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Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency

Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency
Markus G Seidel, MD
Section Editors:
Mark H Wener, MD
Rebecca Marsh, MD
Deputy Editors:
Anna M Feldweg, MD
Philip Seo, MD, MHS
Literature review current through: Nov 2022. | This topic last updated: Oct 18, 2022.

INTRODUCTION — Patients with primary immunodeficiency (PID) have dysregulated immune processes, which can result in an increased susceptibility to infectious diseases, autoimmune disorders, autoinflammation, and malignancies. Thus, the term "inborn errors of immunity (IEI)" was coined to reflect this broader spectrum of potentially deficient immune processes and to encompass all the subgroups of diseases with immune dysregulation or "primary immune regulatory disorders (PIRD)", autoinflammatory syndromes, and tumor predisposition, in addition to those with a predominant deficiency of immunity against infectious microorganisms.

This topic will discuss the most common manifestations of autoimmunity in patients with IEI and review the autoimmune disorders associated with the most prevalent IEI. Malignancies in patients with IEI are reviewed separately. (See "Malignancy in primary immunodeficiency".)

CLASSIFICATION OF IEI — IEI are classified into 10 major categories of disorders [1]:

I – Immunodeficiencies affecting cellular and humoral immunity. (See "Combined immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview".)

II – Combined immunodeficiencies with associated or syndromic features. (See "Syndromic immunodeficiencies".)

III – Predominantly antibody deficiencies. (See "Primary humoral immunodeficiencies: An overview".)

IV – Diseases of immune dysregulation (including hemophagocytic lymphohistiocytosis syndromes, lymphoproliferative syndromes and susceptibility to Epstein-Barr virus, defects of regulatory T cells, and immune dysregulation syndromes with colitis). (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

V – Congenital defects of phagocyte number or function. (See "Primary disorders of phagocyte number and/or function: An overview".)

VI – Defects in intrinsic and innate immunity. (See "An overview of the innate immune system" and "Mendelian susceptibility to mycobacterial diseases: An overview" and "Chronic mucocutaneous candidiasis".)

VII – Autoinflammatory disorders (including periodic fever syndromes, familial cold autoinflammatory syndrome, tumor necrosis factor [TNF] receptor-1 associated periodic syndrome [TRAPS], and others). (See "The autoinflammatory diseases: An overview" and "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)" and "Cryopyrin-associated periodic syndromes and related disorders".)

VIII – Complement deficiencies. (See "Inherited disorders of the complement system".)

IX – Bone marrow failure syndromes. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Dyskeratosis congenita and other telomere biology disorders".)

X – Phenocopies of PID (ie, variations due to a somatic mutation in a gene, autoantibody-mediated destruction of a gene product, or other acquired changes, which mimic a disease caused by an inherited germline mutation of that gene). As an example, an autoantibody to complement factor H can cause atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy (TMA), similar to what is seen in patients with primary factor H deficiency (see "Inherited disorders of the complement system"), or a somatic mutation in TNBFRSF6 causing non-hereditary autoimmune lymphoproliferative syndrome (ALPS) without a germline mutation in FAS. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis", section on 'Pathogenesis'.)

The classification of IEI is discussed in more detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

Autoimmunity may occur in any subgroup of IEI, but it represents a hallmark of the category "diseases with immune dysregulation," or primary immune regulatory disorders (PIRD), which includes category IV above [1]. The phenotypic classification of IEI was published separately [2], and working definitions for the clinical diagnosis of IEI, especially useful in patients whose genetic diagnosis is pending, have been proposed by the European Society of Immunodeficiencies [3].

MANIFESTATIONS OF AUTOIMMUNITY AND IMMUNE DYSREGULATION IN IEI — Autoimmunity is one possible manifestation of deregulated immune function. The defects underlying IEI disorders impact at least three important areas of immune function:

The ability to fend off and eliminate dangerous exogenous pathogens is impaired, resulting in an increased frequency and severity of common infections, infections with unusual or opportunistic pathogens, or chronic infections (including recurring reactivations) with viruses, some of which may cause malignant transformation directly.

The recognition and clearance of altered endogenous cells and cell debris (immune surveillance), DNA damage repair, or leukocyte maturation and function may be defective, leading to increased susceptibility to autoinflammation and malignancies. Of note, predisposition to malignancy may also arise from the disturbed maturation of an immune cell itself, as an intrinsic feature of the IEI, independent of compromised immune surveillance, chronic inflammation, or of impaired clearance of viral infections [4]. (See "Malignancy in primary immunodeficiency".)

