Regulation of disease susceptibility: Decreased prevalence of IgE-mediated allergic disease in patients with multiple sclerosis

The development of restricted cytokine profiles by subsets of CD4⁺ T cells is a pivotal point in the regulation of immune responses. T cells producing Th1 cytokines (IL-2 and interferon-γ) induce cell-mediated immunity, whereas T cells producing Th2 cytokines (IL-4, IL-5, and IL-10) play a prominent role in the induction of humoral immunity. We examined a group of patients with multiple sclerosis, a disease caused by excess production of Th1 cytokines in myelin-reactive T cells, and control patients with noninflammatory neuroconvulsive disorders, for the presence of allergic disease, which is caused by excess production of Th2 cytokines in allergen-specific T cells. The patients with multiple sclerosis had significantly fewer allergic symptoms, a lower number of positive allergen-specific IgE test results, and lower composite allergy indexes than control subjects. These results demonstrate that the prevalence of IgE-mediated allergic disease is decreased in a group of patients with multiple sclerosis and support the hypothesis that genetic factors that promote susceptibility to Th1-mediated inflammatory disease in human beings protect against the development of Th2-mediated disease. (J ALLERGY CLIN IMMUNOL 1996;97:1402-8.)     

Immune responses in the lung and local lymph node of A/J mice to intranasal sensitization and challenge with adjuvant-free ovalbumin

Pathologic features of IgE-mediated allergic airway diseases include airway infiltration of inflammatory cells (eg, lymphocytes, plasma cells, and eosinophils) and mucous cell metaplasia (MCM) in airway epithelium. CD4(+) T lymphocytes, specifically those producing a type 2 (Th2) cytokine profile, are necessary for the induction of IgE-mediated allergic airway responses. Most experimental models of IgE-mediated allergic airway disease use systemic (eg, intraperitoneal) administration of an allergen coupled with an adjuvant to sensitize animals. Cytokine changes are measured in a number of ways including in bronchoalveolar lavage fluid (BALF) or lymph node cells stimulated ex vivo. The primary objective of this study was to test the hypothesis that intranasal sensitization and challenge of mice with ovalbumin in the absence of an adjuvant will induce the pathologic features that are characteristic of IgE-mediated allergic airway disease. Another objective was to determine if intranasal delivery of this allergen will result in the induction of a profile of cytokine gene expression in the lung and tracheobronchial (TB) lymph node, that is typical of immunologic changes associated with IgE-mediated allergic airway disease. Only mice that were intranasally sensitized and challenged with ovalbumin exhibited pulmonary lesions that included marked MCM in the respiratory epithelium lining the nasal and pulmonary airways, and an associated mixed inflammatory cell influx consisting of lymphocytes, plasma cells and eosinophils. Ovalbumin-treated mice also exhibited enhanced expression of the Th2 cytokine mRNAs IL-4, IL-5, IL-10, and IL-13 in the lung and IL-4 in the TB lymph node, and concurrent increases in ovalbumin-specific IgE in the serum. The results of this study indicate that A/J mice intranasally instilled with ovalbumin without adjuvant have the hallmark histopathologic and immunologic features of IgE-mediated allergic airway disease of humans.     

The immune response to intrinsic and extrinsic allergens: determinants of allergic disease

A central role for Th2 effector cells in IgE-mediated allergic disease is well established. However, the question of why some individuals develop allergic disease and others do not remains largely unanswered. Until recently, the prevailing view was that the allergic response reflected a shift in the Th1/Th2 'balance' to favor production of Th2 cytokines and IgE antibody isotype switching. Evidence is now emerging to suggest that distinct allergic responses cannot be distinguished simply on the basis of type 1 and type 2 cytokine profiles. For example, delayed-type hypersensitivity responses to intrinsic allergens derived from the dermatophyte fungus Trichophyton are associated with a paradoxical increase in Th2 cytokines compared with immediate hypersensitivity responses. In contrast, analysis of 'tolerant' responses to extrinsic allergens which are induced by specific immunotherapy or high-dose natural exposure to inhaled allergen (the modified Th2 response) supports a role for both the Th1 cytokine IFN-gamma and the regulatory cytokine IL-10. However, IL-10 may also be a critical mediator in the allergic response. In this article, we examine how analysis of epitope-specific T cell responses may lead to an understanding of how T lymphocyte cytokines relate to distinct allergic phenotypes. The relevance of Th1/Th2 and regulatory cytokines to development of new allergen-specific therapies is also discussed.     

