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Keywords:

  • anti-FcεRIα autoantibodies ;
  • autoimmune disease;
  • intolerance reactions;
  • urticaria

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Background: In recent years, a histamine-releasing anti-FcεRIα autoantibody has been demonstrated in about one-third of patients with chronic urticaria. However, its clinical significance is still unclear. The objective was to detect a possible correlation between the occurrence of the anti-FcεRIα autoantibody and the clinical type or cause of urticaria.

Methods: Sera from 66 consecutively seen in- and outpatients with various types of urticaria and five healthy controls were examined for the presence of anti-FcεRIα autoantibodies with a sandwich ELISA technique. In addition, basophil histamine release was studied in 13 autoantibody-positive sera.

Results: Anti-FcεRIα autoantibodies were found in 17/48 patients with chronic urticaria, in 2/4 with angioedema, in 1/2 with urticarial vasculitis, and in 2/11 with dermographic urticaria. However, no anti-FcεRIα autoantibodies were detected in acute, cold, or delayed-pressure urticaria; in urticaria pigmentosa; or in normal controls. Of all chronic urticaria patients, 22 were classified as idiopathic since no underlying cause could be found. Of this group, seven were seropositive for anti-FcεRIα. However, anti-FcεRIα was also found in patients who went into remission after treatment of identified causes; namely, in one with type I allergy, one with drug intolerance, one with Helicobacter infection, and six with food intolerance. The autoantibody was also detected in 2/4 patients with associated autoimmune diseases. Functional activity was shown in basophil histamine release in 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and in 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes.

Conclusions: These data confirm that anti-FcεRIα autoantibodies in urticaria are mostly found in chronic urticaria. Furthermore, their detection independently of the apparent cause of the urticaria suggests that as yet unidentified mechanisms must be operative, possibly related to the chronic inflammatory process and/or individual predispositions that favor their induction.

Abbreviations
FcεRI

alpha chain of the high-affinity IgE receptor

MHC

major histocompatibility complex

scOD

specific corrected optical density

TNF

tumor necrosis factor

The pathogenesis of urticaria is largely unclarified, although mast-cell-dependent mediator release is generally accepted to be the common denominator of the underlying mechanisms of the diverse subtypes of the disease ( 1). In contrast to generally held opinions, specific IgE sensitization is rare, and, instead, acute urticaria often arises in association with viral diseases ( 2, 3), and pseudoallergens in drugs and food have been shown to elicit the reactions in more than half of chronic urticaria patients ( 4). Chronic urticaria also encompasses whealing reactions in the framework of the so-called physical urticaria, which is elicited on contact of the skin with mechanical stimuli or electromagnetic waves (reviewed in Henz et al. [ 1]).

Major advances in the understanding of the pathogenesis of urticaria were made in recent years with the demonstration that, in about 60% of patients with chronic idiopathic urticaria, whealing reactions can be elicited on injection of the patient's own serum ( 5). Further investigations showed that in about 23% of these patients, an autoantibody to the α-chain of the high-affinity IgE receptor (FcεRIα) was found to induce mediator release from normal donors' blood basophils and skin mast cells ( 6–9). These findings were confirmed independently by other groups ( 10–13). Furthermore, the autoantibodies were also identified in several types of autoimmune disease ( 14) as well as in atopics and healthy individuals ( 15).

Reasons for the development of functional anti-FcεRIα antibodies in a subgroup of patients with chronic urticaria and their potential disease-initiating or sustaining significance are currently unclear. The therapeutic implications have so far been unclarified ( 16).

