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BACKGROUND: A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control. OBJECTIVE: To identify signatures as determinants of asthma disease control, we performed proteomics using Olink proximity extension analysis. METHODS: Up to 3 longitudinal serum samples were collected from 23 controlled and 25 poorly controlled asthmatics. Nine of the controlled and 8 of the poorly controlled subjects also provided 2 longitudinal sputum samples. The study included an additional cohort of 9 subjects whose serum was collected within 48 hours of asthma exacerbation. Two separate pre-defined Proseek Multiplex panels (INF and CVDIII) were run to quantify 181 separate protein analytes in serum and sputum. RESULTS: Panels consisting of 9 markers in serum (CCL19, CCL25, CDCP1, CCL11, FGF21, FGF23, Flt3L, IL-10Rß, IL-6) and 16 markers in sputum (tPA, KLK6, RETN, ADA, MMP9, Chit1, GRN, PGLYRP1, MPO, HGF, PRTN3, DNER, PI3, Chi3L1, AZU1, and OPG) distinguished controlled and poorly controlled asthmatics. The sputum analytes were consistent with a pattern of neutrophil activation associated with poor asthma control. The serum analyte profile of the exacerbation cohort resembled that of the controlled group rather than that of the poorly controlled asthmatics, possibly reflecting a therapeutic response to systemic corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control.

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Mast cell activation involves the rapid release of inflammatory mediators, including histamine, from intracellular granules. The cells are capable of regranulation and multiple rounds of activation. The goal of this study was to determine if there are changes in the content of pre-formed mast cell mediators after a round of activation. After 24 h, the histamine content of bone marrow-derived mast cells (BMMC), but not that of peritoneal mast cells, exceeded the amount in resting cells. Accumulation of histamine in BMMC peaked at 72 h of activation, and returned toward preactivation levels by 96 h. The increase in histamine content was accompanied by an increase in the gene expression of histidine decarboxylase. No increases in beta hexosaminidase or murine mast cell protease-6 were observed. These findings indicate that BMMC respond to activation by increasing total cell-associated histamine content. This increase may be important to the response of these cells upon subsequent exposure to antigens.

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BACKGROUND: IL-13 plays a key regulatory role in asthmatic responses and immunity to parasitic infection. In vivo, IL-13R-alpha2 is a critical modulator of IL-13 bioactivity. When inducibly expressed on the surface of fibroblasts and other cell types under inflammatory conditions, IL-13R-alpha2 contributes to resolution of IL-13 responses. A soluble form of IL-13R-alpha2 (sIL-13R-alpha2) can be detected in murine circulation, and functions as a regulator of IL-13 bioactivity. In humans, sIL-13R-alpha2 has been more difficult to detect. Recently, novel assay systems have been described to quantitate sIL-13R-alpha2 in human circulation, and revealed unexpectedly high levels of sIL-13R-alpha2 in healthy subjects. OBJECTIVE: To verify sIL-13R-alpha2 quantitation in human plasma samples under stringent conditions of signal verification and false-positive detection. METHODS: A standard ELISA protocol was evaluated for specificity using false-positive detection reagents. A more stringent ELISA protocol was developed by optimizing the composition of blocking and dilution buffers. RESULTS: Using the stringent assay protocol, endogenous sIL-13R-alpha2 was undetectable in plasma samples from a total of 120 asthmatics and 20 healthy subjects, and in bronchoalveolar lavage fluid from 10 asthmatics and eight healthy subjects undergoing allergen challenge. CONCLUSION: These results underscore the necessity to perform rigorous assay controls in the biological matrix to be tested. Because the soluble form could not be demonstrated, our findings question a role for sIL-13R-alpha2 in the regulation of IL-13 bioactivity, and highlight the potentially important contribution of the membrane-bound form of IL-13R-alpha2 in humans.