The regulation of immune processes and the induction and maintenance of tolerance to self is compromised, contributing to autoimmunity, chronic (auto)inflammation of the gut and other tissues, rheumatologic manifestations, granuloma formation in parenchymal organs or skin, gut, and other tissues, lymphoproliferation (ie, generalized lymphadenopathy, splenomegaly), focal or diffuse lymphocytic organ infiltration, and/or hemophagocytosis [5-7].

GENERAL PRINCIPLES OF AUTOIMMUNITY IN IEI — A wide variety of autoimmune diseases are found in patients with IEI. There is no general tissue or organ restriction, nor is there a gender or age predominance like that seen in autoimmune diseases affecting the general population.

Autoimmune cytopenias, endocrinopathies, enteropathy, arthritis, hepatitis, glomerulonephritis, lupus-like systemic manifestations, and many other disorders can develop in patients with IEI, and autoimmunity can develop at any age and at any stage in the course of the IEI. However, among patients with IEI and autoimmunity, there tend to be IEI-typical patterns of organ manifestations and a younger age of onset of autoimmunity in patients with combined immunodeficiencies than in those with B cell deficiencies [7]. The quality of life of a patient with IEI may be severely compromised due to the manifestation of autoimmune diseases and consequent immunosuppressive treatment. In addition, the outcome of patients with IEI is worse if autoimmune manifestations or inflammatory complications exist, compared with patients with the same IEI without autoimmunity/inflammation; and pre-existing autoimmunity/inflammation adversely affects the outcomes of hematopoietic stem cell transplantation in IEI patients [7].

Patients with IEI can develop autoimmunity in the strict sense (ie, specific autoantibody-mediated organ destruction), like that seen in autoimmune cytopenias or autoimmune hepatitis. Alternatively, autoreactive cellular immune mechanisms (due to a lack of self-tolerance) and hyperinflammation (based on positive feedback loops of ineffective immune cells via secreted mediators) may cause self-destruction rather than protection. It is unclear why autoimmunity affects one specific organ in one IEI and another organ in a different IEI [8-12].

Selected autoimmune disorders in common forms of IEI — Some PIDs are associated with specific autoimmune diseases, and an awareness of these patterns allows clinicians to monitor patients more effectively. The leading autoimmune organ manifestations of the most prevalent PIDs are cytopenias, endocrinopathies, and enteropathies. The table shows the most common PIDs and the autoimmune disorders most often encountered in patients with these immunodeficiencies (table 1).

Cytopenias — The autoimmune cytopenias most often reported in IEI are [13]:

Immune thrombocytopenia (ITP)

Autoimmune hemolytic anemia (AIHA)

Autoimmune neutropenia (AIN)

Evans syndrome (ie, the combination of Coombs-positive warm AIHA and ITP; less commonly, patients will also have AIN)

Besides cellular or antibody-mediated autoimmunity, mechanisms other than autoimmunity may contribute to cytopenias in IEI, including hemophagocytosis, lymphoproliferation (causing splenic sequestration of blood cells), bone marrow failure, and myelosuppressive viruses or toxins [13]. Diseases involving antibodies against hematopoietic cells of the peripheral blood or against precursor cells of the bone marrow represent one of the most frequent autoimmune manifestations in a variety of IEI, including autoimmune lymphoproliferative syndrome (ALPS), common variable immunodeficiency (CVID), and immunoglobulin A (IgA) deficiency. Immune cytopenias are also seen in a wide range of rare combined immunodeficiencies, such as deficiency of recombinase-activating gene 1 or 2 (RAG1 or RAG2), adenosine desaminase (ADA), purine nucleotide phosphorylase (PNP), serine threonine kinase 4/macrophage-simulating 1 (STK4/MST1), or Ca2+-channelopathies, and in DiGeorge (22q11 deletion) syndrome and Wiskott-Aldrich syndrome (WAS), as well as primary immune regulatory disorders (PIRD) such as the dominant cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency with autoimmune infiltration (CHAI) immune dysregulation syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, CD25 deficiency, or in patients with gain-of-function mutations in STAT1 or STAT3 [2,5,8,9,14-22]. Additionally, immune cytopenias are a typical finding in patients with lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency [23-27], whereas cytopenias in patients with ADA2 deficiency are mainly due to bone marrow failure [28]. Thus, monogenic IEI should be included in the differential diagnosis of cytopenias, especially of Evans syndrome in children [13,29].

Endocrinopathies — Autoimmune thyroid diseases or other endocrinopathies, such as type 1 diabetes mellitus and Addison disease, are seen in IEI. Autoimmune endocrinopathies are most prominent in:

DiGeorge (22q11 deletion) syndrome (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Autoimmune disease')

IPEX and IPEX-like disorders [10,30-32] (see "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked")

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) syndromes [33-35] (see "Chronic mucocutaneous candidiasis", section on 'Autoimmune regulator deficiency')

Enteropathies — Autoimmune or chronic inflammatory enteropathy is another important manifestation of immune dysregulation, which occurs frequently in IEI patients and can represent both a diagnostic and therapeutic challenge (table 1). Various clinical and histopathologic entities of gut disease have been described in IEI, including intractable diarrhea (as seen in IPEX and IPEX-like syndromes), celiac disease, colitis, and enteritis with lymphocytic infiltration.

