- Email: [email protected]
Human Autoantibodies in Urticaria, Angioedema, and Other Atopic Diseases
CHAPTER
Human Autoantibodies in Urticaria, Angioedema, and Other Atopic Diseases
11
Farah Khan1,2 and Christopher Chang1,2 1Department
of Pediatrics, Division of Allergy and Immunology, Alfred I duPont Children’s Hospital/Nemours, Wilmington, Delaware 2Department of Pediatrics, Division of Allergy and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania
Historical notes The official announcement of the discovery of a new immunoglobulin (Ig) called IgE was made in 1968 by the World Health Organization (WHO). This followed almost a decade of work trying to identify the “reagin,” as IgE was initially called, responsible for the Prausnitz-Küstner (PK) test. The PK test is the transfer of a positive skin test from one individual to another first described by Prausnitz and Küstner in 1921. Since then, IgE has redefined allergy as a specialty. It is the basis for the type I hypersensitivity reaction, responsible for the millions of patients who suffer from allergic rhinitis, allergic asthma, food allergy, urticaria, and anaphylaxis, and which may play a role in many other immunologic diseases. In the 21st century, any evaluation of allergy generally includes identification of IgE-specific antibodies to an allergen [2]. The mechanism that drives the biologic effects of IgE involves binding to a receptor on the surface of an effector cell. Subsequent cross-linking leads to degranulation of a variety of mediators including histamine, and it is these mediators that generate the clinical signs and symptoms of type I immediate hypersensitivity diseases. IgE receptors were identified and characterized by the late 1970s by Ishizaka and Teruko.
Structure and function Immunoglobulin (Ig)E is a monomer with four constant regions. As in all Igs, IgE has a four-chain structure as its basic unit. It is composed of two identical heavy (50–70 kD) and two identical light chains (23 kD) held together by interchain disulfide bonds and by noncovalent interactions. Properties of IgE are shown in Table 11.1. The Cε2 constant region is unique to IgE. The Cε3 region is the portion that binds to the IgE receptor (Fig. 11.1). Of recent interest are specific genetic risk factors that lead to IgE dysregulation. Genome-wide association studies (GWAS) have investigated loci that may have a role in IgE synthesis regulation. Among those identified are genes encoding the α chain of the highaffinity receptor for IgE (FcεRIα), STAT 6, and in the gene RAD50/IL-13 cluster [3]. Autoantibodies. http://dx.doi.org/10.1016/B978-0-444-56378-1.00011-3 Copyright © 2014 Elsevier B.V. All rights reserved.
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Table 11.1 Properties of Immunoglobulin E and Its Receptors Property
Value
Molecular weight Serum concentration Percent of total immunoglobulin Glycosylation (by weight) Half-life in days Transport across placenta Receptors Receptors expressed on
200,000 10–400 ng/mL 0.002% 12% 2.3 No FcεRI, FcεRII FceRI – mast cells, basophils, dendritic cells, FceRII – eosinophils None 10.7%
Complement binding Glycosylation
Light Chain
Heavy Chain
Cε3 Binding Site to FCεRI
}
Fab (antigen binding)
Fc (biologic activity mediation)
FIGURE 11.1 Immunoglobulin E is composed of two heavy chains (white) and two light chains (red). The constant region Cε1 resides in the Fab region, while constant regions Cε2, Cε3, and Cε4 form the Fc region.
Immunoglobulin E receptors IgE interacts with high- and low-affinity receptors present on mast cells, basophils, and mononuclear cells. There are three receptors that bind to IgE, the high-affinity IgE receptor (FcεRI), the low-affinity IgE receptor (FcεRII or CD23), and galectin-3.
The high-affinity IgE receptor The high-affinity receptor for IgE is designated FcεRI. The FcεRI consists of an α, a β, and two γ chains (Fig. 11.2). It is the α chain that the IgE binds to with the highest affinity. This receptor is
Immunoglobulin E receptors
IgE
95
= ITAM
α γ γ
β
+P Lyn Syk
Prostaglandin, leukotriene release
PLA2
MAP kinase
PI- PLCγ
PIP2
IP3
DAG
Ca++ ER PKC
+P Myosin light chain protein
FIGURE 11.2 FcεRI structure with α chain, β chain, and two γ chains anchored in the cell membrane. Immunoglobulin (Ig)E antibodies are cross-linked after antigen binding and localize two receptors that induce cellular activation leading to the activation of Lyn and Syk. This leads to the phosphorylation of PLCγ creating phosphatidylinositol-specific phospholipase C (PI-PLCγ). This catalyzes the release of inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol 4,5-bisphosphate (PIP2). Intracellular calcium released from IP3 formation and DAG activate protein kinase C (PKC), which phosphorylates myosin light chain protein and further leads to mast cell degranulation and release of inflammatory mediators. ITAM: immunoreceptor tyrosine-based activation motif; MAP: mitogen-activated protein; PLA2: phospholipase A2.