The role of alpha-galactosylceramide-activated Valpha14 natural killer T cells in the regulation of Th2 cell differentiation

Valpha14 natural killer T (NKT) cells produce large amounts of both IL-4 and IFN-gamma upon stimulation with a ligand, alpha-galactosylceramide (alpha-GalCer), and play a crucial role in various immune responses, including allergic diseases. Interestingly, Valpha14 NKT cells are not essential for the induction of IgE responses but rather induce suppression of specific IgE production upon activation. The suppression in the IgE production is not detected either in Valpha14 NKT cell-deficient mice or in IFN-gamma-deficient mice. Thus, activated Valpha14 NKT cells are likely to exert a potent suppressive activity on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-gamma. In marked contrast, little regulatory effect of IL-4 produced by Valpha14 NKT cells on Th2 cell differentiation is suggested.     

Role of IgE in Th2 cell-mediated allergic airway inflammation

Recent studies with gene knockout mice have demonstrated that T helper 2 (Th2) cell-derived cytokines, including IL-4, IL-5, and IL-13, play important roles in causing allergic airway inflammation. In addition to Th2 cytokines, IgE-dependent activation of mast cells has been suggested to play a role in allergic airway inflammation. In this review, we will discuss the role of IgE in Th2 cell-mediated allergic airway inflammation. We used IgE transgenic mice, which enabled us to investigate the role of IgE without the influence of activated T cells and other immunoglobulins. Whereas IgE cross-linking by antigens did not induce eosinophil recruitment into the airways or airway hyperreactivity, IgE cross-linking induced CD4+ T cell recruitment into the airways. In addition, when antigen-specific Th2 cells were transferred to IgE transgenic mice, IgE cross-linking significantly enhanced antigen-induced eosinophil recruitment into the airways. These findings suggest that IgE-dependent mast cell activation plays an important role in allergic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.     

Evidence for an inflammatory pathophysiology in idiopathic rhinitis

BACKGROUND: The pathophysiology of idiopathic rhinitis is unknown but the disease is classified as being non-allergic on the basis of negative serum IgE radioallergosorbent assay (RAST) and skin prick tests. In contrast, allergic rhinitis has a Th2 type inflammatory pathology mediated by IgE and mast cells. OBJECTIVE: To test the null hypothesis that there would be no difference in the cellular infiltrate for key Th2-associated inflammatory cells between allergic and idiopathic rhinitis. METHODS: We applied strict selection criteria in the recruitment of allergic and idiopathic rhinitis cases. In contrast to previous studies which used cytology or small biopsies, we studied all layers of the mucosa by using whole, full-thickness nasal turbinate specimens with an average length of 2.5 cm. Immunohistochemistry and in situ hybridization techniques were used to compare the distribution and cell populations of mast cells, IgE positive (IgE+) cells, eosinophils and plasma cells in perennial allergic (n = 11) and idiopathic (n = 17) rhinitis, and control nasal mucosal tissue (n = 9). RESULTS: Mast cells and IgE+ cells were significantly increased within the epithelium of allergic and idiopathic mucosa compared to normal mucosa (P < 0.05). More IgE+ cells were present in the allergic group compared to the idiopathic group with the majority of IgE+ cells being mast cells. Both rhinitic groups showed increased eosinophilia localized to the superficial submucosa compared to normal mucosa (P < 0.05). More plasma cells were present in the allergic rhinitic tissue. CONCLUSION: Idiopathic and allergic rhinitic mucosa show similarities in their inflammatory infiltrate suggesting that both groups share a highly localized Th2, IgE-mediated cellular immunopathology.     