Since chronic urticaria encompasses a broad spectrum of clinical subtypes and eliciting causes, we have tried to shed further light on the pathogenetic significance of the anti-FcεRIα antibodies in chronic urticaria by examining routinely collected sera from a group of patients with diverse types of urticaria. The data show that the occurrence of the anti-FcεRIα autoantibodies is also found in patients whose disease responded to cause-related treatment.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Venous blood was collected routinely for diagnostic pur-poses from consecutively presenting urticaria patients at the in- and outpatient departments of dermatology of the Charité in Berlin, Germany, over a 1-year period. After clotting, the sera were stored in aliquots at −60°C. Aliquots were shipped on dry ice and in one lot for anti-FcεRIα autoantibody analysis to the department of dermatology, University of Vienna Medical School, Vienna, Austria.

The diagnosis of different types and causes of urti-caria was made on the basis of a thorough history and physical examination, appropriate provocation and lab-oratory tests, and remission of the disease on elimination of implicated causes, as previously detailed ( 1, 4, 17). Briefly, chronic urticaria was defined as lasting for at least 6 weeks, with a chronic continuous or intermittent overall course. To diagnose pseudoallergies, patients had to improve on a diet free of preservatives, colorings, and natural aromas, with recurrence of symptoms on blinded oral provocation. The diagnosis of dermographic and delayed-pressure urticaria was confirmed with an immediate reaction on application of a shearing pressure with a dermographometer and a deep wheal 4–8 h after application of static pressure with a special device, respectively, as previously described ( 1). For the diagnosis of urticaria vasculitis, leukocytoclastic vasculitis had to be present on lesional histology ( 1).

ELISA measurements were conducted as previously described ( 14). Sera with a specific corrected optical density (scOD) of <40 were classified as negative, those with an scOD of 41–90 as moderately (+) positive, and those with an scOD of >90 as strongly (++) positive. Basophil histamine release was studied as previously described ( 7), at least two different donors and normal as well as IgE-stripped cells being used.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

As with most types of urticaria, there was a predominance of females (68.2%) over males in the present patient population. However, more males (47.6%) than females (31.1%) had detectable autoantibodies in their serum, although strong reactivity was found in more females (8/18) than males (1/8).

When examined for anti-FcεRI autoantibodies in different types of urticaria ( Table 1), most sera were found to be positive in chronic recurrent urticaria, with slightly more patients exhibiting moderately than markedly elevated titers. Anti-FcεRIα autoantibodies were also detected in two patients with angioedema, irrespective of the presence of associated chronic urticaria, in one of two patients with urticarial vasculitis, and in two patients with dermographic urticaria in the absence of chronic urticaria.

Table 1.  Serum antibody reactivity in patients with different types of urticaria
  Number anti-FcεRIα positive§
Clinical type of urticariaNumber tested+++
  1. *This patient suffered also from associated chronic recurrent urticaria. **Two patients suffered also from associated chronic recurrent urticaria. +No associated chronic recurrent urticaria. §+: moderate (scOD titer 41–90); ++: strong reactivity of sera (scOD titer >90) ( 8).

Acute urticaria100
Chronic recurrent urticaria48107
Angioedema41*1+
Urticarial vasculitis201
Dermographic urticaria11**2+0
Delayed-pressure urticaria100
Cold urticaria100
Urticaria pigmentosa100
Normal controls500

In 55.1% of the patients with chronic recurrent urticaria, excluding physical urticaria, an eliciting or probably causative agent could be identified ( Table 2). Among these, anti-FcεRIα autoantibody reactivity was found in the two patients with associated autoimmune phenomena, and in one patient each with type I allergy and an intolerance reaction to the nonsteroidal anti-inflammatory drug paracetamol, respectively. Further-more, elevated anti-FcεRIα autoantibody titers were detected in 6/17 patients in whom natural aromas and food additives were identified as eliciting and sustaining causes of their chronic urticaria.

Table 2.  Serum autoantibody reactivity in chronic urticaria patients with different underlying causes, as proven by provocation tests and remission on omission or after specific treatment targeted at putative cause
  Number anti-FcεRIα positive§
Cause of chronic urticariaNumber tested+++
  1. a To latex and cross-reacting foods. b To paracetamol. c Proven by oral provocation to food additives and natural aromas and remission on diet avoiding these agents ( 14). d Hashimoto's thyroiditis. e Vasculitis and rheumatoid arthritis. §+: moderate (scOD titer 41–90); ++: strong reactivity of sera (scOD titer >90) ( 8).

