Autoimmune Responses in Severe Asthma

Antibodies against beta-2-adrenergic receptors

As early as 1980, circulating autoantibodies against beta-2-adrenergic receptors were reported.13 These autoantibodies indeed correlated with abnormal autonomic responsiveness characterized by alpha-adrenergic and cholinergic hypersensitivity and beta-adrenergic hyposensitivity.14 By 1982, the group confirmed that the circulating immunoglobulins (Igs) inhibited the specific binding of ¹²⁵iodine-labelled hydroxybenzylpindolol to beta-receptors on mammalian lung membrane. By 1991, Wallukat and Wollenberger15 demonstrated that the inhibitory effect of the gamma-globulin serum fraction on the positive chronotropic response of cultured neonatal rat heart myocytes to 2 µmol/L of clenbuterol was pronounced in severe asthmatics (83%) compared to moderate (58%) and mild patients (23%). The group also confirmed the previous observations that the autoantibodies were of the IgG isotype. Though this brought about the first working concept of autoimmunity in context to bronchial asthma, the clinical relevance was doubtful since the incidences of these autoantibodies were low16 and unremarkable between the asthmatics (4/17) and normal healthy controls (3/19).17

Antibodies against common endothelial/platelet antigens

Circulating IgGs against 55 kDa antigens (platelet/endothelial in origin) were detected in 34/97 asthmatics, with corresponding T/B cell reactivity confirmed in vitro. The autoantibodies were mostly restricted to asthmatics who were non-allergic, i.e., skin-prick test negative (P=0.001) and who were maintained on oral corticosteroids (P=0.004).18

Antibodies against bronchial epithelial cells

In the following years, circulating IgG autoantibodies to cytokeratin 18 were more frequently detected in patients with non-atopic asthma compared to those with atopic asthma or healthy controls.19, 20, 116 IgG autoantibodies to alpha enolase were more frequently detected in patients with severe asthma compared with those with mild-to-moderate asthma or healthy controls.20 The subclass was confirmed to be predominantly IgG,1 indicating a possible complement-mediated cytotoxicity.21 Though the cytotoxicity of the detected IgGs against the bronchial antigens were confirmed in vitro, involvement of the complement cascade was not determined.22 Although a clinical correlation was reported with a decline in lung function, the use of immortalised cell-lines (A549 and BEAS-2B) might have restricted the translational merit of these studies.

Antibodies against extracellular matrix protein and cellular junctions

Collagen V, an extracellular matrix protein, was demonstrated to be a self-antigen in asthma, where the isotype of autoantibodies detected was predominantly IgG. At 1:200 titer, the levels correlated with severe asthma (P<0.01) and corticosteroid use (P=0.03). In addition, the study also showed circulating antibodies reactive to other epithelial proteins such as epidermal group factor receptor (EGFr), activin A type 1 receptor and alpha-catenin.23 A major limitation of the study was the lack of mechanistic data or any follow-up on the pathogenesis of the detected autoantibodies.

More recently, in a French cohort study (Cohorte Obstruction Bronchique et Asthme [COBRA]), periplakin (PPL), a component of desmosomes involved in epithelial cohesion, intracellular signal transduction and antigen presentation, was proposed to be a target for autoimmunity in asthma. Based on a 195 kDA band on Western blot analysis, 47 patients out of 260 (18%) were concluded to have anti-PPL IgG reactivity and 12/138 (8.7%) with anti-PPL IgE reactivity. The IgG autoantibodies were present irrespective of the disease severity, while the latter was prevalent more in patients with nasal polyps.24 The data did not provide means to determine any causal relationship with asthma pathogenesis, but an earlier study showed anti-PPL autoantibodies to inhibit epithelial repair in vitro.25

Antinuclear antibodies (ANAs)

Using Hep-2 cells as substrate, ANAs were determined by immunofluorescence (IIF) staining. ANAs were assessed to be prevalent at serum titers of 1:40 or above, in 55% of the asthmatics with aspirin-sensitivity, 41% with intrinsic asthma, and 39% extrinsic asthma compared to 11% in healthy controls.26 Another study showed 21 out of 95 (22%) asthmatics with demonstrable bronchodilator reversibility had circulating ANAs (mean titer of 48), confirmed by Hep-2 IIF and enzyme-linked immunosorbent assay (ELISA). However, another study reported that clinically significant high ANA titers ≥1:160 was detected in 10% of patients with asthma but there was no significant association between ANA positivity and clinical indices of asthma severity.27 There were conflicting reports of clinical signs of ANAs between these studies. While signs of autoimmune manifestations such as rheumatic symptoms, cold sensitivity and Raynaud's phenomenon were reported in patients with low titer 1:40,26 while the study with patients with higher ANA titers (>1:100) reported otherwise.28 The latter study, however, showed that ANAs were predictors of asthma exacerbations, mortality and decrease in lung function. In contrast, the study by Tamai and co-workers27 reported no correlation with clinical indices of severe asthma in patients who showed ANAs at clinically relevant titers of 1:160.