Inflammatory bowel disease (IBD) and IBD-like diseases are regularly observed in CVID, WAS, chronic granulomatous disease (CGD), IPEX and IPEX-like syndromes, the colitis-linked immune dysregulation syndromes of interleukin 10 (IL-10) and interleukin 21 (IL-21) signaling defects [36,37], LRBA deficiency, X-linked inhibitor of apoptosis (XIAP) deficiency (X-linked lymphoproliferative [XLP] disease type 2), as well as in nuclear factor-kappa-B (NF-kappa-B) essential modulator (NEMO) deficiency [5,14,15,38-43]. Gastrointestinal autoimmune or inflammatory manifestations in PID occur more frequently in the category of "innate immunodeficiencies" than in T or B cell disorders [7]. They are reviewed in more detail separately. (See "Gastrointestinal manifestations in primary immunodeficiency".)

POSSIBLE PATHOGENIC MECHANISMS — There are multiple potential pathways to the development of autoimmune disease and immune dysregulation.

Autoimmunity — Common autoimmune disorders in the general population, such as rheumatoid arthritis or systemic lupus erythematosus (SLE), are complex polygenic phenotypes, in which there may be several concomitant defects in immune function underlying disease pathogenesis. In contrast, monogenic diseases, which sometimes result in defects in a specific immune process or pathway, can provide insight into how immunologic tolerance is normally established and maintained, as well as illustrate the consequences of defective tolerance (table 1) [44-46].

One group has categorized some of the known PID/IEI disorders into defects in different overlapping immunologic pathways or processes that underlie autoimmunity [47]. In addition to this oversimplified construct, some monogenic defects impact several pathways simultaneously. Examples of PIDs affecting each pathway are provided.

Defects in central T cell tolerance – Central T cell tolerance results from the deletion of autoreactive T cells during development in the thymus (negative selection). This process involves interaction of developing T cells with thymic stromal cells and requires the product of the autoimmune regulator (AIRE) gene, which is essential for intrathymic presentation of autologous antigens. Mutations in AIRE result in defective presentation of self-antigens in the thymus. More than 70 mutations in AIRE have been identified that result in the disorder autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED), which is characterized by autoimmune disease affecting multiple organs and susceptibility to candidiasis (table 1). (See "Chronic mucocutaneous candidiasis", section on 'Autoimmune regulator deficiency'.)

Defects in B cell function and tolerance – In B cell development, central tolerance is achieved by receptor-editing in the bone marrow, which removes naïve B cells expressing self-reactive antibodies. In some patients with common variable immunodeficiency (CVID), mutations in TNFRSF13B (tumor necrosis factor receptor superfamily member 13B) lead to defects in transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), a molecule that is important in class-switch recombination, as well as in plasma cell differentiation and antibody production. Patients have increases in autoreactive B cells, autoimmunity, and autoimmune cytopenias. (See "Pathogenesis of common variable immunodeficiency".)

Hyperimmunoglobulin M (HIGM) syndrome can result from multiple defects, one of which is deficiency in activation-induced cytidine deaminase (AID), an RNA-editing enzyme important in immunoglobulin class-switch recombination and somatic hypermutation. Patients with AID deficiency classically present with normal or elevated immunoglobulin M (IgM) and low immunoglobulin G (IgG) and immunoglobulin A (IgA), lymphadenopathy with enlarged germinal centers, and recurrent bacterial infections. A subset develops autoimmune cytopenias, Crohn disease, or SLE. (See "Hyperimmunoglobulin M syndromes".)

Defects in peripheral tolerance – Peripheral tolerance refers to mechanisms that inactivate or remove mature T and B cells that recognize and could potentially react to self-antigens, including apoptosis, anergy, and suppression by T regulatory cells (Tregs). Foxp3 is a member of the forkhead box P family of transcription factors and is fundamental to the function of Tregs. Its gene is located on the X chromosome, and when defective, male infants develop autoimmune enteropathy, endocrinopathy, and severe eczematous dermatitis. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Defects in VDJ recombination – VDJ recombination is critical in immunoglobulin and T cell receptor function and maturation (see "Immunoglobulin genetics"). The products of recombinase-activating genes 1 and 2 (RAG1 and RAG2) mediate the creation of double-stranded DNA breaks at the sites of recombination and signal sequences during T and B cell receptor gene rearrangement. When severely defective, a T-B-NK+ SCID (T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency) results, while hypomorphic defects lead to T and B cells that survive but are oligoclonal and often self-reactive. Hypomorphic RAG mutations have been detected in multiple PIDs, including Omenn syndrome, idiopathic CD4 lymphocytopenia, and specific antibody deficiency. (See "Combined immunodeficiencies", section on 'Hypomorphic RAG1 and RAG2 mutations'.)

