Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation.

BACKGROUND: Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen-induced rhinoconjunctivitis. This immunotherapy downregulates TH2 immune responses, induces tolerogenic pathways, and increases regulatory T cells. However, associated immune response markers of allergen desensitization remain undefined. OBJECTIVE: We sought to characterize the kinetics of individual changes in the immunologic response to grass tablet SLIT. METHODS: We evaluated the systemic effects of SLIT in a longitudinal analysis of humoral and cellular immune parameters in peripheral blood samples. RESULTS: Grass tablet SLIT administration induced a 2-phase systemic humoral and cellular response. The TH2 response was initially exacerbated and detected as increased allergen-specific IgE (sIgE) and IgG4 (sIgG4) levels and an increase in IL-4-producing cells, followed by downregulation of the TH2 response with a shift toward a TH1 cytokine profile. T cells with a regulatory phenotype were also elicited. Statistical correlations between immunologic measurements for each patient throughout therapy indicated that TH2 response downregulation and reduction of the immediate SLIT-induced IgE response were associated with increased allergen-specific IgG4 synthesis early in therapy. TH2 response downregulation by month 4 correlated with increased frequency of CD4(+) T cells with a regulatory phenotype by 12 months. CONCLUSION: Changes in sIgE levels after therapy were linked to a specific IgG4 response, and production of blocking antibodies correlated with TH2 response downregulation. Reduced IL-4(+) cell frequency was linked to an increase in the frequency of CD4(+) T cells with a regulatory phenotype. Changes in sIgE levels and reduced IL-4 and blocking antibody levels could thus be used as indicators of a patient's immune response to therapy.

Avidity Studies in Anisakis simplex-Associated Allergic Diseases.

Gastroallergic anisakiasis (GAA) and Anisakis-sensitization-associated chronic urticaria (CU+) differ with respect to specific IgE levels. We hypothesised different immunoglobulin avidities in both entities as well as their dependence on TI and fish consumption. 16 patients with GAA and 17 patients with CU+ were included, and immunoglobulin levels were analysed by CAP (Phadia). IgE and IgG avidity indexes (AvIgE and AvIgG, resp.) were also determined. IgG avidity was higher in GAA than in CU+ (P = 0.035), whereas there was a tendency to lower IgE avidity in GAA (P = 0.095). When analysing all patients, AvIgG was positively correlated with specific IgE, IgG, and IgG4 as well as total IgE (Rho between 0.66 and 0.71; P < 0.002), but AvIgE was negatively correlated with specific IgE (Rho -0.57; P < 0.001), specific IgG4 (Rho -0.38; P < 0.05), and total IgE (Rho 0.66; P < 0.001). In GAA, weekly fish consumption was positively associated with AvIgE (Rho 0.51; P = 0.05). A multivariate regression showed that time interval was the main explaining factor for AvIgE in GAA. We could show a differential behaviour of immunoglobulin isotype avidities in both entities and their dependence on fish-eating habits as well as on the time elapsed to the last parasitic episode.

Different fish-eating habits and cytokine production in chronic urticaria with and without sensitization against the fish-parasite Anisakis simplex.

BACKGROUND: Anisakis simplex sensitization has been associated with acute, but also with chronic urticaria. The objective of this study is to characterize chronic urticaria with (CU+) and without sensitization (CU-) against the ubiquitous fish parasite A. simplex in a transversal and longitudinal evaluation. METHODS: 16 CU+ and 22 CU- patients were included and assessed for Urticaria activity score (UAS), fish-eating habits by standardized questionnaire and cytokine production (assessed by flow cytometric bead-based array) of peripheral blood mononuclear cells after stimulation with A. simplex extract or Concanavalin A (Con A). Patients were randomly put on a fish-free diet for three months and UAS, as well as cytokine production were again assessed. A difference of ≥1 in UAS was defined as improvement. RESULTS: There was no difference in UAS in both groups. Anisakis induced IL-2, IL-4 and IFN-γ production was higher in CU+. Con A induced IL-6 and IL-10 production was higher in CU+. CU+ was associated with higher total fish intake, whereas CU- was associated with oily fish intake. The correlation of UAS was positive with oily fish, but negative with total fish intake. There was a better UAS-based prognosis in CU+ without diet. Improvement was associated with higher Con A induced IL-10/IFN-γ as well as IL-10/IL-6 ratios. Further, previous higher oily fish intake was associated with improvement. CONCLUSIONS: Our data confirm the different clinical and immunological phenotype of CU+. Our results show a complex relationship between fish-eating habits, cytokine production and prognosis, which could have important consequences in dietary advice in patients with CU. When encountering A. simplex sensitization, patients should not be automatically put on a diet without fish in order to reduce contact with A. simplex products.

Graph based study of allergen cross-reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study.

The study of cross-reactivity in allergy is key to both understanding. the allergic response of many patients and providing them with a rational treatment In the present study, protein microarrays and a co-sensitization graph approach were used in conjunction with an allergen microarray immunoassay. This enabled us to include a wide number of proteins and a large number of patients, and to study sensitization profiles among members of the LTP family. Fourteen LTPs from the most frequent plant food-induced allergies in the geographical area studied were printed into a microarray specifically designed for this research. 212 patients with fruit allergy and 117 food-tolerant pollen allergic subjects were recruited from seven regions of Spain with different pollen profiles, and their sera were tested with allergen microarray. This approach has proven itself to be a good tool to study cross-reactivity between members of LTP family, and could become a useful strategy to analyze other families of allergens.