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anti-IgE IgG IgE anti-FcεRI IgG
FcεRI
Mediator release
FIGURE 11.3 Schematic diagram of mast cell degranulation. Anti-IgE IgG antibodies combine with and cross-link receptor-bound IgE. Anti-FcεRI antibodies combine with and cross-link adjacent FcεRI. Both mechanisms cause the release of inflammatory mediators such as histamine, leukotrienes, cytokines, and chemokines. Modified from Greaves [1].
expressed on mast cells and basophils. After an antigen is recognized and bound by IgE, the complex then binds to FcεRI receptors on the surface. Cross-linking of these receptors leads to activation of signaling pathways, which leads to the release of mediators (Fig. 11.3) [1]. The β and γ chains of the FcεRI are composed of immunoreceptor tyrosine-based activation motifs (ITAMs). The initial phosphorylation step is mediated by the protein tyrosine kinase Lyn. Once the ITAMs are phosphorylated, Syk, also a tyrosine kinase, binds to the ITAMs through two SH2 domains resulting in a conformational change in Syk. This leads to the activation of a mitogen-activated protein (MAP) kinase cascade while also forming phosphatidylinositol-specific phospholipase C (PI-PLCγ) by phosphorylation. PI-PLCγ catalyzes the release of inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol 4,5-bisphosphate (PIP2). IP3 causes the release of intracellular calcium from the endoplasmic reticulum. Calcium and DAG activate protein kinase C (PKC), which phosphorylates myosin light-chain protein. This leads to the fusion of the mast cell granule membrane with the plasma membrane followed by a release of histamine. In addition, MAP kinase activates the enzyme cytosolic phospholipase A2 (PLA2), initiating a sequence of events leading to the synthesis and release of prostaglandins and leukotrienes [4]. The release of cytokines, leukotrienes, and prostaglandins has important biologic functions in the development of allergic reactions including urticaria (Fig. 11.3). The Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 promote further IgE production, leading to a late-phase inflammatory response [5].
The low-affinity IgE receptor A low-affinity receptor, FcεRII (CD23), is expressed on B and T cells as well as other hematopoietic cells. The functions of CD23 include regulation of IgE synthesis, antigen capture and presentation, B-cell growth and differentiation, and activation of monocytes. CD23 has multiple ligands, including
Autoantibodies to immunoglobulin E and its receptors
97
IgE, CD21, CD18/CD11b, CD18/CD11c, and thus mediates multiple immunologic functions. CD23 binds to IgE to regulate its activity, and can have either stimulatory or inhibitory functions. One of the most interesting characteristics of CD23 is that it can bind CD21 and IgE simultaneously because the binding sites are different.
Galectin-3 Galectins can bind to IgE or FcεRI on the surface of mast cells and trigger release of mediators. Galectin-3 is a low-affinity receptor for IgE that exists only in soluble form. It is expressed on eosinophils, neutrophils, mast cells, dendritic cells, macrophages, and T and B cells. Macrophages are a key source of galectin-3. Macrophage activation with the Th2-associated cytokines, IL-4 and IL-13, has been found to increase expression and release of galectin-3. Galectin-3 is a potent activator of mast cells via cross-linking FcεRI. Studies have found that eosinophils from sera from allergic donors have increased galectin-3 levels [6].
Autoantibodies to immunoglobulin E and its receptors Anti-immunoglobulin E autoantibodies Anti-IgE antibodies (a-IgE Ab) can exist as any of the isotypes IgM, IgA, or IgG. The IgM and IgA a-IgE Ab have less physiologic significance as they are of low affinity and restricted specificity [7]. However, IgG a-IgE Ab play a significant role in allergic diseases. High levels have been associated with bronchial asthma, atopic dermatitis (AD), hyper-IgE syndrome, cold and chronic urticaria, as well as autoimmune disorders [8–10]. IgG4 subclass anti-IgE in particular is found in higher concentration than other subclasses in sera of patients with filariasis. IgM a-IgE Ab against human monoclonal myeloma IgE has been found to be elevated in patients with parasitosis [9].
Anti-IgE receptor autoantibodies The most well-known association of anti-IgE receptor autoantibodies is with chronic urticaria, but these antibodies can also be found in a number of other immunologic diseases, including pemphigus vulgaris, systemic lupus erythematosus (SLE), dermatomyositis, and bullous pemphigoid. In chronic urticaria, autoantibodies react with the α-subunit of the FcεRI (FcεRIα). Although antiFcεRIα antibodies are found in the sera of healthy donors, a recent paper suggests that anti-FcεRIα antibodies can become pathogenic in certain individuals. This may be dependent on the state of occupancy of the FcεRIα by IgE. When the FcεRIα is not bound by IgE, the anti-FcεRIα antibodies are free to bind and cause mediator release. Therefore, it may be the imbalance between FcεRIα occupancy and anti-FcεRIα antibodies that results in the pathogenesis of autoimmune urticaria [11]. CD203 is expressed specifically on basophils and mast cells, and is upregulated by cross-linking FcεRIα. It has been found that CD203c expression correlates with basophil histamine release. Sera from patients with chronic urticaria significantly upregulate basophil CD203c expression as measured by flow cytometry. Therefore, CD203c may serve as a useful marker to identify patients with chronic urticaria [12].
