Allergy Asthma Immunol Res.  2018 Sep;10(5):428-447. 10.4168/aair.2018.10.5.428.

Autoimmune Responses in Severe Asthma

Affiliations
  • 1Division of Respirology, Department of Medicine, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, Canada. parames@mcmaster.ca

Abstract

Asthma and autoimmune diseases both result from a dysregulated immune system, and have been conventionally considered to have mutually exclusive pathogenesis. Autoimmunity is believed to be an exaggerated Th1 response, while asthma with a Th2 underpinning is congruent with the well-accepted Th1/Th2 paradigm. The hypothesis of autoimmune involvement in asthma has received much recent interest, particularly in the adult late-onset non-atopic patients (the "intrinsic asthma"). Over the past decades, circulating autoantibodies against diverse self-targets (beta-2-adrenergic receptors, epithelial antigens, nuclear antigens, etc.) have been reported and subsequently dismissed to be epiphenomena resulting from a chronic inflammatory condition, primarily due to lack of evidence of causality/pathomechanism. Recent evidence of "˜granulomas' in the lung biopsies of severe asthmatics, detection of pathogenic sputum autoantibodies against autologous eosinophil proteins (e.g., eosinophil peroxidase) and inadequate response to monoclonal antibody therapies (e.g., subcutaneous mepolizumab) in patients with evidence of airway autoantibodies suggest that the role of autoimmune mechanisms be revisited. In this review, we have gathered available reports of autoimmune responses in the lungs, reviewed the evidence in the context of immunogenic tissue-response and danger-associated molecular patterns, and constructed the possibility of an autoimmune-associated pathomechanism that may contribute to the severity of asthma.

Keyword

Autoantibodies; autoimmunity; severe asthma; sputum eosinophils; neutrophils; degranulation; danger associated molecular patterns; sputum; immunoglobulin G

MeSH Terms

Adult
Antigens, Nuclear
Asthma*
Autoantibodies
Autoimmune Diseases
Autoimmunity*
Biopsy
Eosinophils
Humans
Immune System
Immunoglobulin G
Lung
Neutrophils
Sputum
Antigens, Nuclear
Autoantibodies
Immunoglobulin G

Figure

  • Figure Working hypothesis for localized autoimmune phenomenon in asthmatic lung. Classical Th2 pathway leads to IL-5, IL-4, IL-13 release, recruitment of eosinophils (eotaxin) and lymphocytes (CCL17), and favors class-switch to IgE. Eosinophil activation and degranulation releases EPX and mediators of tissue damage. With disease progression and chronic inflammation over time, increased localized expression of BCA-1, BAFF, IL-15, IL-16 and CCL17 will allow homing of lymphocytes into the submucosa. Reduced number of regulatory lymphocytes with possible lower IL-10 production will allow activation of the autoreactive lymphocytes (present as a small percentage of the total lymphocyte pool) in the vicinity of their cognate antigens (products of degranulation and tissue damage). Over time, B cell clusters with interspersed APCs and T cells in near proximity are formed. BAFF, CXCL13, CCL21, IL-15 and IL-16 released by different sources including B cells themselves support ectopic B cell clusters, its organization and autoantibody formation. Low levels of anti-EPX IgG and ANAs (polyclonal IgG autoantibodies) formed initially during earlier episodes of degranulation, trigger Ig-induced cytolysis (EETs) on recruited eosinophils (increased eotaxin), thereby increasing self-antigen exposure. The extracellular traps allow efficient antigen priming by APCs and B cells that further leads to increase in in situ ANA and anti-EPX IgG production. In some patients, pulmonary infection triggers release of pro-inflammatory mediators like IL-18 which along with neutrophil degranulation ‘NETosis’ (with possible NET formation) supports further tissue damage, accumulation of self-autoantigens and autoantibody production. Drawing is not to scale. APC, antigen presenting cell; ANA, anti-nuclear antibodies; BAFF, B cell activating factor; BCA-1, B cell attracting chemokine; CSR, class switch recombination; DAMP, danger-associated molecular pattern; EET, eosinophil extracellular trap; EPX, eosinophil peroxidase; Ig, immunoglobulin; IL, interleukin; NET, neutrophil extracellular trap; MC, mast cell; MPO, myeloperoxidase.


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