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The treatment of autoimmune diseases by targeted down-regulation of autoantigen-specific cells has been accomplished by the administration of high doses of autoantigen. We performed direct comparisons between injection of myelin basic protein peptide and administration by several nonparenteral routes to determine whether route impacted benefit in the treatment of murine allergic encephalomyelitis, a model for multiple sclerosis. The range of effective peptide doses spanned over 1000-fold, and route of delivery played a major role in determining optimal dose. The oral route of administration was the least effective, requiring at least 50- to 100-fold more antigen than subcutaneous injection, which in turn required at least 10-fold more antigen than delivery of peptide to the lung using an intratracheal instillation. Intratracheal delivery was also considerably more effective than inhalation of peptide, and, unlike inhalation, resulted in obvious penetration of delivered material deep into the lung. The increase in therapeutic efficacy did not appear to result from slower systemic delivery of antigen. Accumulation of peptide on antigen presenting cells in the spleen and in the brain was less efficient using the intratracheal route of administration compared to subcutaneous injection, implicating a special role for the lung microenvironment in the induction of immune nonresponsiveness.

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Experimental autoimmune encephalomyelitis (EAE) can be effectively treated during disease exacerbation by administration of a peptide corresponding to the major T cell epitope of myelin basic protein (MBP), but the mechanism by which T cell tolerance leads to clinical improvement is not well-defined. Acute exacerbations of EAE are accompanied by an infiltration of blood-borne leukocytes into the brain and spinal cord, where they mediate inflammation and demyelination. To investigate peptide effects on infiltrating cells, we collected cerebrospinal fluid (CSF) from (PL/JxSJL)F1 mice with MBP-induced EAE. Pleiocytosis by lymphocytes, neutrophils, and macrophages was seen throughout the course of relapsing-remitting disease. A single administration of the MBP peptide analog, Ac1-11[4Y], reduced disease severity, accompanied by a dramatic and selective loss of neutrophil pleiocytosis. A longer course of peptide therapy resulted in complete recovery from clinical signs of disease, and decreased pleiocytosis by all cell types. Clinical severity throughout the course of disease and therapy was directly related to the degree of infiltration by neutrophils and macrophages, and the clinical improvement following peptide therapy was accompanied by decreased central nervous system (CNS) expression of chemoattractants for these cell types. These observations support a model of disease exacerbation mediated by phagocytic cellular infiltration under the ultimate control of T cell-derived factors, amenable to treatment by down-regulation of the T cell activation state.

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To understand whether the distinct VHDJH gene utilization by natural polyreactive Abs reflects the developmentally restricted Ig VHDJH rearrangements putatively expressed by B-1 cells, we generated 11 (8 IgM, 1 IgG3, 2 IgA1), 7 (6 IgM, 1 IgG1), and 7 (2 IgM, 3 IgG1, 2 IgG3) mAb-producing lines using B-1a (surface CD5+, CD45RAlow), B-1b (surface CD5-, CD45RAlow, CD5 mRNA+), and B-2 (surface CD5-, CD45RAhigh, CD5 mRNA-) cells, respectively, sorted from adult human peripheral blood. Most B-1a and B-1b, but no B-2, cell-derived mAbs were polyreactive; i.e., they bound different self and foreign Ags with different affinities. B-1a and B-2 mAbs preferentially utilized VH4 (p = 0.003) and VH3 (p = 0.010) genes, respectively. All three mAb populations utilized DXP, DLR, DN DH genes, and JH6, but no mAb utilized DHQ52. There were fewer unencoded nucleotide (N) additions in the VHDJH junctions of B-1b (3.00 +/- 2.52, mean +/- SD) than of B-1a (12.45 +/- 3.93, p = 1.23 x 10(-5)) or B-2 (8.29 +/- 4.75, p = 0.020) mAbs. Partly due to the fewer N additions and a paucity of D-D fusions, the B-1b mAb CDR3s were significantly shorter than the B-1a mAb CDR3s (p = 0.013), which contained a nonrandom Tyr distribution (p = 0.003). Finally, all but two B-1 cell-derived mAbs were mutated, in a fashion similar to that of the Ag-selected B-2 mAbs. Thus, in the human adult, B-1 cells that make natural polyreactive Abs may not be representative of the predominantly B-1 developmental waves of colonization of the fetal and neonatal B cell repertoires, and are somatically selected.