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Clinical utility Diagnosis and biomarkers Urticaria Urticaria is defined as pruritic raised, well-circumscribed areas of erythema and edema involving the skin. A key characteristic of urticaria is its evanescence. Urticaria can be acute, lasting less than 6 weeks, or chronic, lasting more than 6 weeks. In many cases of acute urticaria, a cause can be identified, and it is usually found to be a food or medication. In most cases of chronic urticaria, an etiology is elusive, and thus most cases are classified as chronic idiopathic urticaria (CIU). It is becoming more obvious that chronic urticaria may have an autoimmune component. For example, an association between thyroid antibodies and chronic urticaria has been known for some time now, and it is also known that urticaria can be a cutaneous manifestation of autoimmune diseases such as SLE. Other autoantibodies found to be associated with chronic urticaria are the anti-FcεR and anti-IgE antibodies (Table 11.2). The pathogenesis of urticaria involves mast cell activation, with subsequent release of histamine and other vasoactive mediators. The pathway that triggers urticaria is complex, involving mast cell signaling via the tyrosine kinase Syk. Early investigations found evidence that IgG and IgM anti-IgE antibodies are associated with cold urticaria, urticarial vasculitis, and chronic urticaria [8]. Further studies demonstrated the presence of IgG autoantibodies to FcεRI in a subset of patients with chronic urticaria [13]. This autoantibody was not present in normal controls or patients with AD, but can be present in other autoimmune dermatologic diseases including pemphigus vulgaris, bullous pemphigoid, and dermatomyositis [9]. The Chronic Urticaria (CU) Index is available from a few reference laboratories and infers the presence of anti-FcεR by measuring basophil histamine release after incubation with patients’ serum. A positive result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present, but it does help in determining an autoimmune basis of urticaria. A strong association between antithyroid antibodies and chronic urticaria is well established. There have also been many studies that found antithyroid (antithyroglobulin and antiperoxidase) antibodies in euthyroid patients with urticaria. Though the exact mechanism is unknown, several theories have been postulated, including direct action of thyroid antibodies on the immune system as well as indirect recruitment of proinflammatory cells. Measurement of thyroid antibodies should be included in the evaluation of chronic urticaria [14]. Additionally, studies have investigated the role of thyroid autoantibodies in asthma and allergic rhinitis [15].
Table 11.2 Allergic Disease
Associated Autoantibody
Urticaria
Anti-IgE IgG, anti-FcεRI IgG, anti-thyroglobulin antibody, anti-thyroid peroxidase antibody Anti-IgE IgG (Hom s 1-5) Autoantibodies to the C1-INH molecule
Atopic dermatitis Angioedema C1-INH: C1 inhibitor molecule; Ig: immunoglobulin.
Clinical utility
99
Angioedema Acquired angioedema (AAE) is a rare disorder. Patients present clinically with edema of the face, lips, tongue, limbs, genitals, and gastrointestinal mucosa. AAE is classified into two forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). AAE-I is associated with B-cell lymphoproliferative disorders, while AAE-II is characterized by the presence of an autoantibody against the C1 inhibitor molecule (C1-INH). C1-INH is a serine protease inhibitor that is primarily synthesized by hepatocytes. The major functions of C1-INH include inhibition of activated C1r and C1s, activated Hageman factor (XIIa), and activated kallikrein, the protease that cleaves kininogen and releases bradykinin [16]. It is bradykinin that is most involved in producing the symptoms and signs of angioedema, as it is the mediator that acts on bradykinin B2 receptors to increase vascular permeability. Bradykinin B2 receptors are expressed on the membranes of endothelial and smooth muscle cells. In AAE-II, a subpopulation of B cells express autoantibodies to the C1-INH molecule. This autoantibody binds to the reactive center of C1-INH, alters its structure, and diminishes its regulatory capacity. C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native 105-kD molecule to a 95-kD fragment. There is a higher affinity of the autoantibody for native C1-INH. Because of this, the 95-kD antibody/C1-INH complex dissociates, and the antibody is free to bind to another native C1-INH molecule, leading to further depletion of C1-INH. Diagnostic evaluation of AAE involves obtaining levels of C1-INH as well as C4 and C1q. C1q is the first subcomponent of the C1 complex of the classical pathway of complement activation. A recent review article found diminished C1q levels in 56% to 94% of cases with AAE. This is in contrast to those patients with hereditary angioedema (HAE) in which C1q levels are normal [17]. In addition, autoantibodies against C1q (antiC1q autoAbs) have been found in hypocomplementemic urticarial vasculitis syndrome (HUVS). Clinical manifestations of the syndrome include chronic, nonpruritic, urticarial vasculitic lesions. Additional laboratory findings often reveal low C1q, C4, and variably decreased C3 levels. Anti-C1q autoAbs have also been associated with patients who have lupus nephritis and glomerulonephritis [18].
