Wilkes, David S.Lott, Jeremy M.Kaplan, Mark H.Smith, Gerald N.Vasko, Michael R.Blum, Janice Sherry, 1957-2013-12-112013-12-112013-12-11https://hdl.handle.net/1805/3759http://dx.doi.org/10.7912/C2/1718Indiana University-Purdue University Indianapolis (IUPUI)Rationale: Tissue remodeling and complement activation are asthma hallmarks. Type V collagen [col(V)], a cryptic antigen, becomes exposed during lung remodeling. IL-17 is key to anti-col(V) immunity, and regulates complement activation. We have reported that col(V)-induced tolerance down regulates IL-17 and prevents immune-mediated lung diseases. Objectives: Determine a role for anti-col(V) immunity in asthma. Methods: Serum anti-col(V) antibodies were measured in asthma patients, and immunohistochemistry utilized to detect interstitial col(V) in fatal asthma. Balb/c mice were tolerized with col(V) prior to sensitization with ovalbumin (OVA), and subsequent OVA intranasal challenge. Airway hyper-responsiveness (AHR) to methacholine was measured; and RT-PCR utilized to determine local Il17 transcripts. Bronchoalveolar lavage levels of C3a¸ C5a and OVA-specific IgE were measured; and immunohistochemistry utilized to detect expression of complement regulatory proteins, expression, CD46/Crry and CD55, in lung tissue. Results: Compared to normal subjects, anti-col(V) antibodies were increased in asthmatics; and interstitial col(V) was over expressed in fatal asthma. OVA-induced AHR up regulated anti-col(V) antibodies systemically, and increased OVA-specific IgE and C3a in BAL, and parenchymal Il17 transcripts. Col(V)-induced tolerance abrogated AHR, down regulated OVA-induced T cell proliferation, as well as total and OVA-specific IgE, C3a, IL-17 expression and tracheal smooth muscle contraction. Crry/CD46 and CD55, key to preventing complement activation, were down regulated on goblet cells in murine allergic airway disease. Conclusions: Anti-col(V) immunity correlates with asthma pathogenesis, and col(V)-induced tolerance may be a novel therapeutic for asthma. Decreased expression of Crry/CD46 and CD55 on goblet cells may in part account for complement activation in asthma.en-USAsthmaToleranceIL-17Type V CollagenAsthma-- ResearchAsthma -- EtiologyRespiratory allergyCollagen -- ResearchImmunological tolerance -- ResearchTissue remodelingLungs -- Diseases -- ResearchInterleukinsImmunosuppression -- ResearchThesis