Defects in apoptosis – Once activated, an immune response must also be downregulated when the threat to the host has been neutralized. Defects in apoptosis pathways lead to uncontrolled lymphoproliferation, with lymphadenopathy, hepatosplenomegaly, autoimmune organ damage, cytopenias, and increased risk of lymphoma. Autoimmune lymphoproliferative syndrome (ALPS) presents in young children, usually as some combination of lymphadenopathy/splenomegaly/hepatomegaly, autoimmune disease (cytopenias), and lymphoma. Flow cytometry shows elevated numbers of T cells in peripheral blood and tissue specimens that express the alpha/beta T cell receptor but lack both CD4 and CD8 (alpha/beta double-negative T cells), elevated levels of interleukin (IL)-10 in blood, increased levels of vitamin B12, and defective Fas-mediated apoptosis in vitro. Multiple autoantibodies are characteristic. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

Hyperactivation of lymphocytes – Defects in molecules in the activation pathways of T and B cells may result in hyperactivation, immune dysregulation, and lymphoproliferation. Specific disorders include activating mutations in phosphoinositide 3-kinase (PI3K), deletions in the autoinhibitory domain of phospholipase C-gamma-2 (PLC-gamma-2), and protein kinase C-delta deficiency.

Increased activation of type 1 interferon pathways – Type 1 interferons (IFN-alpha and IFN-beta), when given therapeutically, can promote autoimmunity. The causative mechanisms of this adverse effect are not fully understood but include inhibition of Tregs, enhanced major histocompatibility complex (MHC) class II antigen expression with subsequent activation of T helper lymphocytes by autoantigens, and induction of proinflammatory cytokines. (See "Principles of interferon therapy in liver disease and the induction of autoimmunity", section on 'Interferon-induced autoimmunity'.)

Monogenic defects that result in increased production of type 1 interferons include gain-of-function mutations in signal transducer and activator of transcription-1 (STAT1), a signaling protein in the pathway initiated by binding of IFN-alpha or IFN-beta to its receptor. Patients present with chronic mucocutaneous candidiasis and an array of autoimmune disorders. (See "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction'.)

Defects in early complement components – Defects in the early complement components (ie, C1q, C1r/s, C2, and C4) are all associated with a greatly increased risk of developing SLE. Some patients have increased susceptibility to infection as well. These complement proteins function as acute-phase reactants and are important for opsonization of immune complexes and apoptotic cells. In patients with a deficiency, self-antigens are more likely to induce autoimmunity. (See "Inherited disorders of the complement system", section on 'Specific disorders'.)

Defective removal of cell debris – Similar to defects in early complement components, defects in phagocyte Fc receptors (Fc-gamma-RII and Fc-gamma-RIII), variants in C-reactive protein (CRP), and defects in the receptor for C3bi on monocytes, all impair normal removal of cell debris and apoptotic cells by phagocytes. These defects have been identified in some patients with SLE [47]. (See "An overview of the innate immune system", section on 'Homeostasis in the innate immune system'.)

A discussion of the known mechanisms of more common autoimmune diseases is found separately. (See "Overview of autoimmunity", section on 'Pathogenetic mechanisms' and "Normal B and T lymphocyte development".)

Immune dysregulation — Some manifestations of immune dysregulation in IEI may arise from uncontrolled processes in multiple components of the immune system and comprise a special form of autoimmunity in a wider sense [5]. Examples include inflammatory bowel disease (IBD), granuloma formation, lymphoproliferation, and hemophagocytosis. A similar, unspecific process of immune dysregulation may be triggered in diseases categorized under "autoinflammatory disorders" (category VII from the IEI classification) [2], some of which may present with autoimmunity, thrombocytopenia, hemolytic anemia, severe enterocolitis, vasculitis, etc. (See "The autoinflammatory diseases: An overview".)