Type I allergy201a
Drug intolerance401b
Food intolerancec1733
Helicobacter pylori100
Intestinal candidosis100
Association with autoimmune diseases21d1e
Idiopathic2243

Seven sera were also positive among the remaining 22 patients with so-called idiopathic urticaria where no obvious cause of the urticaria could be found.

In order to check the functional activity of these autoantibodies, 13 sera of chronic urticaria patients were tested for in vitro basophil-releasing capacity. Exactly 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes showed histamine-releasing activity ( Table 3).

Table 3.  Investigation of basophil histamine releasability in anti-FcεRIα-positive chronic urticaria patients with different underlying causes
Cause of chronic urticaria (n) Positive basophil histamine-release test
Food intolerance (5)3/5
Helicobacter pylori (1)1/1
Idiopathic (4)3/4

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References

The present findings from a sizable number of routinely screened urticaria patients confirm previously published data on the incidence of anti-FcεRIα autoantibodies in about one-third of patients with chronic urticaria ( 7–14). They show also that the antibodies are found not only in patients with idiopathic urticaria, but also in those with obvious eliciting agents, as exemplified by the patient who suffered from IgE-dependent combined latex and fruit allergy, and by the patients with proven intolerance to paracetamol or food ingredients. The occurrence of the autoantibodies in chronic urticaria patients with other associated autoimmune processes and in the patient with urticarial vasculitis is particularly interesting since it suggests that the development of the anti-FcεRIα antibodies may be favored in patients with coexisting autoimmune diseases. The increased incidence of markedly elevated anti-FcεRIα autoantibody titers in women also fits the known predominance of females over males in the development of autoimmune diseases.

From the present data, the mechanisms inducing parts of the FcεRIα-chain to become an auto-immunologic target in seropositive urticaria patients remain unclear. In general, urticaria is not associated with increased IgE levels or atopy ( 1). Furthermore, patients with the anti-FcεRIα autoantibody have even lower serum IgE levels than the autoantibody-negative patients ( 18). On the other hand, TNF-α is upregulated in either the lesional and nonlesional skin or in the serum of patients with all types of urticaria, together with other proinflammatory and immuno-modulatory cytokines, as well as with diverse adhesion molecules, including MHC class II molecules ( 19–23). The chronic upregulation of these proinflammatory and immunomodulatory molecules may favor the development of autoimmune phenomena in predisposed patients. An increased severity of urticaria symptoms in the patients with the anti-FcεRIα autoantibodies ( 18) would also suggest this possibility, although the intensity of the inflammatory infiltrate does not seem to be of significance ( 24).

The present study also shows that the autoantibody-positive sera contain histamine-releasing capacity, suggesting functional autoantibodies ( Table 3). Since the occurrence of the autoantibodies was independent of the underlying cause of the disease or state of disease activity, a possible secondary rather than an initiating nature of the autoantibodies in urticaria is indicated. A possible explanation could also be the demand for cofactors required for an activation in vivo. A similar situation is found in different urticaria subtypes, such as exercise-induced urticaria and anaphylaxis, where in some patients an IgE-dependent allergen leads to clinically significant mast-cell degran-ulation only when a second stimulus, such as exercise, is present.

Final conclusions regarding the possible mechanisms of action involved in the generation of the FcεRIα autoantibodies, as well as their clinical significance, will have to await further studies. In particular, analysis of the autoantibodies in a sizable group of patients suffering from acute urticaria, as well as in the same patients on progression to chronic urticaria, may help to clarify whether the autoantibodies are disease initiating or not, since, by definition, all chronic urticaria must start as acute urticaria.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. References