Atopic dermatitis AD is a dermatologic condition that is characterized by pruritus, eczematous lesions, xerosis, and lichenification. AD is frequently associated with other atopic conditions such as asthma and allergic rhinitis. Studies have shown that IgE autoreactivity can occur in AD and can also be associated with disease severity [19]. The autoantigen Hom s 1 has been found to be expressed in the epidermis, and Hom s 2 is the α-chain of the human nascent polypeptide-associated complex (α-NAC), which acts as a transcriptional coactivator to induce lymphoproliferation in patients with AD. Other autoallergens associated with AD include Hom s 3, Hom s 4, and Hom s 5. Hom s 1 and Hom s 3 have also been detected as circulating IgE immune complexes in sensitized patients with AD. IgE-autoallergen complexes can induce allergic reactions by binding to Fcε-receptors. IgE autoreactivity can also be a marker of chronic inflammation. Patients who had IgE autoantibodies measured during exacerbation of allergic diseases tended to have higher levels. The role of IgE and anti-IgE in the pathogenesis of asthma and other allergic diseases has not been elucidated. Autoallergen can cause cross-linking between IgE autoantibodies and lead to the release of inflammatory mediators that contribute to allergic manifestation. Another proposed mechanism is the activation of autoreactive T cells. This can occur as a result of IgE antibody-mediated presentation of
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autoallergens by dendritic cells or monocytes. It has also been proposed that nonimmunologic mechanisms may play a role in pathogenesis [20].
Treatment Prepared anti-immunoglobulin E antibodies as treatment for asthma Asthma is a chronic inflammatory disease of the airways of varying severity. Because there does not appear to be a common mechanism in all cases, treatment can present unique challenges. Omalizumab is an anti-IgE monoclonal antibody used in the treatment of severe asthma. When added to treatment with oral or inhaled corticosteroids, omalizumab reduces symptoms and exacerbations, improves lung function and quality of life, and reduces the need for rescue medications. Anti-IgE acts by binding to the Cε3 region of IgE, thereby decreasing the amount of unbound (free) IgE available for binding to FcεR. The administration of omalizumab has also been demonstrated to reduce FcεRI receptor density indirectly on cells involved in allergic responses [21].
Anti-CD23 antibodies Because the effects of autoantibodies to the low-affinity IgE receptor are so variable, it is difficult to predict the efficacy of a synthetic monoclonal antibody to FcεRII in the treatment of allergic diseases. Lumiliximab is an anti-CD23 monoclonal antibody that is currently under investigation for the treatment of chronic lymphocytic leukemia (CLL). CD23 is highly expressed on the membrane of CLL B cells and targeting this molecule provides a treatment modality that is specific to CLL with the potential to minimize additional toxicity. Recent clinical trials have found that lumiliximab might enhance the effectiveness of fludarabine, cyclophosphamide, and rituximab without exacerbating the toxicity observed with this chemotherapy [22]. At present, there are no known studies investigating the role of lumiliximab in the treatment of urticaria. Prepared antibodies against cytokines that play a role in allergic diseases have been investigated. These include antibodies against IL-5, IL-4, IL-13, tumor necrosis factor (TNF)α, CCR3, CCR4, and OX40L [23].
Conclusions Autoantibodies can sometimes be detected in allergic and inflammatory diseases. The most well-established connection is the presence of autoantibodies to IgE and the IgE high-affinity receptor in chronic autoimmune (idiopathic) urticaria. Antithyroid antibodies have also been associated with chronic urticaria. In addition, autoantibodies to complement components, in particular, C1-INH and C1q, are found in AAE.
Take-home messages • I gG, anti-IgE antibody, and anti-FcεRI IgG antibodies play a significant role in allergic diseases. • AAI-II is characterized by the presence of an autoantibody against C1-INH. • Omalizumab is an anti-IgE monoclonal antibody used in the treatment of moderate to severe asthma.
