When presented with the term “primary immune deficiencies,” the concept that probably first comes to mind is that these are disorders that cause increased susceptibility to severe and recurrent infections; although this is certainly true for many primary immune deficiencies (PIDs), we now know that there is much more about them than just that.
The past decade, in particular, has witnessed a rapidly expanding spectrum of clinical presentations in patients with defects in known and newly described genes involved in the proper function and regulation of the immune system. This is partly due to the constant improvement of genetic techniques (eg, next-generation sequencing, whole exome and whole genome sequencing) and better understanding of the pathophysiological mechanisms of these diseases.
PIDs are also referred to as inborn errors of immunity to reflect the fact that they are genetic in nature and to distinguish them from secondary immune defects, such as those caused by infections (eg, HIV), severe malnutrition, chemotherapy, and severe burns.
The most recent report from the International Union of Immunological Societies, published in 2018, lists 354 PIDs,1 which is more than double the number described in the same report from 2007.2
Figure 1 illustrates the large and growing diversity of primary immune deficiencies. There are three main categories under the umbrella term “primary immune deficiencies” that describe the different presentations. These are “lack of function,” “inappropriate surveillance and clearance,” and “inadequate control: immune dysregulation,” and also include the disorders that would fall somewhere in between them.
Spectrum of primary immune defects. The bidirectional arrow represents the spectrum of primary immune defects. CID, combined immune deficiency; IBD, inflammatory bowel disease; ILD, interstitial lung disease; SCID, severe combined immune deficiency.
Lack of Function
This category includes disorders that are considered the classic PIDs, which predispose patients to severe, recurrent, and unusual infections. The most severe form of these disorders is severe combined immune deficiency (SCID), followed by combined immune deficiencies (CID), humoral or antibody defects, and innate immunity defects. It is estimated that the prevalence of PIDs is 1 in 2,000 live births,3 which is more common than previously thought.
Severe Combined Immunodeficiency
SCID is a syndrome caused by defects in at least 18 genes.1 The products of these genes are essential for the development and proper function of both T and B cells, although natural killer (NK) cells may also be affected.
The classic manifestations of SCID are severe, recurrent, and opportunistic infections, chronic diarrhea, failure to thrive, and absence of thymic shadow on chest radiograph. SCID is considered a pediatric medical emergency, and if left untreated it can be fatal within the first year of life.
As of December 2018, all 50 states, the District of Columbia, Puerto Rico, and the Navajo Nation are currently screening for SCID in all newborns.4 In addition, Norway, Israel, Taiwan, and some provinces in Canada and Spain have also implemented newborn screening for SCID.4 Identifying most types of SCID through newborn screening allows for prompt isolation and treatment of these patients, which is thought to improve survival and overall prognosis once the definitive treatment is established.
Combined Immune Deficiencies
CIDs represent a heterogeneous group of disorders with variable functional abnormalities in T and B cells but that do not necessarily lead to the patient's death within the first year of life (as occurs in patients with SCID). Patient with CID may also present with severe infections at any point between the first 2 years of life and adulthood. Each particular cause of CID will also exhibit associated findings that characterize the disease.
Approximately 40 gene defects have been identified as causing CID.1 Importantly, CID may also arise from partial defects in genes that would otherwise cause SCID if they were complete or fully penetrant.
Relevant examples for the general pediatrician in this group include 22q11.2 deletion syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia, and hyper-immunoglobulin M (IgM) syndromes.
CIDs usually have characteristic clinical and laboratory findings that help in diagnosing this particular condition. 22q11.2 deletion syndrome shows characteristic facial dysmorphisms and cardiac abnormalities; Wiskott-Aldrich syndrome is known for the triad of thrombocytopenia, eczema, and immune deficiency; ataxia telangiectasia patients develop progressive neurologic abnormalities and oculocutaneous telangiectasias; and the hyper-IgM syndromes display absence of serum immunoglobulins (except for IgM) and specific antibody titers.3
Disorders with impaired antibody production are the most common type of all PIDs, accounting for more than one-half of all cases.5
Antibody deficiencies, also known as humoral immunodeficiencies, usually present with recurrent upper and lower respiratory tract bacterial infections, although these patients can also have specific susceptibility to certain viruses (enterovirus, rhinovirus) and protozoa (Giardia).6
X-linked and autosomal recessive forms of agammaglobulinemia (or absent production of antibodies), hypogammaglobulinemia (or low immunoglobulins), specific antibody deficiencies, and common variable immune deficiency (CVID) are the main examples.