Chronic urticaria is associated with a differential helminth-arthropod-related atopy phenotype.

The relationship between atopic sensitization and chronic urticaria is still controversial. In this study, we aimed to compare the prevalence of aeroallergen sensitization in chronic urticaria patients with (CU/As+) and without (CU/As-) sensitization against Anisakis simplex. Forty-nine CU/As+ and 80 CU/As- patients were studied and skin prick tests (SPT) were performed against aeroallergens. We assessed sensitization in a subgroup of patients with allergic rhinoconjunctivitis and/or bronchial asthma (RCBA) and compared the prevalence with a control group of 522 non-urticaria patients with RCBA. Forty-five percent of CU/As- and 60.4% of CU/As+ patients displayed positive SPT to at least one aeroallergen. CU/As+ patients had a higher prevalence of sensitization against pollen, mould or dander (PMD) (52.2% vs 29.1%, P < 0.01), whereas the prevalence of house dust mite (HDM) sensitization was not statistically different (26.3% in CU/As- and 36.7% in CU/As+). However, in chronic urticaria patients with RCBA, 53.8% of CU/As- and 57.9% of CU/As+ patients differed in the prevalence of HDM sensitization compared to the control group (33.5%, P = 0.03), whereas no difference could be stated for PMD sensitization. Compared to RCBA patients, both CU/As+ and CU/As- patients have a higher clinically relevant sensitization rate against HDM, thus displaying a differential atopy phenotype.

Anisakis simplex sensitization-associated urticaria: short-lived immediate type or prolonged acute urticaria.

Acute urticaria is defined as evanescent wheals with a duration period of up to 6 weeks. Yet within acute urticaria, IgE-mediated urticaria lasts rarely more than 48 h, whereas longer duration periods are frequently unfruitful with respect to diagnostic work-up. We hypothesize the differences in immunologic features in immediate type urticaria versus prolonged acute urticaria within the model of Anisakis simplex (A. simplex) sensitization-associated urticaria. We included 57 patients with gastro-allergic Anisakiasis (GAA) and urticaria duration of less than 48 h and 17 patients with A. simplex sensitization-associated prolonged acute urticaria (PROL), defined as urticaria duration between 3 days and 6 weeks. As control group served 23 patients with A. simplex sensitization-associated chronic urticaria (CU+). We compared total IgE as well as specific IgE, IgG and IgG(4) against A. simplex. Median total IgE was higher in GAA than in PROL or CU+ [442 (interquartile range, IQR 198-995) vs. 117 (68-261) or 251 (94-382) kU/l, respectively]. Median-specific IgE was higher in GAA than in PROL or CU+ [62 (IQR 24.1-99) vs. 12.3 (6-30.9) or 14.2 (6.2-44.9) kU/l, respectively]. The differences were statistically significant at P < 0.001 for GAA against PROL and at P < 0.003 for GAA against CU+. Also, specific IgG and IgG(4) levels were higher in GAA than in PROL or CU+ at the same significance level. The levels of total IgE or specific immunoglobulin isotypes were not significantly different between PROL and CU+. In the model of A. simplex sensitization-associated urticaria, immediate-type urticaria in GAA is immunologically different from prolonged acute urticaria, which, in turn, shows features nearer to chronic urticaria than to gastro-allergic Anisakiasis. Thus, in an allergological evaluation of urticaria, we propose a possible benefit of a distinction of the duration period at 48 h, and not 6 weeks, when differentiating acute versus chronic urticaria.

Sympathomimetic drug allergy: cross-reactivity study by patch test.

INTRODUCTION: Sympathomimetic (alpha-adrenergic) drugs are mainly used because of their vasoconstrictor properties, for nasal congestion, or as mydriatics. Although sympathomimetic drugs are used often, allergic reactions are rare, especially when the drugs are administered systemically. Cross-reactivity may exist among catecholamine derivatives, although reported data on this are contradictory. In this study, we investigate if there is cross-reactivity in patch tests among these drugs. MATERIAL AND METHODS: Patch tests with 10% phenylephrine and 10% pseudoephedrine in petrolatum, and 10% and 20% ephedrine, 10% phenylpropanolamine, 5% fepradinol, 1% methoxamine, and 10% oxymetazoline, all administered in dimethyl sulfoxide (DMSO), were carried out in 14 patients with a history of allergy to any of these drugs. DMSO was used as the negative control. RESULTS: All patients except one (patient number five) showed positive patch-test reactions to at least two different drugs. Nine patients (64.3%) were cross-sensitized to three or more different drugs, and 57.1% of patients were sensitized to four or more sympathomimetic drugs. Patients who experienced generalized rashes caused by orally administered pseudoephedrine had a stronger response and more cross-reactivity with other sympathomimetic drugs in patch tests than those who experienced local contact dermatitis. CONCLUSIONS: We conclude that there is cross-reactivity among the different sympathomimetic drugs tested, especially if the drug is administered systemically.