Chronic IBD/enteropathy is a typical example of immune dysregulation in IEI [48]. Specifically, colitis may be observed as a consequence of immune dysregulation in disorders with defective IL-10 and IL-21 signalling [36,37]. In the colitis associated with chronic granulomatous disease (CGD), the impaired ability of neutrophils to digest phagocytosed material results in secretion of proinflammatory cytokines and the attraction and activation of ever more incompetent leukocytes, causing granulomata to form [39]. In immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, autoantibodies against various gut antigens are thought to be involved, in addition to the lack of direct T cell suppression by Tregs. An imbalance of pro- and anti-inflammatory monocytes/macrophages contributes to the pathology in other IEI. For instance, a gain-of-function mutation in NLRC4 may cause macrophage activation and inflammation due to defective inflammasome regulation, whereas in XIAP deficiency, X-linked lymphoproliferative (XLP) disease type-2 and very-early-onset IBD are mediated by nucleotide-binding oligomerization domain (NOD) signaling defects and an increased susceptibility to cell death [49]. Apoptosis defects also play a role in colitis seen in deficiency of RIPK1 or CASP8 [50].

Lymphoproliferation (generalized lymphadenopathy, splenomegaly), another possible manifestation of immune dysregulation, can also result from multiple mechanisms. It is pathognomonic in ALPS but also a common symptom in CD27 or CD70 deficiency, IL-2-inducible kinase (ITK) deficiency, XLP type 1, and CVID [9,14,51-57]. Lymphoproliferation and lymphoma (Hodgkin and non-Hodgkin lymphoma) are often Epstein-Barr virus (EBV)-associated. Of note, lymphadenopathy and splenomegaly may also be triggered by unspecified infections (not only EBV) in CVID and in almost any other PID and are not always primarily attributable to immune dysregulation. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

Primary or familial hemophagocytic lymphohistiocytosis syndromes also belong to the group of disorders with immune dysregulation (category IV of the IEI classification) and are usually caused by genes involved in cellular cytotoxicity pathways of cytotoxic T effector and natural killer (NK) cells [38,58]. Secondary hemophagocytic syndrome, lymphoproliferation, and lymphoma in the context of IEI may be infection-triggered (most often EBV or another DNA virus) and characteristically occur in T-B cell communication defects like XLP and CD27/CD70 deficiency [55,56,59-61]. However, other mechanisms of malignant transformation, like the underlying lymphocyte maturation defect, may also contribute to the development of lymphoma in this group of IEI [4]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Malignancy in primary immunodeficiency".)

WHEN TO SUSPECT AN UNDERLYING IEI — When signs/symptoms of autoimmunity develop before the patient has experienced recurrent infections, an underlying IEI may be missed and its diagnosis delayed for years. However, if an underlying IEI can be recognized in a timely manner, future infections or additional organ involvement may be prevented by early initiation of proper treatment and implementation of prophylactic measures.

Two clinical clues that a patient with autoimmunity may have an underlying IEI/PID are:

The development of an autoimmune disorder at an age that is younger than usual.

The development of autoimmune processes affecting multiple organ systems, not necessarily at the same time, that cannot be unified under a single rheumatologic diagnosis.

Some patients with IEI demonstrate both of these patterns [5].

Early-onset autoimmunity — Autoimmune disorders developing in patients who are younger than usual should alert the clinician to the possibility of an underlying PID [5]. As an example, infants with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome often present with intractable diarrhea and failure to thrive, with signs and symptoms of allergic inflammation affecting multiple systems (eg, eczema, food allergy, eosinophilia, elevated total and antigen-specific immunoglobulin E [IgE]) within the first year of life. Severe forms of IPEX may develop neonatal type 1 diabetes mellitus, and many patients also develop thyroiditis. Other examples would be severe early-onset inflammatory bowel disease (IBD) (ie, at toddler age) due to a mutation in one of the early-onset/very-early-onset IBD genes [50]; or a lupus-like autoimmunity syndrome before adolescence, eg, in deficiency of protein kinase C delta (PRKCD) [62]. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Multiorgan involvement — The occurrence of autoimmune involvement of multiple organs (often at different times in the patient's life) in the absence of a unifying rheumatologic diagnosis is another pattern suggestive of the presence of an underlying IEI/PID. The following are examples:

In a report of a family affected by the rare IEI, lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) deficiency, one child presented at the age of two years with immune thrombocytopenia (ITP) and generalized lymphoproliferative disease [63]. ITP became chronic and progressed to autoimmune pancytopenia. Generalized lymphadenopathy prompted a lymph node biopsy, which revealed findings consistent with autoimmune lymphoproliferative syndrome (ALPS). Her sister presented with autoimmune hemolytic anemia (AIHA) at five years of age, followed by chronic enteropathy with severe malabsorption and vasculitis, as well as recurring urinary and respiratory tract infections.

