Numbers Of CD8 Research Articles

IFN-alpha-mediated suppression of low-affinity FC(epsilon) receptors on Peyer's patch lymphocytes and augmentation of soluble CD23: implications for IgE responses.

The ability of interleukin (IL)-6 or interferon-alpha (IFN-alpha) to regulate expression of low-affinity Fc(epsilon) receptor (CD23) and serum levels of CD23 was studied in benzylpenicilloyl-keyhole limpet hemocyanin-sensitized BALB/c mice at the peak of a hapten-specific immunoglobulin E (IgE) antibody-forming cell (AFC) response. These responses are analogous to those observed in human atopic disease. To induce peak IgE responses, mice were injected intraperitoneally with BPO-KLH (10 micrograms) in aluminum hydroxide gel (alum) on days 0, 21, and 42. On day 44, mice were injected subcutaneously with IL-6 (100-1000 U) or IFN-alpha (1000-10,000 U). On day 46, numbers of CD23+ lymphocytes in Peyer's patches (PP), mesenteric lymph nodes (MLN), and spleen and levels of soluble CD23 in serum were determined (flow microfluorimetry and enzyme-linked immunosorbent assay, confirmed by competition assay). Data are expressed as percent total cells or as optical density at 490 nm. IFN-alpha treatment strongly suppressed (up to 100%) numbers of CD23+ cells exclusively in PP (i.e., numbers of CD23+ cells in MLN and spleen were unchanged) whereas serum levels of soluble CD23 were dramatically increased (60%). IL-6 treatment had no effect on either numbers of CD23+ lymphocytes or on serum levels of soluble CD23. The data suggest that the mechanism(s) by which IFN-alpha, but not IL-6, regulates IgE responses involves suppression of CD23 expression on lymphocytes in PPs and supports a central role for these organs in regulation of IgE responses in vivo.

Analysis of natural killer‐associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications

The aim of this study was to analyse the expression of NK-associated antigens in both peripheral blood and bone marrow lymphocytes from a large series of newly diagnosed multiple myeloma patients. 112 patients with untreated multiple myeloma (MM) were included in the study. 36 sex- and age-matched healthy volunteers were used as controls for peripheral blood (PB) studies and 14 for the bone marrow (BM) studies. Simultaneous stainings with the CD3/CD56, CD2/CD16 and CD8/CD57 monoclonal antibodies were systematically performed in PB and CD3/CD56 and CD2/CD16 in BM in order to analyse their relationship with the clinical and biological characteristics of the disease and survival. The expression of NK-associated antigens (CD56, CD16 and CD57) assessed within the lymphoid gate, was significantly increased (P < 0.001) in the PB of MM patients both in relative and absolute numbers. In the BM a significant increase in the percentage of CD56+ lymphocytes (P < 0.001) was also observed; in contrast, the proportion of CD16+ cells did not differ significantly from that of normal BM samples. The number of CD56+CD3- lymphocytes increased significantly within high-risk patients (869 +/- 671) as compared to intermediate (388 +/- 212) and low-risk patients (274 +/- 199) (P = 0.04). Moreover, patients with high values of CD56+CD3- lymphocytes showed a statistically significant association with several adverse prognostic factors including anaemia, hypoalbuminaemia, renal failure, high beta 2M, DNA diploidy and high S-phase plasma cells. In addition, patients with higher absolute numbers of PB CD56+CD3-lymphocytes displayed a poorer prognosis, whereas patients with higher values of CD57+CD8- cells had a better outcome.

Effect of 12 Neutralizing Anti‐Cytokine Antibodies on In Vitro Activation of B‐Cells. Interleukin‐12 is Required by B1a but not B2 Cells

