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SARS-CoV-2 spike antigen-specific IgG and IgA elicited by infection mediate viral neutralization and are likely an important component of natural immunity, however, limited information exists on vaccine induced responses. We measured COVID-19 mRNA vaccine induced IgG and IgA in serum serially, up to 145 days post vaccination in 4 subjects. Spike antigen-specific IgG levels rose exponentially and plateaued 21 days after the initial vaccine dose. After the second vaccine dose IgG levels increased further, reaching a maximum approximately 7–10 days later, and remained elevated (average of 58% peak levels) during the additional >100 day follow up period. COVID-19 mRNA vaccination elicited spike antigen-specific IgA with similar kinetics of induction and time to peak levels, but more rapid decline in serum levels following both the 1st and 2nd vaccine doses (<18% peak levels within 100 days of the 2nd shot). The data demonstrate COVID-19 mRNA vaccines effectively induce spike antigen specific IgG and IgA and highlight marked differences in their persistence in serum.

Diisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene diisocyanate (HDI) and may be biologically important in diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1, 2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant diisocyanate-conjugated protein in bronchoalveolar lavage fluid. Keratin was also identified as a predominant diisocyanate-conjugated protein in human skin biopsy samples after epicutaneous exposure to liquid-phase HDI, although the major skin diisocyanate-conjugated protein (56-kD) differed from the predominant lung diisocyanate-conjugated keratin (47-kD). The data from this study identify keratin and other proteins as potential "carriers" for diisocyanates in vivo, and suggest that HDI conjugation of these proteins may play a role in the pathogenesis of diisocyanate-induced asthma.

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Rationale: Associations between oligomeric isocyanate exposure, sensitization, and respiratory disease have received little attention, despite the extensive use of isocyanate oligomers. Objectives: To investigate exposure-response relationships of respiratory symptoms and sensitization in a large population occupationally exposed to isocyanate oligomers during spray painting. Methods: The prevalence of respiratory symptoms and sensitization was assessed in 581 workers in the spray-painting industry. Personal exposure was estimated by combining personal task-based inhalatory exposure measurements and time activity information. Specific IgE and IgG to hexamethylene diisocyanate (HDI) were assessed in serum by ImmunoCAP assay and enzyme immunoassays using vapor and liquid phase HDI-human serum albumin (HDI-HSA) and HSA conjugates prepared with oligomeric HDI. Measurements and Main Results: Respiratory symptoms were more prevalent in exposed workers than among comparison office workers. Log-linear exposure-response associations were found for asthmalike symptoms, chronic obstructive pulmonary disease-like symptoms, and work-related chest tightness (prevalence ratios for an interquartile range increase in exposure of 1.2, 1.3 and 2.0, respectively; P < 0.05). The prevalence of specific IgE sensitization was low (up to 4.2% in spray painters). Nevertheless, IgE to N100 (oligomeric HDI)-HSA was associated with exposure and workrelated chest tightness. The prevalence of specific IgG was higher (2-50.4%) and strongly associated with exposure. Conclusions:The results provide evidence of exposure-response relationships for both work-related and non-work-related respiratory symptoms and specific sensitization in a population exposed to oligomers of HDI. Specific IgE was found in only a minority of symptomatic individuals. Specific IgG seems to be merely an indicator of exposure.

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Diphenylmethane diisocyanate (MDI), the chemical commonly used as a cross-linking agent in commercial polyurethane production, is a well-recognized cause of asthma. Reaction products between MDI and "self" proteins are hypothesized to act as antigens capable of inducing airway inflammation and asthma; however, such MDI antigens remain incompletely understood. We used a variety of analytical methods to characterize the range of MDI-albumin reaction products that form under physiological conditions. Sites of MDI conjugation on antigenic MDI-albumin products, as defined by serum immunoglobulin G (IgG) from MDI-exposed workers, were determined by high-performance liquid chromatography (HPLC) followed by tandem mass spectrometry (MS/MS). The data identified 14 MDI conjugation sites (12 lysines and 2 asparagines) on human albumin and highlight reaction specificity for the second lysine in dilysine (KK) motifs, and this may be a common characteristic of "immune-sensitizing" chemicals. Several of the MDI conjugation sites are not conserved in albumin from other species, and this may suggest species differences in epitope specificity for self protein (albumin)-isocyanate conjugates. The study also describes new applications of contemporary proteomic methodology for characterizing and standardizing MDI-albumin conjugates destined for use in clinical research. KeywordsDiphenylmethane diisocyanate; Human; Albumin; Lysine; Serology; IgG; Isocyanate; Asthma; Polyurethane Diisocyanates are small chemicals, with two reactive N=C=O groups that serve as the obligate "cross-linker" for commercial polyurethane production [1]. The most commonly used diisocyanates, diphenylmethane diisocyanate (MDI), 1 toluene diisocyanate (TDI), and hexamethylene diisocyanate (HDI), are a major cause of occupational asthma worldwide [1,2]. For numerous reasons, MDI is fast overtaking the isocyanate consumer market (e.g., foam, furniture/bedding, insulation, mining/"rock-lock", construction), leading to increased exposure and new cases of occupational asthma [3][4][5][6] The form of isocyanates that stimulates the human immune system (e.g., antigen) has been challenging to define due to the chemicals' high electrophilicity and spontaneous reactivity with proteins [7,8]. In vivo, it is believed that isocyanates react with "self" proteins, resulting in conformational changes (neoepitopes) recognized by the immune system [8][9][10][11]. Such isocyanate-protein conjugates have been shown to trigger both innate and adaptive immune responses and have been hypothesized to represent the antigenic basis for isocyanate asthma [7,[11][12][13][14].To date, only one self protein, albumin, is known to create a pathogenic antigen, specifically recognized by human antibodies, on reactivity with isocyanate in vivo [9,15,16]. The human humoral immune response to isocyanate exposure is highly specific and requires human albumin. Isocyanate conjugated to other carrier proteins, even proteins with strong primary sequence homology to human albumin (e.g., albumin f...

The data suggest that serology may help identify TDI asthmatics and exposed workers if the appropriate form of TDI is used as the antigenic basis for analysis.