References
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References [1] Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000;105:664–72. [2] Hamilton RG. Science behind the discovery of IgE. J Allergy Clin Immunol 2005;115:648–52. [3] Granada M, Wilk JB, Tuzova M, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol 2012;129:840–5. [4] Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 2003;15:639–46. [5] Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010;125:S73–80. [6] Platzer B, Ruiter F, van der Mee J, Fiebiger E. Soluble IgE receptors – elements of the IgE network. Immunol Lett 2011;141:36–44. [7] Magnusson CG. Major differences in specificity among naturally occurring human IgG-subclass anti-IgE autoantibodies. J Allergy Clin Immunol 1995;95:1011–9. [8] Gruber BL, Baeza ML, Marchese MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes. J Invest Dermatol 1988;90:213–7. [9] Magnusson CG, Johansson SG. Clinical significance of anti-IgE autoantibodies and immune complexes containing IgE. Clin Rev Allergy 1989;7:73–103. [10] Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465–74. [11] Horn MP, Pachlopnik JM, Vogel M, et al. Conditional autoimmunity mediated by human natural antiFc(epsilon)RIalpha autoantibodies? FASEB J 2001;15:2268–74. [12] Yasnowsky KM, Dreskin SC, Efaw B, et al. Chronic urticaria sera increase basophil CD203c expression. J Allergy Clin Immunol 2006;117:1430–4. [13] Sabroe RA, Fiebiger E, Francis DM, et al. Classification of anti-FcepsilonRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy Clin Immunol 2002;110:492–9. [14] Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96:901–5. [15] Samareh Fekri M, Shokoohi M, Gozashti MH, et al. Association between anti-thyroid peroxidase antibody and asthma in women. Iran J Allergy Asthma Immunol 2012;11:241–5. [16] Caballero T, Baeza ML, Cabanas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations. J Investig Allergol Clin Immunol 2011;21:422–41. [17] Breitbart SI, Bielory L. Acquired angioedema: autoantibody associations and C1q utility as a diagnostic tool. Allergy Asthma Proc 2010;31:428–34. [18] Buck A, Christensen J, McCarty M. Hypocomplementemic urticarial vasculitis syndrome: a case report and literature review. J Clin Aesthet Dermatol 2012;5:36–46. [19] Mittermann I, Aichberger KJ, Bunder R, Mothes N, Renz H, Valenta R. Autoimmunity and atopic dermatitis. Curr Opin Allergy Clin Immunol 2004;4:367–71. [20] Altman K, Chang C. Pathogenic intracellular and autoimmune mechanisms in urticaria and angioedema. Clin Rev Allergy Immunol 2012; in press. [21] Boushey Jr HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001;108:S77–83. [22] Byrd JC, Kipps TJ, Flinn IW, et al. Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010;115:489–95. [23] Catley MC, Coote J, Bari M, Tomlinson KL. Monoclonal antibodies for the treatment of asthma. Pharmacol Ther 2011;132:333–51.
Human Autoantibodies in Urticaria, Angioedema, and Other Atopic Diseases
11
Farah Khan1,2 and Christopher Chang1,2 1Department
of Pediatrics, Division of Allergy and Immunology, Alfred I duPont Children’s Hospital/Nemours, Wilmington, Delaware 2Department of Pediatrics, Division of Allergy and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania
Historical notes The official announcement of the discovery of a new immunoglobulin (Ig) called IgE was made in 1968 by the World Health Organization (WHO). This followed almost a decade of work trying to identify the “reagin,” as IgE was initially called, responsible for the Prausnitz-Küstner (PK) test. The PK test is the transfer of a positive skin test from one individual to another first described by Prausnitz and Küstner in 1921. Since then, IgE has redefined allergy as a specialty. It is the basis for the type I hypersensitivity reaction, responsible for the millions of patients who suffer from allergic rhinitis, allergic asthma, food allergy, urticaria, and anaphylaxis, and which may play a role in many other immunologic diseases. In the 21st century, any evaluation of allergy generally includes identification of IgE-specific antibodies to an allergen [2]. The mechanism that drives the biologic effects of IgE involves binding to a receptor on the surface of an effector cell. Subsequent cross-linking leads to degranulation of a variety of mediators including histamine, and it is these mediators that generate the clinical signs and symptoms of type I immediate hypersensitivity diseases. IgE receptors were identified and characterized by the late 1970s by Ishizaka and Teruko.
Structure and function Immunoglobulin (Ig)E is a monomer with four constant regions. As in all Igs, IgE has a four-chain structure as its basic unit. It is composed of two identical heavy (50–70 kD) and two identical light chains (23 kD) held together by interchain disulfide bonds and by noncovalent interactions. Properties of IgE are shown in Table 11.1. The Cε2 constant region is unique to IgE. The Cε3 region is the portion that binds to the IgE receptor (Fig. 11.1). Of recent interest are specific genetic risk factors that lead to IgE dysregulation. Genome-wide association studies (GWAS) have investigated loci that may have a role in IgE synthesis regulation. Among those identified are genes encoding the α chain of the highaffinity receptor for IgE (FcεRIα), STAT 6, and in the gene RAD50/IL-13 cluster [3]. Autoantibodies. http://dx.doi.org/10.1016/B978-0-444-56378-1.00011-3 Copyright © 2014 Elsevier B.V. All rights reserved.
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Table 11.1 Properties of Immunoglobulin E and Its Receptors Property
Value
Molecular weight Serum concentration Percent of total immunoglobulin Glycosylation (by weight) Half-life in days Transport across placenta Receptors Receptors expressed on
200,000 10–400 ng/mL 0.002% 12% 2.3 No FcεRI, FcεRII FceRI – mast cells, basophils, dendritic cells, FceRII – eosinophils None 10.7%
Complement binding Glycosylation
Light Chain
Heavy Chain
Cε3 Binding Site to FCεRI
}
Fab (antigen binding)
Fc (biologic activity mediation)
FIGURE 11.1 Immunoglobulin E is composed of two heavy chains (white) and two light chains (red). The constant region Cε1 resides in the Fab region, while constant regions Cε2, Cε3, and Cε4 form the Fc region.
Immunoglobulin E receptors IgE interacts with high- and low-affinity receptors present on mast cells, basophils, and mononuclear cells. There are three receptors that bind to IgE, the high-affinity IgE receptor (FcεRI), the low-affinity IgE receptor (FcεRII or CD23), and galectin-3.