Normal human peripheral blood mononuclear cells, depleted of most monocytes and virtually all CD8-positive cells, were stimulated in vitro with pokeweed mitogen plus Staphylococcus aureus Cowan I in the presence or absence of various neutralizing anti-cytokine antibodies. Numbers of CD5+ and CD5- immunoglobulin-secreting cells were determined using the protein A haemolytic plaque assay after labelling B1a cells with anti-CD5-coated beads. Antibodies against IL-2, IL-5 and IL-10 had little or no effect on plaque-forming cell (PFC) induction; anti-IL-6, -TNF alpha and -TGF beta enhanced PFC induction; anti-IL-1 alpha, -IL-1 beta, -IL-4, -IFN gamma and -IL-13 suppressed PFC induction. B1a and B2 cells were equally affected by cytokine deprivation using these 11 neutralizing antibodies. In contrast, neutralizing anti-IL-12 suppressed induction of CD5+ but not CD5- PFC. Furthermore, recombinant IL-12, if added during the first 48 h of culture, enhanced CD5+ PFC induction while marginally suppressing (IgG-) or not affecting (IgA-, IgM-) induction of CD5- PFC. IL-12 did not preferentially increase survival in culture of B1a cells nor induce expression of CD5 on B2-cells. Further studies are required to determine whether manipulation of B1a and B2 subsets in vivo using IL-12 could be achieved in clinical situations where imbalances in the two populations have been observed.

Bronchial inflammation in occupational asthma due to western red cedar.

Bronchoalveolar lavage cells and bronchial biopsies were obtained from nine patients with red cedar asthma, six atopic asthmatics and six non-atopic, non-asthmatic control subjects. There were similar proportions of neutrophils, mast cells, lymphocytes, and macrophages in BAL samples from all three groups, but eosinophil numbers were elevated in patients with cedar asthma and atopic asthma (3.0 and 2.5% respectively versus 0.5% in control subjects; p < 0.05 for each group). In bronchial mucosal biopsies, mean numbers of T cells were elevated in both asthmatic groups (cedar asthma 9.8 times, and atopic asthma 2.6 times, control values). CD4+ cells accounted for most of the increase in T-cell numbers, while CD8+ cell numbers were elevated in biopsies from a minority of cedar asthma patients. Absolute numbers of CD25+ (IL-2 receptor-bearing) cells were increased in cedar asthma but the proportion of T cells expressing CD25, was similar in all three groups. Activated eosinophils (EG2+) were increased in both asthmatic groups, with mean numbers 2.5 times greater in the cedar asthma biopsies than in atopic asthmatics. Thus both cedar asthma and atopic asthma are associated with increased numbers of T-cells and activated eosinophils in the bronchial mucosa. There was no major histologic difference between atopic asthma and red cedar asthma.

CD25+ T-lymphocytes induce CD11b on eosinophils in allergic nasal mucosa

In the allergic mucosa, there is a significant increase in numbers of CD25+ cells and activated eosinophils. To determine whether a link exists between the activated T-lymphocytes and tissue eosinophils in nasal allergy, we studied CD25+ cells in the nasal mucosa and compared the levels of soluble IL-2 receptor (sIL-2R) both in the serum and the nasal secretions, and further investigated expression of CD11b on eosinophils in the nasal lavage fluids and peripheral blood of patients with nasal allergy. We also examined the effects of the culture supernatant of Con A- and IL-2-activated T-lymphocytes on CD11b expression on eosinophils in the present study. The concentration of sIL-2R in the nasal secretions from patients with Japanese cedar pollinosis (JCP) was significantly higher than that from normal subjects (p < 0.01). The sIL-2R level was significantly higher in the nasal secretions than in the sera in patients (p < 0.01), and CD11b expression on eosinophils from nasal hvage fluid was significandy higher than that of eosinophils from peripheral blood of the same individuals (p < 0.01). The activated T-lymphocytes promoted eosinophil activation with upregulation of CD11b in vitro, and eosinophils in the nasal secretions from patients significantly expressed more CD11b in vivo. These results indicate that activation of T-lymphocytes is linked to eosinophil activation in nasal allergy.

Altered T lymphocyte phenotype at birth in babies born to atopic parents

Flow cytometry was used to analyse the cord blood T cells of 33 babies at high risk 'HR' for developing allergy (born to at least one atopic, asthmatic parent), and 10 low risk 'LR' babies (born to non-atopic parents), following normal term deliveries. Significantly lower numbers of CD25+, (activated) T cells (p < 0.005) were seen in the cord blood of the HR babies who had developed both allergic symptoms and positive skin prick tests by one year of age when compared with the LR group. CD45RO+ (memory) T cells were detected in both HR and LR babies with a trend for lower numbers of memory cells to be detected in HR infants who later developed allergic symptoms and/or positive skin prick tests. Significantly lower numbers of CD4+/CD45RO+ were seen in the cord blood of HR babies who developed allergic symptoms compared to HR babies who showed no sign of allergy by one year and to the LR babies (p < 0.05 and p < 0.005). The presence of activated and memory T cells at birth implies intra-uterine priming. The significantly lower numbers of memory T cells in the HR babies suggests a suppression of T cell activation or lack of antigenic priming in this group. This prenatal influence on babies born to atopic parents may have important implications with regard to the mechanisms underlying atopic sensitisation.