Mucosal immunity and allergic responses: lack of regulation and/or lack of microbial stimulation?

Summary: Allergic hyperreactivity is defined as an exaggerated immune response [typically immunoglobulin E (IgE) but also non‐IgE mediated] toward harmless antigenic stimuli. The prevalence of allergic disease has increased dramatically during the last 20 years, especially in developed countries. Both genetic and environmental factors contribute to susceptibility to allergy. Evidence has emerged supporting the hypothesis that a reduction in antigenic stimulation brought about by widespread vaccination, improvements in standards of hygiene, and extensive use of antibiotics has contributed to the dysregulation of T‐helper 2 cell (Th2) type responsiveness that typifies allergy. Regulation of the inherently Th2‐biased mucosal immune response is crucial both to the maintenance of homeostasis at this strategic defensive barrier and to the prevention of allergic disease. The ability of Th1 responses to counter‐regulate Th2 reactivity is well characterized. More recently, interest has centered on regulatory T cells, which can suppress both Th1 and Th2 cells through the secretion of immunosuppressive cytokines such as interleukin‐10 and transforming growth factor‐β. In this review, we discuss the basic cellular mechanisms of allergic diseases at mucosal surfaces, focusing on allergic responses to food, before examining newer work that suggests the induction of allergic hyperreactivity is due to a deficient immunoregulatory network, a lack of microbial stimulation, or both.     

Regulation of the human allergic response

Over the last several years our laboratory has been engaged in the in vitro study of the regulation of IgE synthesis. We have found that polyclonal B cell activators fail to induce IgE synthesis in human B cells. Alloreactive T cell helper clones induced synthesis in B cells only under conditions of interaction and in B cells from allergic donors under cognate conditions of bystander stimulation as well. Isotype-specific regulation of the IgE response was mediated in the secretion of IgE-binding factors by T cells suppressing Fc receptors for IgE. Finally, IgE immune complexes in sera from patients with hyper-IgE states were shown to downregulate T cell proliferation to antigen and to stimulate monocytes to resorb 45Ca-labelled bone and to release prostaglandins. The implications of these in vitro findings for disease states in which IgE is elevated are discussed.     

The role of interleukin 10 in the regulation of allergic immune responses.

Several clinical studies and animal models have shown that Th2 lymphocytes play a key role in the pathophysiology of IgE-mediated allergic immune responses like allergic rhinitis and asthma or venom anaphylaxis. Classical specific immunotherapy (SIT) that has been proven to be clinically effective can serve as a role model for immunological changes that are associated with amelioration of allergic diseases. During SIT, the Th2-dominated immune response is modified towards a Th1 response leading to a decline in allergen-specific IgE and an increase in allergen-specific IgG production. Most importantly, however, production of the immunosuppressive/-regulatory cytokine interleukin 10 (IL-10) is also induced leading to T cell tolerance and prevention of tissue inflammation. In this article the role of IL-10-producing T cells in the regulation of allergic immune responses will be discussed.     

T regulatory cells and their counterparts: masters of immune regulation

The interaction of environmental and genetic factors with the immune system can lead to the development of allergic diseases. The essential step in this progress is the generation of allergen-specific CD4⁺ T-helper (Th) type 2 cells that mediate several effector functions. The influence of Th2 cytokines leads to the production of allergen-specific IgE antibodies by B cells, development and recruitment of eosinophils, mucus production and bronchial hyperreactivity, as well as tissue homing of other Th2 cells and eosinophils. Meanwhile, Th1 cells may contribute to chronicity and the effector phases. T cells termed T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles distinct from that of either Th1 or Th2 cells, have been intensely investigated during the last 13 years. Treg cell response is characterized by an abolished allergen-specific T cell proliferation and the suppressed secretion of Th1 and Th2-type cytokines. Treg cells are able to inhibit the development of allergen-specific Th2 and Th1 cell responses and therefore play an important role in a healthy immune response to allergens. In addition, Treg cells potently suppress IgE production and directly or indirectly suppress the activity of effector cells of allergic inflammation, such as eosinophils, basophils and mast cells. Currently, Treg cells represent an exciting area of research, where understanding the mechanisms of peripheral tolerance to allergens may soon lead to more rational and safer approaches for the prevention and cure of allergic diseases.     