CVID is defined as low IgG and/or low IgA or IgM, as well as abnormal production of specific antibodies. For most patients with CVID, the exact genetic cause is unknown; however, the list of genetic defects leading to CVID is at least 18, and the number will most likely continue to grow.1
Innate Immunity Defects
The innate components and mechanisms of the immune system represent the first line of defense against “danger signals,” mostly from microbes but also from the host. A functional innate immune system is not only important for the clearance of pathogenic microorganisms but also for the activation of the adaptive immune system (cellular and humoral branches) and for restoring homeostasis.
The list of components of innate immunity is long and includes the physical barriers of the body (eg, skin, mucous membrane surfaces), soluble factors in the plasma (eg, complement system, acute phase reactants, lectins), cells (phagocytes, NK cells, and innate lymphoid cells), and a growing list of membrane-bound and soluble innate receptors such as Toll-like receptors (TLRs), NOD-like receptors, RIG-I-like receptors, C-type lectin receptors, and cytosolic DNA receptors.7
The complement system is a group of plasma proteins that, when activated by a pathogen or pathogen-bound antibody, generate a cascade of reactions that lead to activation of inflammation, opsonization (ie, marking for phagocytosis), and lysis of the infectious organisms. There are three complement pathways: classical, alternative, and lectin. Patients with defects in the terminal components of the classical pathway (C5–C9), and also with abnormalities in the alternative and lectin pathways, can present with severe pyogenic infections, with special susceptibility to meningococcal infections. Complement deficiencies represent only 1% to 6% of all PIDs.8
Phagocytic defects are a relevant group within the innate defects. There are disorders with abnormal production (ie, congenital neutropenias), impaired chemotaxis and transendothelial passage to the site of infection (leukocyte adhesion deficiencies), and impaired killing of the infective microorganism, either from impaired phagocytosis (eg, Chédiak-Higashi syndrome) or abnormal oxidative burst or reactive oxygen species production from a dysfunctional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme (ie, chronic granulomatous disease [CGD]). These defects are characterized by increased susceptibility to bacterial and fungal infections but normal resistance to viral infections.9
NK cells are innate lymphocytes that are critical not only in the defense against viral-infected cells, but in tumor surveillance as well. Patients with NK cell deficiencies suffer from severe, recurrent, or atypical infections with herpes viruses.10
From the group of innate receptors, the most studied are the TLRs. TLRs are cell surface and intracellular receptors that sense and react to microbial antigens. Specific TLR signaling pathway defects have been described. For example, TLR-3 signaling pathway defects (TLR3 mutations, UNC93b deficiency, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency) can cause increased susceptibility for herpes simplex virus type 1 encephalitis.11
Inappropriate Surveillance and Clearance
On the opposite side of the spectrum we can place disorders that develop when the mechanisms of immune surveillance fail to identify autoreactive or abnormally transformed cells, leading to autoimmunity and malignancy, respectively.