SEVERE B CELL DEPLETION IN NEWBORNS FROM RENAL TRANSPLANT MOTHERS TAKING IMMUNOSUPPRESSIVE AGENTS

There have been several reports of successful pregnancies of kidney transplant mothers receiving immunosuppressive agents such as CsA and/or AZA. However, few papers have investigated immune function of neonates from those mothers. We investigated the lymphocyte subpopulations and T cell subsets in cord blood of newborn infants from those mothers. The subjects were 6 infants born to mothers following renal transplantation, who all were receiving CsA, AZA, and methylprednisolone. Cord blood and peripheral blood at 1 month and 3 months of age were obtained from the subjects. Control samples were obtained from 5 normal newborns. The polyclonal antibody used to investigate B cells was anti-F(ab')2 fragment of human immunoglobulin. Direct immunofluorescence staining and flow cytometry were used for the investigation. The number of B cells and the percentage of B cell in total mononuclear cells were significantly lower in the subjects than in normal controls. There was no significant difference between numbers of CD2+, CD4+, or CD8+ cells in the subjects and the controls. This severe B cell depletion remained low at 1 month and 3 months of life in many cases. From our result, it is very possible that the B cell line is more sensitive to immunosuppressants in utero than the T cell line. Infants of mothers taking immunosuppressive agents during their pregnancy should be followed carefully for possible insufficiency of immune function.

Subpopulations of T and B Cells in Perinatally HIV-Infected and Noninfected Age-Matched Children Compared with Those in Adults

Peripheral blood mononuclear cells were quantified for the subsets of CD4, CD8, and CD19 lymphocytes by using CD45RA (2H4), CD29(4B4), CD57, CD5, CD10, Leu8, HLADR, and TCRγδ-1 monoclonal antibodies and dual color immunofluorescence. A comparative analysis of lymphocyte subpopulations was made among 52 HIV-infected and 50 age-matched control children and 30 HIV-seropositive and 27 negative control adults. A significant decrease in the CD4 +CD45RA + "naive" cells was much more marked in HIV-infected children than in HIV-infected adults. A significant percentage increase in the CD4 +CD29 + "memory" cells was observed in HIV-infected children but not in infected adults; however, the absolute numbers were usually decreased in all age groups. The mean percentage and absolute numbers of CD4 +CD7 + and CD4 +Leu8 + cells were decreased in HIV-infected children, although usually not significantly. The CD3 +TCRγδ-1 + did not show any change in the infected children tested. The mean percentage and absolute number of the CD8 +HLA-DR + cells increased significantly in HIV-infected persons of all ages. The CD8 +CD57 + cells were increased in percentage and absolute number in HIV-infected children ages 1-4 and 4-8 years. In the adults, no change was noted in either the percentage or absolute number of CD19 +CD5 + B cells, a finding similar to that noted in HIV-infected children above 1 year of age. Although adults showed a significant decrease in both percentage and numbers of CD5 - B cells, an increase was noted in the 7- to 12-month-old HIV-infected children. The CD19 +CD10 + cells showed a slight but significant decrease in the youngest age group and a significant increase in the older age groups of HIV-infected children. These findings indicate that several lymphocyte subpopulations are altered differentially during HIV infection in children of varying ages and in adults.

CD5 is associated with the human B cell antigen receptor complex.

On human B cells the antigen receptor complex is composed of the membrane form of the immunoglobulin molecule and the non-covalently associated Ig alpha/beta heterodimer. A small subpopulation of normal B cells and chronic lymphocytic leukemia B cells express (analogous to T cells) the transmembrane molecule CD5, a counterstructure of B cell-specific CD72. Numbers of CD5+ B cells are increased in several physiological and pathological conditions. Moreover, CD5+ B cells are being held responsible for the production of autoreactive antibodies and seem to have signaling characteristics distinct from conventional B cells. On T cells, CD5 associates with the T cell receptor CD3 complex and ligation of CD5 leads to the generation of co-stimulatory signals, that act on T cell activation. We here demonstrate that CD5 is associated with the B cell receptor (BCR) complex and serves as substrate for BCR-induced tyrosine kinase activity. Hence, CD5+ B cells have a unique potential to modulate BCR signals.