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Canis familiaris allergen 1 (Can f 1) and Canis familiaris allergen 2 (Can f 2) are the two major allergens present in dog dander extracts. We now report the isolation of cDNAs encoding both proteins and present their nucleotide and deduced amino acid sequences. Can f 1, produced by tongue epithelial tissue, has homology with the von Ebner's gland (VEG) protein, a salivary protein not previously thought to have allergenic properties. Can f 2, produced by tongue and parotid gland, has homology with mouse urinary protein (MUP), a known allergen. Both VEG protein and MUP are members of the lipocalin family of small ligand-binding proteins. Recombinant forms of Can f 1 and Can f 2 were produced and tested for immunoglobulin E (IgE) reactivity. Among dog-allergic subjects, 45% had IgE directed exclusively to rCan f 1, and 25% had IgE to both rCan f 1 and rCan f 2. In addition, both recombinant proteins were able to cross-link IgE and elicit histamine release from peripheral blood leucocytes in vitro. These findings confirm that Can f 1 and Can f 2 are major and minor dog allergens, respectively, and demonstrate that recombinant forms of dog allergens retain at least some IgE-binding epitopes.

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Interleukins 3 and 5 and GM-CSF enhance histamine release from basophils triggered by various stimuli. In this report, we describe a subset of allergic patients whose basophils release histamine in response to allergen only when primed with cytokine. In the absence of cytokine, there is no detectable response to allergen. These patients, who represent 4-13% of the allergic population, cannot be distinguished by skin test reactivity or severity of allergic symptoms. Allergen nonreleasers tend to have lower titers of allergen-specific IgE than the majority of atopic subjects, but this difference is not significant (average titer of 29.8 for nonreleasers vs. 188 for typical allergies; p = 0.15). They release histamine normally with anti-IgE and with fMLP, indicating that basophils are responsive to signalling through the IgE receptor, and there is no intrinsic defect in degranulation. Thus, in these patients, the IgE-mediated release of inflammatory mediators from basophils is dependent on, rather than merely enhanced by, T cell cytokines. The relationship between these patients and the previously described anti-IgE 'nonreleasers' is discussed.

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As a potent inducing agent for IgE production and differentiation factor for allergen-specific Th2 cells, IL-4 is a key regulatory cytokine both in the pathogenesis of allergic disease and in the ongoing allergic response. The assay of in vitro IL-4 production has often been used to compare the allergen responses of T cells isolated from atopic and non-atopic subjects. Because peripheral blood basophils also have the capacity to respond to specific allergen by producing IL-4, we investigated the relative contribution of these two cell types to IL-4 production in allergen-stimulated primary cultures. Among unfractionated peripheral blood mononuclear cells (PBMC), the major producers of detectable IL-4 in primary in vitro cultures were found to be basophils based on: (i) an allergen dose-response corresponding closely to that required for basophil histamine release and lower than that required for T cell activation; (ii) a rapid time course for IL-4 production (detectable at 3 h), inconsistent with the typical activation requirements of fresh T cells; (iii) the production of comparable levels of IL-4 in cultures stimulated with allergen or anti-IgE; and (iv) the complete loss of detectable IL-4 production following specific depletion of basophils from PBMC. The T cells in these cultures were functionally able to produce IL-4, as demonstrated by mitogen activation of basophil-depleted PBMC. These findings demonstrate that although IL-4 production in primary in vitro cultures can be used as a sensitive indicator of allergen responsiveness, the accurate interpretation of this result requires identification of the responding cell type. Furthermore, these findings raise the possibility that basophil production of IL-4 early in the course of allergen stimulation may shape subsequent T cell responses both in vivo and in vitro.

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BACKGROUND: The production of specific IgE, which underlies the allergic response, may be a normal correlate of the immune response to a certain class of antigen (allergens), or could represent a unique response driven by regulatory signals that are absent in non-allergic individuals. If atopic subjects do possess a regulatory environment favoring IgE production, they may display not only allergen-specific IgE, but also higher levels of total IgE and higher frequencies of IgE-producing B lymphocytes. OBJECTIVE: To address the contribution of antibody-producing cell number to the circulating IgE titre in atopic vs non-atopic subjects. METHODS: Frequency determination by limiting dilution of EBV transformants and Poisson distribution analysis. Titres of total and allergen-specific IgM, IgG, and IgE by specific ELISA. RESULTS: In contrast to findings reported by others, the atopic subjects had a significantly higher frequency of IgE-producing B cells than non-atopics (0.79% of total Ig-producing cells, as compared with 0.17% for the control group; P < 0.01), suggesting that one factor contributing to the high plasma IgE titres in atopic subjects is the high frequency of B lymphocytes with the potential to produce IgE. Although only the atopic subjects produced allergen-specific IgE, the frequency of specific IgE-producing B cells was undetectable in both groups. CONCLUSION: Atopic subjects have higher frequencies of IgE-producing B cell precursors than non-atopics. A correlation exists between IgE-producing B cell frequency and levels of circulating IgE.