Taken together, evidence over the past few decades suggest that an association between asthma and circulating autoantibodies against antigens derived from diverse tissues, in addition to the classic nuclear antigens (Table 1). The disparities in the clinical significances reported in the different studies question the contribution of these autoimmune markers to disease severity and therefore, the pathological relevance of these circulating autoantibodies. However, there are 3 striking features that are common to these observations. First, all reported autoantibodies were predominantly of the IgG subclass. Secondly, the incidence of autoantibodies though variable between the studies, was significantly higher in non-atopic patients with noted severity (reported either as annual exacerbations requiring hospitalisation, or dependence on oral corticosteroid). Therefore, though autoantibodies of IgE subclass have been suggested at driving atopic asthma, it will not be the focus henceforth, and has been extensively reviewed elsewhere.12 Thirdly, reported prevalence (percentage of seropositive patients) of circulating autoantibodies within the study cohorts showed a decline with sophistication of immunoassay techniques (improved specificity).

Introduction to immunological theories

Before constructing a working hypothesis, it is pertinent that we review the concepts of immunology with context to autoimmunity. The concept of ‘self/non-self’ when introduced by MacFarlene Burnet in 1949, was neither a theory nor a metaphor, but an analogy for descriptive host-defence that failed to explain the phenomenon of autoimmunity. This remained true even for Charles Janeway's ‘Infectious non-self model’ (1989) that introduced the concept of antigen presenting cells (APCs) recognising evolutionarily conserved consensus patterns on infectious agents termed pathogen-associated molecular patterns (PAMPs) to be triggers for an immune response. ‘Autoimmunity’ is defined as an anomaly within the body's immune response where the immune cells generate antibodies that attack self, leading to injury, falls outside the realm of both theories. A fresh perspective was offered by Matzinger's ‘Danger model’ around early 2000s,39, 40 based on Paul Ehrlich's forethought on ‘horror autotoxicus.’41 Autoimmune responses were described to stem from deficiencies in normal physiological processes and specific tissue response to danger-associated molecular patterns (DAMPs) released as a result of inflammation, continual tissue-injury and impaired repair.

As discussed in previous section, the disparity in the reported studies with questionable causal relationship between the detected circulating autoantibodies and the clinical indices of asthma severity may be resolved by implicating the concept of tissue-specific response to danger signals.42 Indeed, in an interview, Dr. Matzinger43 hints that underlying immunology of asthma and allergy could be explained by the Danger model if one considers tissue-specific response compartmentalized in the lungs.

Studies supporting localized lung autoimmunity: evidence from other diseases

Breach of immune tolerance in the lungs is not uncommon. Chronic ‘unresolved’ inflammation is considered an acute trigger for inducible bronchus associated lymphoid tissue (iBALT) formation,44 which are essentially ectopic clusters of B cells in different stages of differentiation sparsed with T cells, and APCs like macrophages/dendritic cells (DCs), capable of de novo antibody production on local stimuli and antigen exposure.45 Additionally, iBALTs have been shown to be centres for localized autoantibody production in organ-specific specific autoimmune disorders like Sjogren's disease46 and RA47, 48 presenting with pulmonary complications. Of particular interest is a recent study where anticyclic citrullinated peptide.3 antibody (anti-CCP3), a diagnostic marker for RA, was detected in the induced sputum of at-risk seronegative patients, in addition to those with seropositive ‘early’ and ‘active’ disease.49 In fact, in RA there is growing interest in proposing breach in lung mucosal immunology to be the seat of autoimmune development.50 With regard to the respiratory tract, IgG autoantibodies against several self-antigens (such as dsDNA and thyroid peroxidase [TPO]) were detected in the nasal polyp tissues, extracted from 44 patients with chronic rhinosinusitis (CRS), out of which 24 had concurrent asthma.51 Ectopic lymphoid clusters triggered by cigarette smoke and chronic inflammation have been observed in lung tissue specimens from patients with chronic obstructive pulmonary disorder (COPD). ANAs were present in the induced sputum from COPD patients, otherwise absent in the serum.52 However, we need to exercise caution with the interpretation of the human data, since the sputum ANAs reported were detected using a horse radish peroxidase-based ELISA platform, which might not be ideally suited for sputum samples.53 Nevertheless, the possible presence of luminal ANAs in COPD patients' refractory to steroid treatment further highlights the importance of identifying tissue-specific autoimmune mechanisms latent in obstructed airways.