Expression of the costimulatory molecule B7/BB1 in autoimmune thyroid disease

Efficient antigen presentation requires the provision of a costimulatory signal, the best characterized of which is B7/BB1. It is unclear whether thyroid cells expressing class II molecules can present autoantigens to T cells, although this has been suggested as an important mechanism in the initiation of Graves' disease and Hashimoto's thyroiditis. We have found that thyroid cells from patients with thyroid autoimmunity do not express B7/BB1 in vivo or in vitro, even after activation with the cytokines interleukin-1 or gamma-interferon, or with a phorbol ester. Increased numbers of CD20+ B cells and CD14+ dendritic cells expressing B7/BB1 were found in intrathyroidal lymphocyte preparations from such patients compared to peripheral blood. These results suggest that conventional antigen-presenting cells rather than thyroid cells provide B7/BB1 costimulatory activity in autoimmune thyroid disease, and argue against a role for the thyroid cells themselves in autoantigen presentation to T cells via the B7/BB1 pathway.

A comprehensive analysis of peripheral blood lymphocytes in healthy aged humans by flow cytometry

This study used a panel of mAb and multiparameter flow cytometry to assess the composition of PBL from healthy aged individuals. The results showed that while total lymphocyte numbers altered only marginally in the aged (> or = 70 years) there were significant changes in the distribution of various sub-populations; for example, there were lower numbers of CD3+ and CD8+ cells, and higher numbers of CD16+ (NK) cells. As a direct result of these changes the numbers of CD2+ cells remained unchanged in the aged compared with young adult controls (18-25 years). The number of CD4+ T cells expressing CD45RO isoform (memory cells) exceeded the number of CD4+CD45RA+ (naive) cells in aged donors, whereas the converse was true for young donors. In addition, associated with this increase in CD45RO+ cells, the aged showed an expanded population of CD45RO+ T cells displaying low surface levels of CD45RO. These data suggest that shifts in the distribution of regulatory T cell subsets may play a role in age-related changes in immune response.

Immunological Characteristics of Umbilical Cord Blood Cells: Phenotypic and Functional Analysis

The purpose of this study was to phenotype and assay immunological function on cord blood from 70 samples. Immunophenotyping indicated similar numbers of CD2, 3, and 8-positive cells as in adult bone marrow. CD4-positive cells were increased and CD19, 20, and CD56-positive cells were decreased in numbers. Proliferative responses to nonspecific mitogens were lower in cord blood cells than in adult cells, as was NK activity and spontaneous secretion of IL-6 and TNF-alpha. This study confirms the relative immaturity of cord blood cells even when some functional assays appear normal.

Impaired activity of natural killer cells in patients with acute brucellosis.

Researchers have claimed that natural killer (NK) cells are involved in the mechanisms of defense of the host against infections. We have investigated the activity of NK cells in peripheral blood mononuclear cells (PBMNC) from 12 patients for whom acute brucellar infection has been diagnosed and from 14 healthy controls. The sera of eight of the patients were also analyzed 3 months after initiation of a 45-day course of antibiotic treatment, at which time they had no evidence of relapse. PBMNC from patients with acute brucellar infection showed a significantly depressed NK cell activity (P < .01) when compared with those from healthy controls; this depressed activity was not related to a deficient number of NK cells since the numbers of CD56+ and CD16+ cells present in PBMNC were similar in patients and controls. Incubation of PBMNC from patients with acute brucellar infection with recombinant interleukin-2, but not with interferon-gamma, can correct this impaired cytotoxic activity. In treated patients, there was a significant enhancement (P < .05) and normalization of the previously defective NK cell activity. It is concluded that acute brucellar infection is associated with a deficient cytotoxic activity of NK cells that can be overcome by in vitro incubation with interleukin-2 and that reverts to normal after antibiotic treatment.

CD5 and immunoglobulin VH gene expression in B-cell lines from patients with autoimmune diseases.