IgE‐expressing memory B cells and plasmablasts are increased in blood of children with asthma,food allergy,and atopic dermatitis

Despite the critical role of soluble IgE in the pathology of IgE‐mediated allergic disease, little is known about abnormalities in the memory B cells and plasma cells that produce IgE in allergic patients. We here applied a flow cytometric approach to cross‐sectionally study blood IgE+ memory B cells and plasmablasts in 149 children with atopic dermatitis, food allergy, and/or asthma and correlated these to helper T(h)2 cells and eosinophils. Children with allergic disease had increased numbers of IgE+CD27‐ and IgE+CD27+ memory B cells and IgE+ plasmablasts, as well as increased numbers of eosinophils and Th2 cells. IgE+ plasmablast numbers correlated positively with Th2 cell numbers. These findings open new possibilities for diagnosis and monitoring of treatment in patients with allergic diseases.     

Regulation of interleukin 4 production and of interleukin 4-producing cells.

Interleukin 4 (IL-4) is a cytokine with a broad range of functions on immune cells including the stimulation of IgE synthesis by B cells. IL-4 is synthesized by freshly isolated T cells following appropriate stimulation with either lectins or antibodies against selected surface antigens. IL-4 production has also been observed by freshly isolated FceR+ non-T, non-B cells. With T cell clones, IL-4 is produced by clones of the Th2 and Th0, but not of the Th1 type. The molecular basis for restricted cytokine production by such clones as well as the signals responsible for differentiation into either phenotype are only at the beginning to be understood.     

Differential regulation of human T cell cytokine patterns and IgE and IgG4 responses by conformational antigen variants

Bee venom phospholipase A₂ (PLA) represents the major allergen and antigen in allergic and non-allergic individuals sensitized to bee sting. We have studied specific activation of peripheral T cells by different structural and conformational variants of PLA and secretion of cytokines regulating IgE and IgG4 antibody (Ab) formation. PLA molecules expressing the correctly folded tertiary structure, which show high affinity to membrane phospholipids and were recognized by Ab from bee sting allergic patients, induced high IL-4, IL-5 and IL-13 production in peripheral blood mononuclear cell cultures. In contrast, non-refolded recombinant PLA (rPLA) and reduced and alkylated native PLA (nPLA) induced more IFN-γ and IL-2 and higher proliferative responses. Differences in proliferation and cytokine patterns among correctly folded and non-refolded PLA resulted from conformation-dependent involvement of different antigen-presenting cell (APC) types. Antigen (Ag)-presenting B cells recognized PLA only in its natural conformation, stimulated Th2 type cytokines and induced IgE Ab. Non-refolded PLA was recognized, processed and presented exclusively by monocytes and induced a Th1 dominant cytokine profile leading to IgG4 production by B cells. The possibility that production of particular cytokine patterns and Ig isotype was influenced by the enzymatic activity of PLA was excluded by using enzymatically inactive H34Q point-mutated, refolded rPLA. These findings demonstrate the decisive role of specific Ag recognition by different APC, depending on structural features, membrane phospholipid binding property and the existence of conformational B cell epitopes, in the differential regulation of memory IgE and IgG4 Ab. Furthermore, they show that a change from IgE-mediated allergy to normal immunity against a major allergen can be induced by rPLA variants that are not recognized by specific Ab and B cells but still carry the T cell epitopes. These features may enable new applications for safer immunotherapy.     