Evidence of localized autoimmune responses in asthmatic lungs

Two recent studies suggest the possibility of a localized autoimmune phenomenon in an asthmatic lung with persistent eosinophils, despite maintenance oral steroid therapy. First, ‘asthmatic granulomatosis’ based on the immunohistological evidence of cellular aggregates or ‘granulomas’ in the lung parenchyma of prednisone-dependent severe asthmatics was described in 2012 by Wenzel and colleagues.54 Though the study did not include autoantibody detection, the steroid-sparing response to drugs like methotrexate and azathioprine, classically prescribed for autoimmune diseases, provided evidence of a possible autoimmune-type anomaly.54 More direct evidence was reported recently. Antieosinophil peroxidase (EPX) IgGs were reported in the sputa (and not sera) of 24/65 of eosinophilic asthmatics (37%), levels of which correlated positively with the sputum ANAs (detectable in 25/56 asthmatics).55 Similar to some aforementioned studies in section 3 (Table 1), there were diverse IIF patterns observed ranging from speckled to homogenous. Further similarity can be drawn from the fact that only 4/15 severe asthmatics had circulating ANAs and was comparable to be the healthy controls (3/15). It is to be noted that this data was collected from 15 severe eosinophilic asthmatics who had high titers of sputum autoantibodies (both ANA and anti-EPX IgG). Taken together, the authors suggest the presence of a polyclonal autoimmune event localized to the airways.55 More importantly, the airway autoantibodies were pathogenic to naïve eosinophils triggering degranulation in vitro, which in turn significantly correlated with the clinical indices of airway eosinophil activity (EPX and free eosinophil granules)56 documented clinically. Both free eosinophil granules and EPX are significantly pathogenic57 and are indicative of ‘active’ disease.56 The study was limited in terms of determining the mechanism/source of in situ autoantibody generation in the lungs, though an increased B cell activity was evident in patients with the sputum autoantibodies.55 Intriguingly, patients who were determined to have ‘asthmatic granulomatosis’ (‘granulomas’ consisting of eosinophils and plasmacytoid lymphocytes in lung biopsies) had similar clinical characteristics to the autoantibody-positive subset described by Mukherjee et al.,55 with adult-onset asthma, persistent eosinophilia despite prednisone use, unremarkable total serum IgE and sinus disease.54 The presence of such ‘granulomas’ or even ectopic lymphoid structures with higher organisation iBALT enclosing follicular T cells, APCs and B cells at different stages of development, in patients with sputum autoantibodies is justifiable. The presence of such structured clusters will support local production of autoantibodies as detectable in the induced sputum.