Despite the apparent paradoxical coexistence of immune deficiency and autoimmunity, autoimmunity is in fact the second most common presentation of PIDs.12
A recent study with more than 2,000 patients with PIDs found that almost one-third of these patients had one or more autoimmune manifestations.13 The most common, by far, are autoimmune cytopenias, followed by inflammatory bowel disease and rheumatoid arthritis. Moreover, the study showed that all the different types of PIDs cause an increased risk of autoimmunity, particularly in those patients with T-cell defects, innate immunity defects, and CVID. In addition, autoimmunity can develop at any age and at any stage in the course of the PID.13
A classic autoimmune disorder, systemic lupus erythematosus, is associated with deficiencies in early components of the classical pathway of complement (ie, C1q, C1r/s, C2, C4), CGD, antibody deficiencies, and some combined immune deficiencies such as Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome (ALPS), and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).12
APECED is a great example of inappropriate surveillance leading to autoimmunity, as the genetic defect of this syndrome (mutations in the AIRE gene) causes an inability to eliminate autoreactive T cells during their development in the thymus, a process that is called central T-cell tolerance. Patients with APECED have chronic mucocutaneous candidiasis and endocrinological autoimmunity (ie, hypoparathyroidism, adrenal insufficiency, and primary ovarian failure).14
A second illustrative example is ALPS, which results from defective lymphocyte apoptosis leading to lymphoproliferation and autoimmunity, mainly in the form of cytopenias, but also to autoimmune glomerulonephritis, hepatitis, uveitis, and iridocyclitis.15
An important message is that PIDs should be considered in all patients with early-onset manifestations of autoimmunity. In some, autoimmunity may be the first sign of disease.
Although autoimmunity is the second most common manifestation of PIDs, malignancy is the second most common cause of death in these patients, after infections. Hematological malignancies (eg, lymphomas) are the most common type of cancer seen. In some cases, it may be the presenting manifestation of the immune defect.16
Patients with all types of primary immune deficiencies are at a higher risk of malignancy when compared to the general population, but there are some of these disorders with an even higher incidence, particularly ataxia telangiectasia, CVID, Wiskott-Aldrich syndrome, and SCID.17
Abnormal lymphoproliferation is another manifestation of primary immune deficiencies. There is a growing list of disorders with recognized increased susceptibility to Epstein-Barr virus (EBV)-driven lymphoproliferation leading to malignancies.18 Relevant examples are X-linked lymphoproliferative disease type 1 (XLP1) ataxia telangiectasia, X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease, interleukin-2-inducible T-cell kinase (ITK) deficiency, and Wiskott-Aldrich syndrome.
Inadequate Control: Immune Dysregulation
Our immune system is equipped with multiple mechanisms for self-control and regulation. When those mechanisms fail, disorders of immune dysregulation may arise.
Hallmark examples of primary immune deficiencies in which immune dysregulation is the main manifestation include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and defects in the interleukin (IL)-10 pathway (ie, IL-10 deficiency, IL-10RA, and IL-10RB deficiencies). IPEX is characterized by absent or abnormal regulatory T cells (Tregs). Tregs and IL-10 represent two crucial mechanisms of immune modulation or control.
Tregs are essential for peripheral (extra-thymic) tolerance or the suppression of abnormal and autoreactive T- and B- cell clones. Thus, Treg dysfunction can result in uncontrolled inflammation and autoimmunity. In IPEX syndrome, inflammation is manifested mainly as severe enteropathy and dermatitis with the autoimmune component being that of targeting endocrine glands, leading to early-onset diabetes and/or thyroiditis.19
IL-10 is one of the main immunomodulatory cytokines. Thus, in either the absence of this cytokine or its receptors, uncontrolled inflammation can occur. Similarly to IPEX syndrome, inflammation targets mainly the gut, but also the skin and joints.20
Beyond these well-identified primary immune deficiencies and within this broad category of inadequate immune control, we can also find other systemic diseases in which inflammation (uncontrolled, cytokine-induced, or allergic) is at the core of the pathogenesis.
Inflammatory bowel diseases. Classical inflammatory bowel disease (IBD) is comprised mainly of Crohn's disease and ulcerative colitis. The exact pathogenesis is still being understood; however, it is now clear that genetically determined factors contribute to the susceptibility for IBD. More than 200 loci have been identified, with most of these being part of the innate and adaptive immunity pathways.21 When IBD presents in children younger than age 6 years it is referred to as very early onset IBD, and the distinction is important as more and more monogenic primary immune deficiencies are being identified as the cause.22
Interstitial lung disease. Interstitial lung disease (ILD), also referred to as diffuse lung disease, is a heterogeneous group of disorders that involve the pulmonary parenchyma affecting normal gas exchange. In infancy, many of the known types of ILD are secondary to developmental disorders of the lung and surfactant production. However, monogenic PIDs leading to uncontrolled inflammation and dysregulated immune responses have also been identified as important causes. Examples of this include mutations in STAT3, LRBA, CTL4, TMEM173, and COPA genes. CGD and CVID are also primary immune deficiencies that can lead to development of ILD.23
Similar examples of diseases in which a dysregulated immune system leads to uncontrolled inflammation can be found in other systems (eg, central nervous system, kidney, and musculoskeletal), and those too should be considered primary immune deficiencies if a secondary cause, such as infection or environmental exposure, is not found.