The high-affinity IgE receptor The high-affinity receptor for IgE is designated FcεRI. The FcεRI consists of an α, a β, and two γ chains (Fig. 11.2). It is the α chain that the IgE binds to with the highest affinity. This receptor is
Immunoglobulin E receptors
IgE
95
= ITAM
α γ γ
β
+P Lyn Syk
Prostaglandin, leukotriene release
PLA2
MAP kinase
PI- PLCγ
PIP2
IP3
DAG
Ca++ ER PKC
+P Myosin light chain protein
FIGURE 11.2 FcεRI structure with α chain, β chain, and two γ chains anchored in the cell membrane. Immunoglobulin (Ig)E antibodies are cross-linked after antigen binding and localize two receptors that induce cellular activation leading to the activation of Lyn and Syk. This leads to the phosphorylation of PLCγ creating phosphatidylinositol-specific phospholipase C (PI-PLCγ). This catalyzes the release of inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol 4,5-bisphosphate (PIP2). Intracellular calcium released from IP3 formation and DAG activate protein kinase C (PKC), which phosphorylates myosin light chain protein and further leads to mast cell degranulation and release of inflammatory mediators. ITAM: immunoreceptor tyrosine-based activation motif; MAP: mitogen-activated protein; PLA2: phospholipase A2.
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anti-IgE IgG IgE anti-FcεRI IgG
FcεRI
Mediator release
FIGURE 11.3 Schematic diagram of mast cell degranulation. Anti-IgE IgG antibodies combine with and cross-link receptor-bound IgE. Anti-FcεRI antibodies combine with and cross-link adjacent FcεRI. Both mechanisms cause the release of inflammatory mediators such as histamine, leukotrienes, cytokines, and chemokines. Modified from Greaves [1].
expressed on mast cells and basophils. After an antigen is recognized and bound by IgE, the complex then binds to FcεRI receptors on the surface. Cross-linking of these receptors leads to activation of signaling pathways, which leads to the release of mediators (Fig. 11.3) [1]. The β and γ chains of the FcεRI are composed of immunoreceptor tyrosine-based activation motifs (ITAMs). The initial phosphorylation step is mediated by the protein tyrosine kinase Lyn. Once the ITAMs are phosphorylated, Syk, also a tyrosine kinase, binds to the ITAMs through two SH2 domains resulting in a conformational change in Syk. This leads to the activation of a mitogen-activated protein (MAP) kinase cascade while also forming phosphatidylinositol-specific phospholipase C (PI-PLCγ) by phosphorylation. PI-PLCγ catalyzes the release of inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol 4,5-bisphosphate (PIP2). IP3 causes the release of intracellular calcium from the endoplasmic reticulum. Calcium and DAG activate protein kinase C (PKC), which phosphorylates myosin light-chain protein. This leads to the fusion of the mast cell granule membrane with the plasma membrane followed by a release of histamine. In addition, MAP kinase activates the enzyme cytosolic phospholipase A2 (PLA2), initiating a sequence of events leading to the synthesis and release of prostaglandins and leukotrienes [4]. The release of cytokines, leukotrienes, and prostaglandins has important biologic functions in the development of allergic reactions including urticaria (Fig. 11.3). The Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 promote further IgE production, leading to a late-phase inflammatory response [5].
The low-affinity IgE receptor A low-affinity receptor, FcεRII (CD23), is expressed on B and T cells as well as other hematopoietic cells. The functions of CD23 include regulation of IgE synthesis, antigen capture and presentation, B-cell growth and differentiation, and activation of monocytes. CD23 has multiple ligands, including
Autoantibodies to immunoglobulin E and its receptors
97
IgE, CD21, CD18/CD11b, CD18/CD11c, and thus mediates multiple immunologic functions. CD23 binds to IgE to regulate its activity, and can have either stimulatory or inhibitory functions. One of the most interesting characteristics of CD23 is that it can bind CD21 and IgE simultaneously because the binding sites are different.
Galectin-3 Galectins can bind to IgE or FcεRI on the surface of mast cells and trigger release of mediators. Galectin-3 is a low-affinity receptor for IgE that exists only in soluble form. It is expressed on eosinophils, neutrophils, mast cells, dendritic cells, macrophages, and T and B cells. Macrophages are a key source of galectin-3. Macrophage activation with the Th2-associated cytokines, IL-4 and IL-13, has been found to increase expression and release of galectin-3. Galectin-3 is a potent activator of mast cells via cross-linking FcεRI. Studies have found that eosinophils from sera from allergic donors have increased galectin-3 levels [6].
Autoantibodies to immunoglobulin E and its receptors Anti-immunoglobulin E autoantibodies Anti-IgE antibodies (a-IgE Ab) can exist as any of the isotypes IgM, IgA, or IgG. The IgM and IgA a-IgE Ab have less physiologic significance as they are of low affinity and restricted specificity [7]. However, IgG a-IgE Ab play a significant role in allergic diseases. High levels have been associated with bronchial asthma, atopic dermatitis (AD), hyper-IgE syndrome, cold and chronic urticaria, as well as autoimmune disorders [8–10]. IgG4 subclass anti-IgE in particular is found in higher concentration than other subclasses in sera of patients with filariasis. IgM a-IgE Ab against human monoclonal myeloma IgE has been found to be elevated in patients with parasitosis [9].