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Allergy to the house dust mite Dermatophagoides pteronyssinus is mediated by IgE to the major allergens Der p I and Der p II in the majority of mite-allergic patients. In recent years, standardized preparations of D. pteronyssinus, commercially available from several sources, have become widely used for the diagnosis and immunotherapy of mite allergy. As standardization implies uniformity of allergen composition and potency, we directly compared the absolute and relative quantities of Der p I and Der p II in six different commercial standardized extracts of D. pteronyssinus. Our findings reveal variability in levels of both Der p I and Der p II, producing ratios of Der p I/Der p II ranging from 1.1/1 to 6/1. Although the content of minor allergens in the extracts was not evaluated here, their contribution to the overall reactivity of mite-allergic patients to the commercial extracts was judged to be minimal. This was demonstrated by showing that plasma depleted of reactivity to both Der p I and Der p II had virtually no residual IgE directed against extract components. The variation in the proportion of Der p I and Der p II among different D. pteronyssinus extracts is likely to influence their biological effectiveness. Patients with reactivity against only Der p I or Der p II, who were found to comprise approximately one-third of the mite-allergic population, may not respond optimally to extracts containing relatively low levels of the allergen to which they are sensitive.

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Anti-DNA IgA autoantibodies play an important immunopathologic role in SLE patients. To analyze the cellular origin and the VH and VL structure of anti-DNA IgA autoantibodies, we generated five IgA1 mAbs to DNA using B lymphocytes from three SLE patients. Two mAbs bound to ssDNA only and one to both ssDNA and dsDNA (monoreactive antibodies). The remaining two mAbs bound to DNA (one to ssDNA and the other to both ssDNA and dsDNA) and to other self and foreign Ag (polyreactive antibodies). The IgA mAb relative avidity for DNA ranged from 7.5 x 10(-8) to 8.0 x 10(-10) g/microliters. The anti-DNA IgA mAb used VH segments of the VHI(VI-3b), VHII (VH2-MC2), VHIII (WHG16G and VH26c), and VHIV (V71-2) families in conjunction with V kappa I, V kappa IIIb, or V lambda I segments. All IgA mAb VH segments were juxtaposed with JH4b segments. The heavy chain CDR3 sequences were divergent in composition and length. When compared with those of the closest reported germ line genes, the IgA mAb VH and VL gene sequences displayed a number of differences. That these differences represented somatic point mutations was formally proved in both the monoreactive IgA mAb 412.67.F1.3 and the polyreactive IgA mAb 412.66.F1 VH segments by differential PCR amplification and cloning and sequencing of genomic DNA from the mAb-producing cell lines and autologous polymorphonuclear cells. The sequences of the germ line genes that putatively gave rise to the mAb 412.67.F1.3 and mAb 412.66.F1 VH segments were identical with those of the WHG16G and VH26c genes, respectively. In not only the monoreactive mAb 412.67.F1.3 but also the polyreactive mAb 412.66.F1 and mAb 448.9G.F1 VH segments, the higher concentration of replacement (R) mutations and the higher R:S (silent) mutation ratios in the complementarity-determining region (infinity; 19:0) than in the framework region (1.0) (p = 0.00001, chi 2 test) were highly consistent with selection by Ag. In the five IgA mAb VH and VL segments, the putative and verified somatic point mutations yielded 68 amino acid replacements, of which 38 were nonconserved. Twenty of these yielded positively charged or polar residues that play a major role in DNA binding, including seven Arg, five Lys, three Tyr, two Gln, two His, and a Thr. The conserved amino acid changes included seven Asn. These findings suggest that anti-DNA IgA autoantibodies use a broad selection of VH and VL genes and enhance their fit for Ag by undergoing somatic hypermutation and Ag selection.(ABSTRACT TRUNCATED AT 400 WORDS)