Chronic Inflammation and tissue injury in asthmatic airways

Persistent airway inflammation is pivotal to the pathophysiology of asthma. Epithelial damage from airway inflammation may result in exposure of self-antigens or their determinants resulting in immune response which may contribute to disease pathology. There is evidence of autoantibodies against epithelial antigens such as cytokeratin and PPL (Table 1) that are further equipped to cause cellular damage.19 Epithelial and parenchymal damage may result directly due to environmental/extraneous insults, infection or by cytotoxicity induced by granule proteins released by degranulation of innate cells such as eosinophils, mast cells, neutrophils, etc., (recruited to the lungs in response to inflammatory stimuli). Increased frequency of immune cell degranulation over time leads to peroxidase release that has known immunogenic properties.58 Myeloperoxidase and TPO are known autoantigens, antibodies (IgGs) against which have established pathomechanism in autoimmune diseases such as eosinophilic granulomatosis and polyangiitis (eGPA)59 and Hashimoto's thyroiditis,60 respectively. Intranasal IgGs against TPO was detected in nasal polyp extracts from patients with CRS.51 Pathogenic antibodies against EPX have recently been described in a small subset of eosinophilic asthmatics with increased frequency of eosinophilic degranulation and EPX.55 Therefore, with progression of disease and persistence of inflammation, the airways are constantly exposed to immunogenic entities such as a EPX, and subsequent markers of tissue injury (DAMPs), capable of triggering the adaptive immune response (Figure). We speculate that with recruitment of the diverse lymphocyte subsets due to ongoing inflammation (allergen/infection/damage), the host micro-environment starts accumulating a cocktail of chemokines such as B cell activating factor (BAFF), B cell chemoattractant (BCA-1/CXCL13), that would support ectopic lymphoid neogenesis (or initial B cell clusters), in situ autoantibody generation,61 cytokines that induce/facilitate class switch recombination to IgG, etc., events critical for a localized autoimmune response (Figure). Indeed, BAFF and CXCL1362, 63 have been suggested to be important in asthma pathogenesis, and increased levels were reported in the airways of asthmatic children64 and adults with sputum autoantibodies.55

Extensive degranulation and extra-cellular DNA traps

Ig-induced eosinophil degranulation was demonstrated by Gleich and co-workers65 as early as 1991 to be to be unresponsive to dexamethasone. In addition to piecemeal degranulation by activated intact eosinophils,66 there has been recent evidence of extracellular histone-coated DNA traps (eosinophil extracellular traps [EETs]) released by eosinophil cytolysis in vitro.67 In fact, evidence of EETs was recently demonstrated in nasal polyps from patients with CRS.68 The authors commented on a plausible association between the EETs and the pathogenesis of CRS, in context to the recently described localized autoimmune responses.51 In vitro evidence of EETs triggered by sputum autoantibodies (from eosinophilic asthmatics) was provided recently.55 The event was quantified by the evaluating the release of dsDNA (a known DAMP), and lactose dehydrogenase (indicator of loss of membrane integrity). The autoantibody-induced eosinophil cytolysis releasing EET could not be effectively curbed by physiologically relevant concentrations of dexamethasone(10^-6 M). Though at a nascent stage, it can be said that sputum autoantibodies are pathogenic in nature and can lead to extensive airway degranulation, an event that remains possibly uncurbed by the maintenance dose of corticosteroid.

One of the phenotypes of asthma is characterized by mixed granulocytic sputum, i.e., increased sputum cell count indicative of infection, increased neutrophil content, and evidence of underlying eosinophilia69 and poor lung function.70 These patients have recurrent incidences of chest infection, and have been shown to have detectable sputum ANAs and anti-EPX IgGs.55 In addition to EETs, we speculate the presence of bacterial induced neutrophil-derived extracellular DNA traps (neutrophil extracellular traps [NETs]) in the underlying pathomechanism. Indeed, NETs released due to NETosis, a novel neutrophil degranulation machinery, has established pathomechanism including development of specific autoantibodies against neutrophil-targets in autoimmune diseases such as eGPA.71, 72 Choi and co-workers73 demonstrated that NETs formed (in vitro) by neutrophils extracted from severe asthmatics have the ability to induce secretion of cytokeratin-18 autoantibodies from airway epithelial cells. Furthermore, peripheral blood neutrophils from severe asthmatics (n=30) demonstrated greater ability of NET production and neutrophil autophagy compared to neutrophils from non-severe asthma (n=38). In fact, IL-8-induced NET production levels negatively correlated with lung function (r=-0.700, P=0.016).74 More recently, release of NETs by neutrophils recruited as an immune response to rhinovirus infection has been demonstrated in mice models of type-2 allergic asthma.75, 76 The study suggests the release of cellular dsDNA content as a consequence of NETosis is pathogenic and might be central to asthma exacerbations due to rhinovirus infections. Though dsDNA is a known DAMP, investigating autoantibodies to dsDNA was not included in the study design. Therefore, a possible localized autoimmune pathology leading to exacerbation of a type-2 inflammation cannot be dismissed.

The trigger for inducing NETosis is mostly infectious agents such as bacteria and viruses, while EETs seems to be triggered by autoantibodies as demonstrated in vitro by Mukherjee and co-workers.55 Increased IgG-load in the eosinophilic airways could lead to extensive EETs, in addition to formation of NETs in an infective environment, thereby allowing a less-conservative presentation of autoantigens like histone and dsDNA to the plausible submucosal B cell clusters (T-cell independent mechanism) or the follicular T cells/DCs allowing T-cell: B-cell interactions in an organized iBALT (Figure).