Anti-IgE receptor autoantibodies The most well-known association of anti-IgE receptor autoantibodies is with chronic urticaria, but these antibodies can also be found in a number of other immunologic diseases, including pemphigus vulgaris, systemic lupus erythematosus (SLE), dermatomyositis, and bullous pemphigoid. In chronic urticaria, autoantibodies react with the α-subunit of the FcεRI (FcεRIα). Although antiFcεRIα antibodies are found in the sera of healthy donors, a recent paper suggests that anti-FcεRIα antibodies can become pathogenic in certain individuals. This may be dependent on the state of occupancy of the FcεRIα by IgE. When the FcεRIα is not bound by IgE, the anti-FcεRIα antibodies are free to bind and cause mediator release. Therefore, it may be the imbalance between FcεRIα occupancy and anti-FcεRIα antibodies that results in the pathogenesis of autoimmune urticaria [11]. CD203 is expressed specifically on basophils and mast cells, and is upregulated by cross-linking FcεRIα. It has been found that CD203c expression correlates with basophil histamine release. Sera from patients with chronic urticaria significantly upregulate basophil CD203c expression as measured by flow cytometry. Therefore, CD203c may serve as a useful marker to identify patients with chronic urticaria [12].
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Clinical utility Diagnosis and biomarkers Urticaria Urticaria is defined as pruritic raised, well-circumscribed areas of erythema and edema involving the skin. A key characteristic of urticaria is its evanescence. Urticaria can be acute, lasting less than 6 weeks, or chronic, lasting more than 6 weeks. In many cases of acute urticaria, a cause can be identified, and it is usually found to be a food or medication. In most cases of chronic urticaria, an etiology is elusive, and thus most cases are classified as chronic idiopathic urticaria (CIU). It is becoming more obvious that chronic urticaria may have an autoimmune component. For example, an association between thyroid antibodies and chronic urticaria has been known for some time now, and it is also known that urticaria can be a cutaneous manifestation of autoimmune diseases such as SLE. Other autoantibodies found to be associated with chronic urticaria are the anti-FcεR and anti-IgE antibodies (Table 11.2). The pathogenesis of urticaria involves mast cell activation, with subsequent release of histamine and other vasoactive mediators. The pathway that triggers urticaria is complex, involving mast cell signaling via the tyrosine kinase Syk. Early investigations found evidence that IgG and IgM anti-IgE antibodies are associated with cold urticaria, urticarial vasculitis, and chronic urticaria [8]. Further studies demonstrated the presence of IgG autoantibodies to FcεRI in a subset of patients with chronic urticaria [13]. This autoantibody was not present in normal controls or patients with AD, but can be present in other autoimmune dermatologic diseases including pemphigus vulgaris, bullous pemphigoid, and dermatomyositis [9]. The Chronic Urticaria (CU) Index is available from a few reference laboratories and infers the presence of anti-FcεR by measuring basophil histamine release after incubation with patients’ serum. A positive result does not indicate which autoantibody (anti-IgE, anti-FcεRI, or anti-FcεRII) is present, but it does help in determining an autoimmune basis of urticaria. A strong association between antithyroid antibodies and chronic urticaria is well established. There have also been many studies that found antithyroid (antithyroglobulin and antiperoxidase) antibodies in euthyroid patients with urticaria. Though the exact mechanism is unknown, several theories have been postulated, including direct action of thyroid antibodies on the immune system as well as indirect recruitment of proinflammatory cells. Measurement of thyroid antibodies should be included in the evaluation of chronic urticaria [14]. Additionally, studies have investigated the role of thyroid autoantibodies in asthma and allergic rhinitis [15].
Table 11.2 Allergic Disease
Associated Autoantibody
Urticaria
Anti-IgE IgG, anti-FcεRI IgG, anti-thyroglobulin antibody, anti-thyroid peroxidase antibody Anti-IgE IgG (Hom s 1-5) Autoantibodies to the C1-INH molecule
Atopic dermatitis Angioedema C1-INH: C1 inhibitor molecule; Ig: immunoglobulin.
