called Wiskott -Aldrich syndrome protein (WASp). WASp is expressed exclusively in cells of the hematopoietic lineage and is critical for cytoskeletal remodeling via actin polymerization. Its role in cell and organelle motility, immune cell polarization, immunological synapse formation and T cell receptor (TCR) signaling was found from studies in WAS patients and WASp deficient mice . WASP deficiency can affect NK and T cell cytolytic function and T cell help for B cells. WAS patients have reduced antibody responses to polysaccharide vaccines and increased susceptibility to a wide variety of bacterial, viral and fungal infections. Mast Cell, NK cell, platelet and neutrophil function are also affected in WAS [39–41]. WASp deficient mice were found to develop immune-mediated colitis and other autoimmune manifestations[42,43], but how WASp deficiency predisposes to autoimmunity remained obscure until recently.
WASp deficient T cells are defective in their production of Interleukin-2, a cytokine known to be required for survival of regulatory T cells. Several groups have recently investigated the role of WASp in the development and function of regulatory T cells, which are essential in the control of T-cell mediated autoimmunity [43,44,45] Humblet-Baron et al. reported normal thymic development but compromised peripheral survival and function of WASp-deficient murine Tregs. Maillard et al. found decreased numbers of both thymic and peripheral Tregs along with impaired homing and suppressive function of the WASp-deficient Treg cells, partly resulting from deficient production of IL-2 and IL-10. Adriani et al. described defective Treg function in WASp deficient T cells from mice and humans and restoration of Treg function by addition of IL-2, reinforcing the concept that defective IL-2 production in WAS may compromise Treg function and lead to autoimmunity. Defective Treg function may not be the only mechanism contributing to autoimmunity in WAS. Our own work has also suggested a role for defective production of Fas Ligand, a TNF-family member that enforces self-tolerance through inducing apoptosis via its receptor (Fas/CD95) in the pathogenesis of autoimmunity in WAS (Nikolov et al, manuscript submitted). Defective clearance of apoptotic cells, which can contribute to autoimmunity, was also suggested to play a role in the pathogenesis of autoimmunity in WAS . These findings illustrate how even in a single-gene PID, multiple mechanisms may contribute to autoimmune complications.
It is being increasingly recognized that the activation of innate immune cells such as macrophages, neutrophils and dendritic cells is regulated independently from lymphocytes. The autoinflammatory diseases, genetic syndromes resulting from mutations that affect negative regulators of inflammation or hyperactivate components of the ‘inflammasome’ responsible for the generation of the active form of the pro-inflammatory cytokine IL-1, offer clear clinical evidence that molecular mechanisms regulating innate immune responses exist and are relevant to human disease. Autoinflammatory diseases often result in arthralgias, arthritis, periodic fevers, and like other chronic rheumatic diseases, can predispose to secondary amyloidosis. The discovery that uric acid crystals and other particulate compounds can activate the inflammasome has linked many of the purely inflammatory disorders seen by rheumatologists to the same pathway. Interestingly, genetic autoinflammatory syndromes and acquired autoinflammatory diseases such as gout do not predispose to the development of antibody and T cell-mediated autoimmunity, suggesting that these types of inflammatory conditions do not prime the adaptive immune system in ways that predispose to autoimmunity.
Conversely, diseases that impair innate immunity have been associated with chronic inflammation that can mimic rheumatic conditions. A good example of this is chronic granulomatous disease (CGD), which is linked to mutations in the genes coding for the multisubunit phagocytic NADPH oxidase complex. Two thirds of patients have an x-linked mutation in gp91phox, a subunit of the NAPDH oxidase enzyme complex, while the rest possess mutations in other NOX subunits[47,48]. Phagocytic NADPH oxidase generates the ‘respiratory burst’ in macrophages and neutrophils that facilitates bacterial killing, adhesion and other functions. . With the exception of a few cases in which low levels of ROS generation have been detected, patients with the disease have a total failure of respiratory burst activity [47,48]. Patients with CGD present with chronic recurrent infections, but inflammatory complications are prominent, including the development of granulomas and severe inflammatory bowel disease .
The finding that CGD patients present with hyperinflammation seems at first to be paradoxical, since ROS have been shown to induce activation of the NF-κB transcription factor complex which facilitates production of proinflammatory cytokines such as TNF, IL-6 and IL-1β. One would expect a defect in ROS production to result in decreased production of inflammatory cytokines; however, studies of leukocytes from CGD patients and mouse models consistently show hyperresponsiveness to a number of proinflammatory stimuli in terms of cytokine prodction, and enhanced infiltration of neutrophils in the peritoneum in sterile peritonitis.  Gene expression profiling results from PMNs of 8 CGD patients showed upregulation of numerous proinflammatory molecules. In addition, it has been shown that the inflammatory manifestations of CGD are not due to increased cell survival, and CGD cells are capable of executing normal NF-κB signaling in the absence of NOX2- generated ROS. These results suggest that another NOX family member or a parallel NOX-independent pathway is responsible for NF-kB activation and inflammatory sequelae in CGD. The hyperinflammation in CGD shows that in addition to an important function in pathogen clearance, ROS appear provide a signal for cessation of the inflammatory response, which is absent in CGD. Leukocyte adhesion deficiency 1 (LAD-1) is another primary innate immune system PID in which neutrophils lack expression of β2 integrin (CD18), an adhesion molecule essential in the process of neutrophil extravasation from blood vessels. Despite this block in what would seem to be a critical pathway for generating an inflammatory response, LAD-1 patients have been reported to develop inflammatory bowel disease.
Given that PID patients are by definition immunocompromised, a thorough exclusion of infections coincident with or possibly causative of autoimmune complications should be undertaken before initiating specific treatments for autoimmune complications in these patients. In the absence of any trial data for these rare diseases, most therapies are empirical. Nevertheless, one valuable approach is to consider the clinical severity of any particular autoimmune complication and need for treatment, as one would do in a patient without underlying immunodeficiency. Specific therapy can then be tailored to avoid those known to predispose to infections to which a patient may already be susceptible given the specific immunodeficiency involved. In cases where it is clinically indicated, non-immunosuppressive therapeutics such as Intravenous Immunoglobulin (IV-Ig) would be preferable. Targeted therapies that affect specific immune cell subsets, such as Rituximab for B-cell mediated pathologies, CTLA4-Ig for T cells, or anti-TNF for inflammatory bowel disease, may be preferable over the broad immunosuppressive activity of glucocorticoids. With the recent advances uncovering molecular causes of PID and specific pathways responsible for the development of autoimmune complications, it is hoped that more rational treatment will evolve for these challenging patients.