Patients with common variable immunodeficiency (CVID) may present with AIHA, ITP, or both (Evans syndrome) in childhood or adolescence and later develop frequent or recurrent sinopulmonary and respiratory tract infections, at which point the underlying immunodeficiency is often detected. Disorders that are common in CVID and may present at any point in the patient's life include IBD, granulomatous-lymphocytic interstitial lung disease (GLILD), thyroiditis, and a seronegative inflammatory arthritis. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

WHEN TO REFER — Patients with IEI may be under the care of generalists or specialists in allergy/immunology, hematology, infectious diseases, rheumatology, oncology, or gastroenterology, depending on the type of disorder that has necessitated medical care. It is not uncommon for the diagnosis of an underlying IEI to be delayed for years until someone recognizes that the combination of disorders afflicting the patient might be unified under the diagnosis of IEI.

When a patient's presentation or clinical course raises the possibility of an underlying IEI/PID, initial testing can be performed by the generalist. The evaluation is reviewed in detail separately. (See "Laboratory evaluation of the immune system" and "Primary immunodeficiency: Overview of management".)

Of note, the laboratory parameters analyzed for the diagnosis of autoimmunity, such as autoantibodies and inflammation markers, may be nonspecific and similar between patients with or without underlying IEI.

Definitive diagnosis of an IEI usually requires the input of a specialist, since more advanced immunologic tests require varying degrees of expertise to perform and interpret, may not be widely available, and are often costly. In addition, knowledge about the possible diagnoses in question is invaluable in deciding the type of testing to pursue first. Depending on the setting, clinicians with expertise in immunology are most often trained in allergy/immunology, infectious diseases, rheumatology, or pediatric hematology/oncology.

MONITORING FOR AUTOIMMUNITY — It is helpful to understand the associations between specific IEI and autoimmune disorders (table 1). Monitoring for these diseases can be accomplished with a periodic review of systems. In some cases, the patient can be educated about the most common signs of the most dangerous autoimmune conditions. If a new sign or symptom consistent with autoimmunity or immune dysregulation emerges, cooperation with the respective subspecialties, such as hematology, endocrinology, gastroenterology, and infectious diseases, should occur without delay.

Considering alternative etiologies — When assessing a patient with IEI for possible autoimmunity, it is important to begin with a broad differential diagnosis, since infectious diseases, adverse effects of medications, and malignancies can mimic autoimmune processes:

Viral and other infections may lead to myelosuppression and (pan)cytopenia, enterocolitis, or generalized lymphadenopathy and hepatosplenomegaly [13]. Mycobacterial infections may lead to granuloma formation. DNA viruses, norovirus, and Campylobacter and Salmonella (in some IEI) are typical microorganisms that may cause acute or chronic infection with cytopenia, enteropathy, or hepatitis.

Certain drugs given to patients with PID are myelotoxic or hepatotoxic and may lead to a clinical picture of cytopenia or hepatitis (eg, antibiotics, antiviral drugs, anticonvulsants, antipyretics, or immunosuppressants).

Malignancies, especially lymphomas, can be misinterpreted as "normal (polyclonal)" lymphoproliferation. In the setting of rapidly evolving or persistent lymphadenopathy/lymphoproliferation, a patient should be referred to a hematology/oncology specialist. A histopathologic assessment of lymph node and/or bone marrow tissue, including analyses of clonality and Epstein-Barr virus (EBV) integration, might be required to confirm or exclude lymphoma.

Conversely, absence of typical autoantibodies in a patient with a specific phenotype of an autoimmune disease might prompt searching for a monogenic IEI that might mimic the autoimmune disease, such as autoantibody-negative polyarteritis nodosa and other forms of vasculitis in patients with ADA2 deficiency; or alveolar proteinosis (more commonly associated with anti-GM-CSF antibodies) in patients with GATA2 deficiency.

THERAPIES — Most autoimmune diseases in patients with an IEI are managed with the same therapies that are used in patients without IEI. In many of these cases, the treatment required to control the autoimmune process may cause secondary immunodeficiency and further increase the risk of infection or malignancy. However, untreated autoimmune disease or chronic tissue damage due to uncontrolled inflammation may cause even equal or greater harm. Cross-specialty cooperation is invaluable when such therapies are required.

Some treatments seem overtly counterintuitive, such as the use of rituximab to eliminate autoreactive B cells in a patient with an underlying antibody deficiency. One example is the use of rituximab to control autoimmune hemolytic anemia (AIHA) in patients with common variable immunodeficiency (CVID). Another example is the use of T cell immunosuppression in a patient with a combined immunodeficiency. When such therapies are required, it is helpful to ensure that the patient understands the treatment strategy and is informed about specific risks and complications of the medications that are to be used.

Targeted therapies — With the advent of next-generation sequencing tools as part of the routine clinical diagnostic repertoire, a genetic diagnosis can be made in more and more IEI patients over time. Aligning the clinical phenotype with a defined signaling pathway often enables the identification and use of a drug that specifically targets the impaired pathway. This is especially valuable in IEI patients with immune dysregulation, as broader additional immunosuppression may be avoided by using a specific drug. As an example, abatacept, a soluble CTLA4 immunoglobulin, can ameliorate the phenotype of patients with insufficiency of CTLA4 or deficiency of LRBA by (partially) restoring regulatory T cell function [24].