Peripheral tolerance and lymphopenia

The fact that not all severe asthmatics show airway autoantibodies indicates the presence of regulatory mechanisms that maintain local immune tolerance. During development, the B and T cells with self-reactive antigen receptors (also called autoreactive lymphocytes) are generally deleted from the repertoire of lymphocytes released into the peripheral circulation to avoid autoimmune events. However, a small percentage of self-reactive clones do exist in the circulation, which are thereafter regulated by Foxp3⁺-regulatory T cells (Tregs), a key mechanism for peripheral tolerance.77 To counter the development of autoimmunity due to recognition of self-antigens during tissue injury, Tregs and B cells present in the pool of lymphocytes ‘homed’ from the circulation, act as sentinels that induce apoptosis in the activated lymphocytes with autoreactive receptors.77, 78 Concepts of regulatory B cells are being investigated for their role in suppressing T cell-independent activation of B cells with self-reactive B cell receptors (BCRs)79 and IL-10-mediated regulation of autoimmune responses.80 In context to asthma, there is evidence of both compromised peripheral tolerance in severe asthmatics with significant low levels of Foxp3⁺-Treg cells81, 82 and reduced IL-10 expression.81, 83 Furthermore, CD25⁺ CTLA4⁺ Foxp3⁺-T cells with regulatory functions were enumerated to be significantly reduced in induced sputum from atopic asthmatics compared to healthy volunteers.84 Again, none of these studies investigated autoantibodies and therefore neither association nor causality can be derived. However, it can be speculated that transient lymphopenia could lead to dysregulation of regulatory lymphocytes85 and reduce the numbers ‘homed’ to the airways, and consequently the IL-10 expression (Figure). Animal models with T-cell lymphopenia have been shown to spontaneously develop organ-specific autoimmune diseases with an array of autoantibodies, due to compensatory homeostatic expansion of autoreactive T cells.86, 87 In fact, lymphopenia is not uncommon in human autoimmune disorders. In patients with both systemic autoimmune disorders like SLE and organ-specific autoimmune disorder like RA, a strong association with lymphopenia and thereby, reduced regulatory cells has been established to be accountable for the inability to suppress self-reactive T cells, leading to loss of peripheral tolerance.88 Patients with a history of transient lymphopenia in addition to a history of intense airway eosinophil degranulation were seen to be have higher detection of sputum autoantibodies.55 In this context, the triad of variables, viz., lymphopenia, long-term corticosteroid use and development of autoantibodies, leads to the classic situation of which came first, the chicken or the egg?

Response to maintenance therapy

Presence of autoantibodies in the lungs could be one of the mechanisms that contribute to the observed steroid subsensitivity in severe asthmatics (reviewed recently89). The prednisone-sparing effect of classical autoimmune drugs (such as azathioprine, methotrexate and cyclosporine) in severe eosinophilic prednisone-dependent patients with biopsy evidence of granulomas is indicative of the same, even though airway autoantibody titers were not investigated.54 One of the potential mechanisms may be attributed to the increase in autoantibody titers in an eosinophil-rich tissue, and the consequent autoantibody-induced eosinophil degranulation with EETs. As discussed earlier in previous section, the event was shown to be a steroid-unresponsive ex vivo,55 and therefore could explain the concurrent presence of high eosinophil activity and sputum autoantibodies despite intake of daily prednisone in those patients. In an autoimmune tissue, increased doses of corticosteroid will be able to reduce the lymphocytic infiltration and eosinophils, but will not be efficient in reducing the number of autoantibodies or suppressing their immediate mechanism of action on effector cells (e.g., eosinophils). Again, in the same microenvironment of increased IgG load, the cross-linking of Fc-gamma receptors on eosinophils can negatively affect glucocorticosteroid-induced apoptosis, promoting survival.90, 91 Furthermore, earlier studies (Table 1) could address impaired response to bronchodilators in patients who showed circulating autoantibodies to beta-2-adrenergic receptors.13, 17