Neuronal nitric oxide synthase gene polymorphism and IgE-mediated allergy in the Central European population

BACKGROUND: Several findings suggest that nitric oxide (NO) plays a significant role in the regulation of the Th1/Th2 balance and contributes to the development of allergic diseases. Our study investigates a possible association of C/T transition located 276-bp downstream from the translation termination site in exon 29 of the human nitric oxide synthase type 1 (NOS1) gene with immunoglobulin E (IgE)-mediated allergic diseases in the Czech population. METHODS: The study included 688 subjects - 368 patients with clinically manifested allergic diseases and 320 unrelated controls with negative familial history of asthma/atopy. The NOS1 genotypes were determined by polymerase chain reaction (PCR) and restriction analysis by Eco72I. RESULTS: No significant differences were found for allele or genotype frequencies of the 5266 C/T polymorphism in exon 29 of the NOS1 gene between IgE-mediated allergic diseases (or asthma alone) and healthy subjects. However, this common polymorphism showed a significant association with signs of atopy, especially with total serum IgE levels [log(e) IgE levels (mean +/- SD): CC genotype = 4.34 +/- 1.40; CT genotype = 4.58 +/- 1.53; TT genotype = 5.01 +/- 1.61; P < 0.05). CONCLUSIONS: Our findings suggest that NOS1 gene may participate in the pathogenesis of high total serum IgE levels in allergic diseases in our population. These findings provide support for NOS1 as a candidate gene for IgE-mediated allergy.     

Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses

Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions.     

IgE-dependent enhancement of Th2 cell-mediated allergic inflammation in the airways

T helper 2 (Th2) cell-derived cytokines, including interleukin (IL)-4, IL-5 and IL-13, play important roles in causing allergic airway inflammation. In contrast to Th2 cells, however, the role of IgE and mast cells in inducing allergic airway inflammation is not understood fully. In the present study, we addressed this point using transgenic mice expressing trinitrophenyl (TNP)-specific IgE (TNP-IgE mice), which enable us to investigate the role of IgE without the influence of antigen-specific T cell activation and other immunoglobulins. When the corresponding antigen, TNP-BSA, was administered intranasally to TNP-IgE mice, a large number of CD4+ T cells were recruited into the airways. In contrast, TNP-BSA administration did not induce eosinophil recruitment into the airways or airway hyperreactivity. Furthermore, when ovalbumin (OVA)-specific Th2 cells were transferred to TNP-IgE mice and the mice were challenged with inhaled OVA, TNP-BSA administration increased OVA-specific T cell recruitment and then enhanced Th2 cell-mediated eosinophil recruitment into the airways. These results indicate that IgE-induced mast cell activation principally induces CD4+ T cell recruitment into the airways and thus plays an important role in enhancing Th2 cell-mediated eosinophilic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.     

Developmental changes in interleukin-12-producing ability by monocytes and their relevance to allergic diseases

BACKGROUND: The T helper type-2 (Th2)-dominated situation can be observed in allergic diseases such as asthma or atopic dermatitis. A reduced ability to produce IL-12, which is a key cytokine for the induction of Th1 responses, has been proposed to lead to aberrant Th2 development in these disease conditions. OBJECTIVE: This study was intended to examine how IL-12-producing ability might associate with allergic diseases as a function of age. METHODS: IL-12 production by monocytes at various ages was assessed in patients with bronchial asthma and/or atopic dermatitis (n = 100) in comparison with non-allergic control subjects (n = 144). Whole blood cells were stimulated with lipopolysaccharide (LPS) after priming with IFN-gamma, then intracellular cytokine expression of IL-12 and IL-8 as a control cytokine of CD14-positive cells was assessed by flow cytometric analysis. RESULTS: In the control subjects, the ability of monocytes to produce IL-12 was negligible at birth and gradually increased with advancing age, whereas IL-8 production was intense throughout the human life. At more than 7 years of age, IL-12 production of patients with allergic diseases was significantly lower compared with that of control subjects. The unexpected finding was that infants and children below 6 years of age with allergic diseases tended to produce more IL-12 compared with age-matched controls. In this young group, it was noted that enhanced IL-12 production by monocytes was especially observed in allergic patients with specific IgE antibodies against some food allergens. Significant inverse relationships between serum IgE levels and IL-12-producing ability were found in the teenage and adult groups, but not in the younger children. CONCLUSION: IL-12 appeared to play different roles in the pathogenesis of allergic diseases between younger and older ages.