Transplantation and gene therapy — Ultimately, allogeneic hematopoietic stem cell transplantation may be curative in certain severe monogenetic IEI with autoimmunity, if no targeted therapies are available (as is still the case in most IEI). In the future, gene therapy may represent another approach to cure an increasing number of these disorders.


Dysregulation of immune processes in primary immunodeficiency (PID), also called inborn errors in immunity (IEI), can lead to classic autoimmune disorders, chronic inflammation of the gut and other tissues, granuloma formation, lymphoproliferation and focal or diffuse lymphocytic organ infiltration, and/or hemophagocytosis. (See 'Manifestations of autoimmunity and immune dysregulation in IEI' above.)

A wide variety of autoimmune diseases are found in patients with IEI. There is no general tissue or organ restriction, nor is there a gender or age predominance like that seen in autoimmune diseases affecting the general population. However, very early onset and multi-organ autoimmunity are typical features of immune dysregulation in IEI. (See 'General principles of autoimmunity in IEI' above.)

The leading autoimmune organ manifestations of the most prevalent IEI are cytopenias, endocrinopathies, and enteropathies. The table shows the most common IEI and the autoimmune disorders most often encountered in patients with these immunodeficiencies (table 1). (See 'Selected autoimmune disorders in common forms of IEI' above.)

Autoimmunity and immune dysregulation can arise from defects in many different immunologic processes in the general population. Most common autoimmune disorders, such as rheumatoid arthritis or systemic lupus erythematosus (SLE), are complex polygenic phenotypes. In contrast, monogenic diseases, which often affect a specific immune process or pathway, can provide insight into how immunologic tolerance is normally established and maintained, as well as illustrate the consequences of defective tolerance. (See 'Possible pathogenic mechanisms' above.)

When autoimmunity develops before a patient has experienced recurrent infections, the diagnosis of an underlying IEI may be more difficult and delayed. However, if an underlying IEI is recognized in a timely manner, future infections or additional organ involvement may be prevented by early initiation of proper, ideally targeted, treatment and implementation of prophylactic measures. (See 'When to suspect an underlying IEI' above.)

Two clinical clues that an underlying IEI may be present are the development of an autoimmune disorder at an unusually early age and the presence of autoimmune processes that affect multiple organ systems and cannot be unified under a single (eg, rheumatologic) diagnosis. (See 'Early-onset autoimmunity' above and 'Multiorgan involvement' above.)

Awareness of associations between specific IEI and autoimmune disorders is helpful in monitoring patients (table 1). If a new sign or symptom consistent with autoimmunity or immune dysregulation emerges, cooperation with the respective subspecialties, such as hematology, endocrinology, gastroenterology, and infectious diseases, should occur without delay. (See 'Monitoring for autoimmunity' above and 'When to refer' above.)

Most autoimmune diseases in patients with IEI are managed with the same therapies used in patients without IEI. In some cases, targeted drugs are available that may partially restore the impaired signaling pathway without causing deleterious immunosuppression. In other cases, the treatment required to control the autoimmune process may cause secondary immunodeficiency and further increase the risk of infection or malignancy. In such situations, cross-specialty cooperation is critical. (See 'Therapies' above.)