Response to novel biologics

Autoantibodies to IgE reported in asthmatic patients92 could interfere with omalizumab (IgG1 monoclonal antibody, mAb targeting IgE) and compromise clinical response. The possible involvement of anti-IgE IgG competitively inhibiting the therapeutic antibody requires to be investigated since the effectiveness of omalizumab in severe prednisone-dependent asthmatics is not as marked as its effects in decreasing exacerbations in poorly-controlled asthmatics on inhaled corticosteroids.93 Unlike omalizumab, there is circumstantial proof of asthma-worsening in a prototype severe eosinophilic patient after mepolizumab therapy (anti-IL-5 mAb, 100 mg subcutaneous [SC]) associated with a localized airway autoimmune response.94 The said patient showed IL-5 complexed to Igs post treatment, associated with drop in lung function and increase in autoantibody titers. Indeed, we have demonstrated that patients who showed less than optimal response to 100 mg SC mepolizumab had increased sputum IL-5 (along with Ig-bound IL-5) and anti-EPX IgG in their titers post treatment.95 Reslizumab treatment (anti-IL-5 mAb, intravenous [IV], 3 mg/kg) effectively reduced autoantibody titers in the airways of the same ten eosinophilic prednisone-dependent asthmatics who were assessed for mepolizumab therapy previously. When the receptor was targeted instead of the ligand with benralizumab (anti-IL-5R alpha IgG1, SC), 20% of the study population were reported to have suboptimal clinical response,96 although the overall study population showed a 75% reduction in their maintenance dose of prednisone. In the Canadian sub-study of the ZONDA trial, despite reducing both blood and sputum eosinophils, benralizumab was inefficient in ameliorating sputum anti-EPX IgGs97 unlike reslizumab (3 mg/kg IV)95 and mepolizumab (750 mg/kg, IV).117 We have tabulated our observations in Table 2, and it is interesting to note that greater amelioration of eosinophils and EPX is associated with greater reduction in anti-EPX IgGs. In fact, sputum anti-EPX IgGs was one of the predictors of response to anti-IL-5 mAb therapy.95

Table 2
Autoimmune responses to the different anti-eosinophil monoclonal antibody therapies

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The difference in the treatment response to anti-IL-5 mAb therapies may be contributed to 1) route of administration (IV vs SC) that allows an adequate dose to reach the target tissue; 2) administered dose itself (fixed dose vs weight-adjusted dose), ensuring the mAb is in excess to the target antigen and formation of aggregates (immune complexes) are avoided; and 3) difference in Fc backbone where mepolizumab is an IgG1 molecular capable of binding complement C1q,98 and reslizumab, an IgG4 which does not bind complement and inhibits complement-associated lysis.99 All 3 factors have a common denominator, that they can have a deleterious effect in a scenario when the patient has an ongoing localized autoimmune response. In the instance where the target mAb is in equivalent proportion to the target antigen in the tissue, it may form aggregates. Though large immune complexes are unlikely to form with IL-5 and mepolizumab based on the stoichiometric design of the molecule;100 nevertheless, the molecule being an IgG1 mAb can potentially bind complement C1q.98 In the tissue, with additional IgG autoantibodies, a complement-mediated tissue injury can occur with heightened inflammation.101 Secondly, reslizumab being an IgG4 molecule holds the ability of not only avoiding C1q binding but also inhibiting complement-mediated lysis.99 Therefore, in an autoimmune-prone tissue, any increase in IgG4 load (in this instance, reslizumab) can potentially reduce complement-mediated inflammation in addition to neutralising IL-5.

This concept might be relevant for all novel biologics currently approved or under development for severe asthma. Effectiveness of therapies such as benralizumab that include an extra variable i.e., the component of antibody-mediated cytotoxicity (ADCC) might be implicated if there are autoantibodies present against CD16 (Fc-gamma-receptor IIIa) epitopes, crucial for initiating ADCC or autoantibody-associated macrophage dysfunction and apoptotic cell clearance. This is speculative for asthma, but evidence for autoantibodies against CD16102 and scavenger receptors on macrophages103 have been reported.