We studied the CD5 mRNA expression and VH gene family usage in Epstein-Barr virus (EBV)-immortalized B-cell lines derived from the blood of patients with type 1 diabetes (IDDM) of recent onset and of patients with polyneuritis cranialis multiplex (cranial neuritis; CN). After immortalization with EBV, at least 10 cell lines from each subject were tested for surface CD5 and CD20. mRNA expression was studied using cDNA probes for the six VH families as well as for CD5. The EBV lines from the IDDM patients used the VHIV family more frequently and VHI and VHII families less frequently than lines from controls. EBV lines from CN patients expressed the VHI and VHII families more often than those of the controls. When the IDDM and CN lines were compared, the lines derived from IDDM patients were found to use VH families I and II less frequently and VH families IV and V more frequently than lines from CN patients. There were no significant differences in the mean numbers of CD5+ B cells in the cell lines tested. More than half of the lines from each patient expressed CD5 at the mRNA level. No correlation was seen between the expression of surface CD5 and the level of CD5 mRNA expression. There was, however, a positive correlation between the usage of VH families III, V and VI, and the CD5 mRNA expression. In conclusion, the usage of VH families I to VI seemed to differ in patients with IDDM and CN. No differences were seen in the surface CD5 expression, but the lines expressing CD5 mRNA preferentially used the VH families III, V and VI.

Levels of CD5+ B lymphocytes do not differ between patients with myasthenia gravis and healthy individuals.

CD5+ B cells might be involved in autoimmunity mainly as autoantibody-producing cells. To investigate the possible role of these cells in myasthenia gravis, we studied the numbers of CD5+ B cells, CD5- B cells, and CD19+ B cells as well as CD5+ T cells in the peripheral blood from 31 patients with myasthenia gravis and 31 healthy individuals. Both absolute percentages (percent of peripheral blood mononuclear cells) and relative percentages (percent of total CD19+ B cells) of CD5+ B cells were the same in patients as in controls. The numbers of CD5- B cells and CD19+ B cells were the same in both groups, whereas CD5+ T cells were lower in the patients. There was no correlation between clinical stage, sex, thymectomy, or pathology of thymus and the levels of CD5+ B cells, CD5- B cells, or CD19+ B cells. Patients treated with azathioprine had lower levels of CD5+ B cells than untreated patients and controls. Our results show that patients with myasthenia gravis have the same levels of CD5+ B cells as healthy individuals.

Peripheral Blood Mononuclear Cell Subsets in Patients With Severe Inherited Forms of Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a group of inherited disorders in which slight trauma to the skin results in blister formation. Patients with severe types of EB suffer cutaneous infections that sometimes progress to septicemia and cutaneous and gastrointestinal carcinomas that are locally aggressive and frequently metastasize. Previous studies have shown deficits in natural killer (NK) cell activity as well as in lymphokine and monokine production in patients with severe forms of EB. Alterations in peripheral blood mononuclear cells, however, which may reflect on immune functions in patients with EB, have received little attention. A prospective study was designed to ascertain if differences existed between subsets of peripheral blood mononuclear cells in patients with severe forms of EB vs healthy control subjects. Thirty patients with clinical and histologic diagnoses of EB and 30 healthy volunteers were studied. Flow cytometric analysis of labeled cells was performed. Absolute numbers of CD3+, CD2+, CD4+, CD19+, NK+, CD29+, and CD45R+ cells were lower in patients with severe types of EB in comparison with controls. The T cells showed decreased numbers of interleukin 2 receptors. An increase in numbers of CD20+, CD4+ CD8+, and CD4-CD8- cells was also observed in patients with severe types of EB. Alterations in monocyte and lymphocyte subsets known to affect host immune response were observed in patients with severe forms of EB. Quantitative changes relative to controls included decreased total numbers of T cells with greater decreases in helper cells, decreased NK cells, and a diminished number of interleukin 2 receptors. Such changes have been associated previously with a lower resistance to infections and to neoplasia. The changes in subsets correlated with the severity of the cutaneous and extracutaneous disease in the patients with EB.