  1. Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022.
  2. Bousfiha A, Jeddane L, Picard C, et al. Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification. J Clin Immunol 2020; 40:66.
  3. Seidel MG, Kindle G, Gathmann B, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2019; 7:1763.
  4. Hauck F, Voss R, Urban C, Seidel MG. Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders. J Allergy Clin Immunol 2018; 141:59.
  5. Carneiro-Sampaio M, Coutinho A. Early-onset autoimmune disease as a manifestation of primary immunodeficiency. Front Immunol 2015; 6:185.
  6. Farmand S, Baumann U, von Bernuth H, et al. [Interdisciplinary AWMF guideline for the diagnostics of primary immunodeficiency]. Klin Padiatr 2011; 223:378.
  7. Fischer A, Provot J, Jais JP, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol 2017; 140:1388.
  8. Feske S. Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci 2011; 1238:74.
  9. Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014; 123:1989.
  10. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a model of immune dysregulation. Curr Opin Allergy Clin Immunol 2002; 2:481.
  11. Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol 2007; 120:227.
  12. Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun 2005; 25 Suppl:56.
  13. Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood 2014; 124:2337.
  14. Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program 2012; 2012:301.
  15. Buchbinder D, Nugent DJ, Fillipovich AH. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet 2014; 7:55.
  16. Gennery AR. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci 2012; 69:17.
  17. Schubert D, Bode C, Kenefeck R, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014; 20:1410.
  18. Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345:1623.
  19. Toubiana J, Okada S, Hiller J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016; 127:3154.
  20. Olbrich P, Freeman AF. STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol 2018; 14:1029.
  21. Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 2015; 125:591.
  22. Haapaniemi EM, Kaustio M, Rajala HL, et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood 2015; 125:639.
  23. Lopez-Herrera G, Tampella G, Pan-Hammarström Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet 2012; 90:986.
  24. Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 2015; 349:436.
  25. Gámez-Díaz L, August D, Stepensky P, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol 2016; 137:223.
  26. Habibi S, Zaki-Dizaji M, Rafiemanesh H, et al. Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review. J Allergy Clin Immunol Pract 2019; 7:2379.
  27. Tesch VK, Abolhassani H, Shadur B, et al. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol 2020; 145:1452.
  28. Lee PY, Kellner ES, Huang Y, et al. Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol 2020; 145:1664.
  29. Hadjadj J, Aladjidi N, Fernandes H, et al. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Blood 2019; 134:9.
  30. Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 2013; 25:708.
  31. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002; 39:537.
  32. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057.
  33. De Martino L, Capalbo D, Improda N, et al. APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Front Immunol 2013; 4:331.
  34. Ahonen P. Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet 1985; 27:535.
  35. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol 2015; 35:463.
  36. Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 2012; 143:347.
  37. Salzer E, Kansu A, Sic H, et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J Allergy Clin Immunol 2014; 133:1651.
  38. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 2014; 5:162.
  39. Leiding JW, Holland SM. Chronic granulomatous disease. In: GeneReviews, Pagon RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2012.
  40. Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 2008; 112:277.
  41. Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 2011; 117:1522.
  42. Guerrerio AL, Frischmeyer-Guerrerio PA, Lederman HM, Oliva-Hemker M. Recognizing gastrointestinal and hepatic manifestations of primary immunodeficiency diseases. J Pediatr Gastroenterol Nutr 2010; 51:548.
  43. Huppmann AR, Leiding JW, Hsu AP, et al. Pathologic Findings in NEMO Deficiency: A Surgical and Autopsy Survey. Pediatr Dev Pathol 2015; 18:387.
  44. Todoric K, Koontz JB, Mattox D, Tarrant TK. Autoimmunity in immunodeficiency. Curr Allergy Asthma Rep 2013; 13:361.
  45. Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood 2002; 99:2694.
  46. Saifi M, Wysocki CA. Autoimmune Disease in Primary Immunodeficiency: At the Crossroads of Anti-Infective Immunity and Self-Tolerance. Immunol Allergy Clin North Am 2015; 35:731.
  47. Grimbacher B, Warnatz K, Yong PF, et al. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. J Allergy Clin Immunol 2016; 137:3.
  48. Kelsen JR, Sullivan KE. Inflammatory Bowel Disease in Primary Immunodeficiencies. Curr Allergy Asthma Rep 2017; 17:57.
  49. Chirieleison SM, Marsh RA, Kumar P, et al. Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease. J Biol Chem 2017; 292:9666.
  50. Ouahed J, Spencer E, Kotlarz D, et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis 2020; 26:820.
  51. Alkhairy OK, Perez-Becker R, Driessen GJ, et al. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 2015; 136:703.
  52. Ghosh S, Bienemann K, Boztug K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. J Clin Immunol 2014; 34:892.
  53. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency: an update. Arthritis Res Ther 2012; 14:223.
  54. Rensing-Ehl A, Warnatz K, Fuchs S, et al. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. Clin Immunol 2010; 137:357.
  55. Izawa K, Martin E, Soudais C, et al. Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J Exp Med 2017; 214:73.
  56. Abolhassani H, Edwards ES, Ikinciogullari A, et al. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med 2017; 214:91.
  57. Caorsi R, Rusmini M, Volpi S, et al. CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever. Front Immunol 2017; 8:2015.
  58. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 2012; 63:233.
  59. Veillette A, Pérez-Quintero LA, Latour S. X-linked lymphoproliferative syndromes and related autosomal recessive disorders. Curr Opin Allergy Clin Immunol 2013; 13:614.
  60. Salzer E, Daschkey S, Choo S, et al. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica 2013; 98:473.
  61. van Montfrans JM, Hoepelman AI, Otto S, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol 2012; 129:787.
  62. Salzer E, Santos-Valente E, Keller B, et al. Protein Kinase C δ: a Gatekeeper of Immune Homeostasis. J Clin Immunol 2016; 36:631.
  63. Seidel MG, Hirschmugl T, Gamez-Diaz L, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol 2015; 135:1384.
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