Revisiting intravenous immunoglobulin (IVIG) clinical trials

Before the availability of mAb therapies, IVIG trials in asthma were conducted on the rationale that they will effectively reduce recurrent airway infections in asthmatic patients with associated immunodeficiency syndromes.104 In addition, where infection was not apparent, IVIG could work by inhibiting mononuclear cell proliferation, B-cell differentiation (anti-BAFF activity), IgG-Fc-receptor blockage, modification of complement activation and reduction of IgE synthesis by anti-idiotype antibodies.105 An open label trial of IVIG (2 g/kg every 4 weeks) conducted by Mazer and Gelfand,106 in 8 severe atopic prednisone-dependent children resulted in improvements of symptoms including spirometry, and reduction in daily corticosteroid use. In fact, the authors suggested IVIG as a steroid-sparing treatment option in asthma and atopic dermatitis.107 However, subsequent double-blind placebo-controlled trials in severe asthma could not confirm the beneficial effect of IVIG.108, 109 This could be explained by injudicious patient selection. For example, in the Kishiyama et al.108 trial, patients recruited ranged between 6 and 68 years. Most of the mentioned trials were in children and adolescents, and as evident from the ongoing discussion, autoimmune mechanisms in asthma might be more prevalent in the adult-onset patient group. IVIG could potentially be an effective therapy in patients whose asthma severity is driven by autoantibodies. In fact, autoantibodies to cytokeratin 18 in serum samples from patients with bronchial asthma and CRS was suggested as a biomarker for monitoring response to IVIG therapy (United State Patent Application Publication #US20050208583; Page 9, Table 4, paragraph [0103]). In addition, a case study was recently reported where IVIG was effective in improving FEV1, and ameliorating airways autoantibodies in a patient with severe eosinophilic refractory asthma.94 In the current light of evidence, it is perhaps prudent that we re-visit the idea of IVIG as a therapeutic option for those asthmatics who show evidence of autoantibodies in conjunction with other indices of severity (such as high airway eosinophil activity and corticosteroid sub-sensitivity).

Systemic autoimmune diseases with pulmonary manifestations

Numerous systemic autoimmune diseases such as eGPA, Sjogren's syndrome, RA, mixed connective tissue disease and SLE present with pulmonary complications.110 In RA, the pulmonary complications can be addressed by the presence of iBALT and airways anti-CCP3 antibodies.47 In fact, as previously discussed, anti-CCP3 autoantibodies were detectable in the sputum of at-risk RA patients, and therefore exhibited immediate prognostic value.49 Though the presence of circulating autoantibodies are considered biomarkers and associated with specific disease severity, the sensitivity and specificity can often be a problem. This is apparent for patients with eGPA, only 40% of whom show the characteristic circulating anti-neutrophil cytoplasmic antibody (ANCA).111 In brief, eGPA is a distinct form of autoimmune systemic vasculitis, diagnosed as the presence of 4 or more of the following 6 criteria (American College of Rheumatology guideline): peripheral blood eosinophilia, paranasal sinus abnormality, neuropathy, extravascular evidence of eosinophils, asthma (often severe enough to require daily maintenance corticosteroids) and transient pulmonary infiltrates.112 Again, eGPA evolves through an initial pro-dermic allergic phase characterized by asthma and/or rhinosinusitis, followed by an eosinophilic phase with increased blood eosinophil levels and organ-involvement, and finally a ‘vasculitis’ phase showing clinical manifestations of small-vessel vasculitis.113 If the progression of the disease is to be followed, then there is an indication of the early allergic/inflammatory events giving rise to the autoimmune conditions. This natural course of eGPA suggests that asthma can be a prodromal condition of this systemic autoimmune eosinophilic vasculitis (eGPA) and that an autoimmune mechanism can be involved in both severe asthma and eGPA. However, it is likely that the seat of autoimmunity is localized to the lungs since most patients who are serum-ANCA negative present with severe pulmonary complications, while the sero-positive population have a prominent vasculitis component.113, 114 In fact, we have recently shown sputum ANCA in 16/22 (72%) eGPA patients irrespective of their serum ANCA status.115 Localized autoimmune phenomenon may be more relevant in understanding the severity of asthma and CRS observed in these eGPA patients and choosing the optimal treatment strategy.

Caution needs to be exercised in ascertaining the dose of anti-IL5 mAb therapies in patients presenting with severe asthma and a known systemic autoimmune pathomechanism such as eGPA. If the mAb dose is not adequate, these severe patients with increased IgG load (ongoing autoimmunity), and increased levels of IL-5 molecules present with a higher probability of falling into the ‘zone of antibody-antigen equivalence’ leading to heightened inflammation/immune-complex mediated complications. Investigating target specificities of sputum autoantibodies against disease-specific autoantigens or adopting an ‘omics’ approach can provide a tool for prognosis, diagnosis and monitoring response to biologics for several systemic autoimmune diseases that present with pulmonary complications.