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Angioedema Acquired angioedema (AAE) is a rare disorder. Patients present clinically with edema of the face, lips, tongue, limbs, genitals, and gastrointestinal mucosa. AAE is classified into two forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). AAE-I is associated with B-cell lymphoproliferative disorders, while AAE-II is characterized by the presence of an autoantibody against the C1 inhibitor molecule (C1-INH). C1-INH is a serine protease inhibitor that is primarily synthesized by hepatocytes. The major functions of C1-INH include inhibition of activated C1r and C1s, activated Hageman factor (XIIa), and activated kallikrein, the protease that cleaves kininogen and releases bradykinin [16]. It is bradykinin that is most involved in producing the symptoms and signs of angioedema, as it is the mediator that acts on bradykinin B2 receptors to increase vascular permeability. Bradykinin B2 receptors are expressed on the membranes of endothelial and smooth muscle cells. In AAE-II, a subpopulation of B cells express autoantibodies to the C1-INH molecule. This autoantibody binds to the reactive center of C1-INH, alters its structure, and diminishes its regulatory capacity. C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native 105-kD molecule to a 95-kD fragment. There is a higher affinity of the autoantibody for native C1-INH. Because of this, the 95-kD antibody/C1-INH complex dissociates, and the antibody is free to bind to another native C1-INH molecule, leading to further depletion of C1-INH. Diagnostic evaluation of AAE involves obtaining levels of C1-INH as well as C4 and C1q. C1q is the first subcomponent of the C1 complex of the classical pathway of complement activation. A recent review article found diminished C1q levels in 56% to 94% of cases with AAE. This is in contrast to those patients with hereditary angioedema (HAE) in which C1q levels are normal [17]. In addition, autoantibodies against C1q (antiC1q autoAbs) have been found in hypocomplementemic urticarial vasculitis syndrome (HUVS). Clinical manifestations of the syndrome include chronic, nonpruritic, urticarial vasculitic lesions. Additional laboratory findings often reveal low C1q, C4, and variably decreased C3 levels. Anti-C1q autoAbs have also been associated with patients who have lupus nephritis and glomerulonephritis [18].
Atopic dermatitis AD is a dermatologic condition that is characterized by pruritus, eczematous lesions, xerosis, and lichenification. AD is frequently associated with other atopic conditions such as asthma and allergic rhinitis. Studies have shown that IgE autoreactivity can occur in AD and can also be associated with disease severity [19]. The autoantigen Hom s 1 has been found to be expressed in the epidermis, and Hom s 2 is the α-chain of the human nascent polypeptide-associated complex (α-NAC), which acts as a transcriptional coactivator to induce lymphoproliferation in patients with AD. Other autoallergens associated with AD include Hom s 3, Hom s 4, and Hom s 5. Hom s 1 and Hom s 3 have also been detected as circulating IgE immune complexes in sensitized patients with AD. IgE-autoallergen complexes can induce allergic reactions by binding to Fcε-receptors. IgE autoreactivity can also be a marker of chronic inflammation. Patients who had IgE autoantibodies measured during exacerbation of allergic diseases tended to have higher levels. The role of IgE and anti-IgE in the pathogenesis of asthma and other allergic diseases has not been elucidated. Autoallergen can cause cross-linking between IgE autoantibodies and lead to the release of inflammatory mediators that contribute to allergic manifestation. Another proposed mechanism is the activation of autoreactive T cells. This can occur as a result of IgE antibody-mediated presentation of
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autoallergens by dendritic cells or monocytes. It has also been proposed that nonimmunologic mechanisms may play a role in pathogenesis [20].
Treatment Prepared anti-immunoglobulin E antibodies as treatment for asthma Asthma is a chronic inflammatory disease of the airways of varying severity. Because there does not appear to be a common mechanism in all cases, treatment can present unique challenges. Omalizumab is an anti-IgE monoclonal antibody used in the treatment of severe asthma. When added to treatment with oral or inhaled corticosteroids, omalizumab reduces symptoms and exacerbations, improves lung function and quality of life, and reduces the need for rescue medications. Anti-IgE acts by binding to the Cε3 region of IgE, thereby decreasing the amount of unbound (free) IgE available for binding to FcεR. The administration of omalizumab has also been demonstrated to reduce FcεRI receptor density indirectly on cells involved in allergic responses [21].
Anti-CD23 antibodies Because the effects of autoantibodies to the low-affinity IgE receptor are so variable, it is difficult to predict the efficacy of a synthetic monoclonal antibody to FcεRII in the treatment of allergic diseases. Lumiliximab is an anti-CD23 monoclonal antibody that is currently under investigation for the treatment of chronic lymphocytic leukemia (CLL). CD23 is highly expressed on the membrane of CLL B cells and targeting this molecule provides a treatment modality that is specific to CLL with the potential to minimize additional toxicity. Recent clinical trials have found that lumiliximab might enhance the effectiveness of fludarabine, cyclophosphamide, and rituximab without exacerbating the toxicity observed with this chemotherapy [22]. At present, there are no known studies investigating the role of lumiliximab in the treatment of urticaria. Prepared antibodies against cytokines that play a role in allergic diseases have been investigated. These include antibodies against IL-5, IL-4, IL-13, tumor necrosis factor (TNF)α, CCR3, CCR4, and OX40L [23].
Conclusions Autoantibodies can sometimes be detected in allergic and inflammatory diseases. The most well-established connection is the presence of autoantibodies to IgE and the IgE high-affinity receptor in chronic autoimmune (idiopathic) urticaria. Antithyroid antibodies have also been associated with chronic urticaria. In addition, autoantibodies to complement components, in particular, C1-INH and C1q, are found in AAE.
Take-home messages • I gG, anti-IgE antibody, and anti-FcεRI IgG antibodies play a significant role in allergic diseases. • AAI-II is characterized by the presence of an autoantibody against C1-INH. • Omalizumab is an anti-IgE monoclonal antibody used in the treatment of moderate to severe asthma.
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