Phenotypic analysis of CD23+ peripheral blood mononuclear cells in atopic dermatitis

There is an increase in the number of CD23+ cells in peripheral blood mononuclear cells (PBMC) in atopic dermatitis (AD). We analysed the subpopulation of CD23+ PBMC in 11 patients with AD and in 10 healthy controls and found that B cells (CD20+) and non-T, non-B cells (CD3- CD20-) (mainly monocytes) were responsible for the elevation of CD23+ cells. CD23+ T cells (CD3+) comprised only 4.6% of total CD23+ cells in AD. The percentage of CD23+ cells did not correlate with the serum log IgE level nor with clinical severity of AD. Interleukin 4 (IL-4) induced the expression of CD23 antigen in PBMC both in AD and in healthy controls in a dose-dependent manner in vitro. This enhancing effect of IL-4 was completely abrogated by the addition of anti-IL-4 monoclonal antibody. Other cytokines such as IL-1, IL-2, IL-3, IFN-alpha, IFN-gamma and TNF-alpha had no significant effects on CD23 expression.

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. II. Immunologic evaluation

Immunologic functions are studied in conjunction with a placebo-controlled trial of lymphoblastoid interferon (IFN) in patients with chronic progressive (CP) multiple sclerosis. Prior to treatment, CD4+ cells are significantly increased and CD8+ cells decreased in the blood of MS patients. Both CD5+ and CD4+ cells increase significantly with IFN therapy early during the treatment phase of the trial, while the number of CD8+ cells decreases steadily, becoming significant at 6 months. CNS IgG synthesis rates increase with IFN treatment and maximize at 3 months. Serum antiviral activity also increases with IFN treatment. In the IFN-treated group, a trend toward improvement, determined clinically and by MRI, likely reflects the influence of a subpopulation of 10 patients. This subpopulation is now further characterized by an early increase in CNS IgG synthesis and numbers of CD5+ cells in the blood. Although these immune functions may identify a number of CP MS patients who might benefit from IFN, it is unlikely that these mechanisms actually mediate the potentially beneficial effects of this cytokine.

Mononuclear cell-bound CD23 is elevated in both atopic dermatitis and psoriasis

As patients with atopic dermatitis (AD) frequently have elevated serum IgE levels, the relation of this disease to CD23/FcεRII, a low affinity Fc receptor for IgE, and its soluble forms, sCD23, was studied. We examined the expression of CD23 on peripheral blood mononuclear cells (PBMC) as well as the serum IgE and sCD23 levels in 33 patients with AD and in 9 patients with psoriasis in comparison with 10 healthy donors. In AD patients, the numbers of CD23 + unfractionated PBMC and CD23 + small adherent cells were significantly elevated ( P < 0.05, resp. P < 0.005). In psoriatic patients however, CD23 was also significantly elevated on PBMC ( P < 0.05) and on small adherent cells ( P < 0.05). There was no significant difference in the frequencies of CD23 + cells between AD and psoriasis patients. In all donors, CD23 could be detected only on B cells, but not on monocytes/macrophages. In AD patients who were examined twice, an increase or decrease of the clinical AD score was always accompanied by an increase or decrease, resp., of cell-bound CD23. The serum sCD23 level was not significantly increased in either group of patients. Our results suggest that CD23 should be considered as a nonspecific marker for B cell activation in the context of inflammation and not as a specific marker for AD.

T Cells and Asthma

Abnormalities of peripheral-blood lymphocyte subsets and activation markers were detected in patients with both allergic and nonallergic asthma. Most allergic asthmatics were characterized by increased numbers of IL-2R&lt;sup&gt;+&lt;/sup&gt; helper T cells and CD23&lt;sup&gt;+&lt;/sup&gt;B cells. In contrast, nonallergic asthmatics showed increased numbers of IL-2R&lt;sup&gt;+&lt;/sup&gt; and HLA-DR&lt;sup&gt;+&lt;/sup&gt; helper and cytotoxic T cells, and a clear redistribution from naive (CD45RA&lt;sup&gt;+&lt;/sup&gt;) to memory (CD45RO&lt;sup&gt;+&lt;/sup&gt;) cells. The number of IL-2R&lt;sup&gt;+&lt;/sup&gt; T cells correlated with the number of CD23&lt;sup&gt;+&lt;/sup&gt; B cells in allergic asthma. These changes in the distribution and activation state of T cells suggest an active role for T cells in the pathogenesis of both allergic and nonallergic asthma.