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The interaction of fluorescein-labeled nerve growth factor (NGF) with human melanoma cells (A875) has been studied in order to assess better methodology for rigorous NGF binding studies. The NGF was modified at a single carboxyl group with iodoacetamidofluorescein after reaction with carbodiimide and cystamine. The modified NGF showed full binding competence in competition with radiolabeled NGF and full biological activity in neurite outgrowth assays compared to native NGF. Binding to unfixed, viable cells was assayed using flow cytometry. This method offers the advantage that unbound ligand need not be separated from that which is cell-associated, thus avoiding perturbation of the binding equilibrium, and accurate, extensive statistical analysis is possible. Binding of fluorescein-NGF was mainly specific and saturable, with analysis by three methods of data treatment indicating a Kd of 0.8 to 3 nM at 4 degrees C. Time-based data acquisition allowed a continuous time course for binding to be generated. Binding reached a steady-state level within 5 min of exposure of the cells to the ligand. Kinetic and steady-state results obtained using fluorescein-NGF agree well with previous data produced by 125I-NGF binding studies. The main limitation of the flow cytometric method in the NGF system is the relative lack of sensitivity compared to the binding of radiolabeled NGF, partially due to unusual quenching of the fluorophore bound to NGF.

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Polyreactive (natural) antibodies are primarily IgM and account for a major proportion of circulating Ig in humans. They use various V gene segments, in general, in germ line (unmutated) configuration. To analyze the VH regions of polyreactive antibodies, with particular attention at their somatically mutated status, we generated five IgG (three IgG1 and two IgG3) mAb (using B cells from a healthy subject, a patient with insulin-dependent diabetes mellitus and a patient with SLE), which bound with various efficiencies a number of different self and foreign Ag. Gene cloning experiments showed that the VH region sequences were unique to each IgG mAb. The H chain complementary determining region (CDR3) of two IgG (mAb10 and mAb426.4.2F20) displayed an identical stretch of five amino acids (RFLEW), but the other three IgG mAb CDR3 were divergent in both length and composition. The VH gene sequences of two IgG, mAb426.4.2F20 and mAb410.7.F91, were 99% identical to those of the germ line VH4.11 and VH4.21 genes, respectively. Those of the remaining three IgG mAb displayed a number of differences (93.6 to 95.9% identity) when compared with the germ line VH4.18, VH4.11, and hv1263 gene sequences. These and the VH4.21 gene have been found to encode polyreactive IgM and IgA and, in mutated configuration, monoreactive high affinity autoantibodies and antibodies induced by foreign Ag. When compared with the respective framework region, the CDR of three IgG mAb VH segment sequences displayed a significantly higher: 1) frequency of total nucleotide differences (6.1 x 10(-2) vs 4.5 x 10(-2) difference/base); 2) frequency of putative nucleotide changes yielding amino acid replacements (5.6 x 10(-2) vs 1.4 x 10(-2) replacement change/base); and 3) ratio of overall putative replacement to silent (R:S) mutations (11.0 vs 0.4). Thus, the distribution and nature of the nucleotide differences were consistent with a process of somatic mutation and Ag-dependent clonal selection. This was formally proved in IgG mAb426.12.3F1.4 and IgG mAb10 by differentially targeted polymerase chain reaction amplification and cloning and sequencing of the germ line genes that gave rise to the expressed VH segments, using DNA from polymorphonuclear cells of the same subjects whose B cells were used for the generation of these IgG mAb. Somatic mutations might have been responsible for bringing about polyreactivity in originally monoreactive antibodies or, more likely, they accumulated in originally polyreactive antibodies, which after undergoing a process of Ag selection, retained polyreactivity and may have or may have not acquired a higher affinity for the selecting Ag.