Autoinflammatory diseases are those in which the inflammatory manifestations are not driven by autoantibodies or autoreactive immune cells (ie, autoimmunity), but rather by abnormally enhanced and dysregulated inflammatory signals of innate immunity. As such, they have been classified into inflammasomopathies (eg, familial Mediterranean fever, cryopyrin-associated periodic syndrome), protein folding disorders (eg, tumor necrosis factor receptor-associated periodic syndrome), nuclear factor-kappa beta activation disorders (eg, Blau syndrome), interferenopathies (eg, proteasome-associated autoinflamatory syndrome), other cytokine-signaling disorders (eg, deficiency of IL-36 receptor antagonist), and complementopathies (eg, atypical hemolytic uremic syndromes).24
Autoinflammatory diseases present mainly in childhood with inflammatory signs and symptoms such as periodic fevers, rash, serositis, arthritis, meningitis, and uveitis. Inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate are elevated during disease flares.
Allergic inflammation manifested by atopic diseases (eg, atopic dermatitis, allergic rhinitis, asthma, and food allergies) is another form of dysregulation of the immune system, leading it to react abnormally to stimuli (eg, foods, environment) that should otherwise not be harmful.
Allergic diseases are an important expression of dysregulated immunity, and certain PIDs are frequently associated with severe atopy. A few examples include the autosomal dominant and autosomal recessive forms of hyper-IgE syndrome (ie, STAT3 and DOCK8 deficiencies, respectively), IPEX syndrome, Wiskott-Aldrich syndrome, and some subtypes of CVID.25
Crossover Within the Spectrum
It is important to note that the categories presented Figure 1 are not mutually exclusive and that many PIDs will crossover in different directions within the gamut of manifestations.
An example of that would be CGD, a phagocytic disorder discussed earlier. Inheritance of chronic granulomatous disease is X-linked in up 70% of cases and autosomal recessive in the remainder. Patients with X-linked CGD usually present at a younger age with serious bacterial and fungal infections that are due to the lack of function of the neutrophil oxidative burst, whereas cases that are autosomal recessive can present later in life with manifestations that would fall into the “inadequate control/immune dysregulation” category such as IBD or ILD, but also from the “inappropriate surveillance and clearance” category, with some patients having SLE, immune thrombocytopenia, and juvenile idiopathic arthritis.26
Age of Presentation
Even though the vast majority of PIDs have their onset in childhood and adolescence, these conditions are not exclusive to these populations, and many PIDs make their debut in adulthood.
Antibody deficiencies, particularly some forms of CVID, may not present until adulthood. Other PIDs that may have adult-onset are usually associated with hypomorphic or compound heterozygous mutations in genes, such as those present in hyper-IgE syndrome, partial adenosine deaminase deficiency, autoimmune lymphoproliferative syndrome, and cartilage-hair-hypoplasia, to name a few.27
With the growing discovery of genes and the better understanding of the pathophysiological mechanisms through which defects in these genes cause disease, there has been a paradigm shift in our classical view and understanding of primary immune deficiencies; from rare diseases that mainly predispose to severe or recurrent infections, to the current inclusion of more frequent than expected disorders that can also manifest with autoimmunity, malignancy, and immune dysregulation in the form of exaggerated or uncontrolled inflammation, autoinflammation, allergy, atopy, granulomatosis, and lymphoproliferation.
The vast majority of these disorders will have their debut in childhood and adolescence; hence, it is of paramount importance that general pediatricians be aware and suspicious of primary immune deficiencies when a patient presents with any combination of the described manifestations, particularly those with early onset.
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