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The delineation of distinct subsets committed to the production of antibodies with different antigen-binding activities supports the view of a compartmentalization and specialization of function in the B cell repertoire and is consistent with the hypothesis of a developmentally layered immune system; as originally proposed by Herzenberg and Herzenberg. On the basis of the data by Solvason and Kearney in the human fetus and our data in the adult, and in agreement with the findings of Herzenberg et al. and Hardy et al. in the mouse, we propose that the human B cell repertoire includes at least three distinct B cell subsets: B-1a cells, which develop from progenitors in the fetal splanchnic district, namely the omentum, and are maintained in adult life by virtue of their self-replenishing nature; B-1b cells, progenitors of which can be found in the splanchnic district and, perhaps, adult bone marrow; and, finally, B-2 cells, which arise in the fetal liver and are continuously replenished in adult life by progenitors in the bone marrow (Figure 5). The different B cells types are distinguished by their differential expression of surface CD5 and, perhaps, CD11b and CD14, their differential expression of CD5 mRNA, and the different classes and specificities of the Ig they produce (Figure 5). B-1 lymphocytes play a major role in autoimmunity and constitute the physiological equivalent of the neoplastic forms in various lymphoproliferative disorders, such as CLL and SLL, which are often associated with the production of monoclonal antibodies to self antigens. Human B-1a (CD5+ B) and B-1b (CD5- CD45RAlo B) cells are responsible for the production of natural (polyreactive and monoreactive) antibodies in the fetus, neonate, and adult, and can give rise to the autoantibody-producing cells characteristic of several autoimmune disease states. Our recent findings suggest that while in healthy subjects the majority of natural polyreactive antibodies is encoded in V genes in germline configuration, some polyreactive antibodies are encoded in somatically mutated V genes, in a fashion consistent with an antigen-driven process of selection of such mutations. The nature of the antigen(s) involved in these selection processes remains to be determined. Under possibly different circumstances, the application of an antigen-driven process of clonal selection to B-1a and/or B-1b cells, previously committed to natural antibody production, can result in the generation of monoreactive high affinity and possibly pathogenic autoantibodies (Figures 5A and 5B).(ABSTRACT TRUNCATED AT 400 WORDS)

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The production of "natural" autoantibodies or antibodies, i.e., Ig that bind a variety of self- and/or exogenous Ag and arise independently of known immunization, is though to be a feature of CD5+ B lymphocytes. To determine whether other lymphocyte subsets exist that might be committed to the production of natural antibodies, human peripheral blood B cells were sorted on the basis of surface CD5 expression and differential expression of surface CD45RA (CD5+CD45RAintermediate(int), CD5-CD45RAlow(lo), and CD5-CD45RAhigh(hi)), and analyzed for the type of Ig produced after EBV infection and culture. Like their CD5+ counterparts, most CD5-CD45RAlo B lymphocytes were precursors of cells producing IgM, a major proportion of which displayed the Ag-binding features of natural antibodies. In contrast, CD5-CD45RAhi B cells comprised a high frequency of IgG-producing cell precursors, possibly including memory B lymphocytes. Six of seven IgM mAb generated from sorted CD5-CD45RAlo B cells and three of four IgM mAb from sorted CD5+ B cells were polyreactive, binding with different affinities (Kd, 10(-5) to 10(-8) M) to two or more Ag; the remaining mAb from CD5-CD45RAlo and the mAb from CD5+ B cells each bound to a single Ag (Kd, 10(-7) to 10(-8) M), beta-galactosidase and ssDNA, respectively. CD5-CD45RAlo B cells account for 4.1 +/- 1.2% (mean +/- SD in 11 healthy subjects; CD5+ B cells, 23.3 +/- 6.9%) of total B lymphocytes and display the features of quiescent cells. In a given individual, the number of CD5-CD45RAlo B cells remains constant over time. CD5-CD45RAlo and CD5+ B cells bear surface CD11b and CD14, at densities and/or frequencies apparently higher than those of CD5-CD45RAhi B lymphocytes. Despite their surface CD5- phenotype, CD45RAlo B cells express CD5+ mRNA at levels comparable with those of CD5+ B lymphocytes, whereas CD5-CD45RAhi B cells express only trace amounts of CD5 mRNA. The commitment to natural antibody production and the degree of CD5 mRNA expression suggest that the newly defined CD5-CD45RAlo B cell subset is related to CD5+ B lymphocytes, and may constitute the human homologue of the mouse Ly-1-"sister" B cell population.

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