Pathophysiology And Specific

The pathophysiology is well defined for allergic, infectious, some medication-related, and select systemic disease-associated rhinitis syndromes. The pathophysiology of allergic rhinitis stems from the degranulation of mast cells and the subsequent mucosal recruitment of inflammatory cells, particularly eosinophils (Table 2, Fig. 1). Mast cell degranulation has been established by nasal allergen challenge, nasal lavage with analysis of mediators, nasal cytology, and nasal biopsy. Inflammation, characterized by recruitment of eosinophils into the nasal mucosa, is an essential component of the pathology of allergic rhinitis.

The symptoms of allergic rhinitis are a composite of the effects of mediators on receptors, for example, histamine with H1 receptor or leukotrienes (LTD4 specifically) with cysteinyl-leukotriene receptor 1, and of cell recruitment with inflammation. The mediators released from mast cells are responsible for the acute symptoms of allergic rhinitis, primarily itching and sneezing (Table 3, Fig. 2). The inflammation is primarily a result of eosinophil immigration, activation, and persistence, largely due to factors released by the mast cell. The mast cell degranulates when high-affinity immunoglo-bulin (Ig)E receptors are crosslinked by antigen (allergen). IgE specific for a causal allergen is bound to the mast cell, enabling the triggering of degranulation on exposure to the allergen. The production of specific IgE is a result of the complex interaction of genetic predisposition and the environment. Exposure to environmental allergens, which is a risk factor for sensitization, does not result in uniform immune responses, even in subjects with similar, or even identical, genetic backgrounds. Modulation of the IgE response is dependent on variables such as the type of allergen, the route and dose of exposure, the timing of exposure (e.g., childhood vs adulthood), and concomitant or preceding exposure to infectious organisms or adjuvants, such as endotoxin. Genetic factors affect the epitope or specific portion of the antigen to which the individual responds (some epitopes are more likely to evoke an IgE response) as well as the immunological regulation that modulates the tendency to produce IgE. Interaction between antigen-presenting cells, such as dendritic cells and B-lymphocytes, T-regu-latory cells, and TH1- and TH2-like cells (types of helper T-cells) affect the probability of IgG antibody formation vs IgE antibody formation vs tolerance to a specific allergen. To further complicate the understanding of this process, individuals may simultaneously be sensitized and tolerant to different allergens, for example, dust mite and cat, emphasizing that antigen properties and genetic factors regulate individual antigen responses. Finally, neither the blood concentration of specific IgE nor the size of the skin test response for a selected allergen does not generally correlate with the severity of symptoms upon exposure to that allergen. Thus, a simple unifying explanation of the allergic response or a measurable parameter that will consistently predict symptoms is not available.

Table 1

Differential Diagnosis of Rhinitis

Allergic rhinitis

Seasonal or intermittent Perennial or persistent Infectious rhinitis

Viral

Adenovirus Respiratory syncytial virus

Influenza virus Rhinovirus

Parainfluenza virus Bacterial

Streptococcus Haemophilus Structural nasal disorders Nasal septal deviation Nasal polyps (Fig. 4) Adenoid hyperplasia or cyst Concha bullosa (Fig. 5) Choanal atresia Neoplasm

Squamous cell carcinoma (more common in cigarette smokers) Angiofibroma (more common in adolescent boys) Esthesioneuroblastoma (resembles a benign nasal polyp) Lymphoma Sarcoma

Inverted papilloma Foreign body Encephalocele Ciliary defects Cerebrospinal rhinorrhea Other Forms of Rhinitis

Atrophic rhinitis

Perennial nonallergic rhinitis (vasomotor rhinitis) Nonallergic rhinitis with eosinophilia (NARES with or without polyps) Rhinitis medicamentosa Topical decongestants Oxymetazoline Cocaine Neosynephrine Systemic therapies Beta blockers Alpha antagonists

Estrogen supplements or oral contraceptives Nonsteroidal antiinflammatory drugs Systemic diseases

Endocrine/hormonal Hypothyroidism Pregnancy or breast feeding Diabetes mellitus Inflammatory Sarcoidosis

Wegener's granulomatosis Relapsing polychondritis

Reticular histiocytosis (lethal midline granuloma) Infiltrative Amyloidosis Irritant rhinitis Gastroesophageal reflux Fungal hypersensitivity sinusitis

NARES, nonellergic rhinitis with eosinophilia.

Table 2

Mast Cell Mediators of Allergy

Mediator

Acrion

Preformed

Histamine

Increases vascular permeability,

Increases mucous production,

Anti-inflammatory effects via

H2 receptors

Neutral proteases

Protein degradation and activation

Tryptase(s)

of protein precursors

Chymotryptase(s)

Carboxypeptidase(s)

Synthesized during cellular activation

Leukotriene C4,D4 (LTC4, LTD4)

Increases vascular permeability,

Increases mucous production

Leukotriene B4 (LTB4)

Increases neutrophil chemotaxis

Prostaglandin D2 (PgD2)

Smooth muscle contraction

Thromboxane A2

Platelet aggregation, vasoconstriction

Platelet-activating factor (PAF)

Platelet aggregation, Increases neutrophil

and eosinophil chemotaxis and

activation, Increases vascular

permeability, Smooth muscle

contraction

Cytokines

Interleukin-4

Increases endothelial expression of

VCAM-4

Increases IgE production,

Stimulation of TH2 and inhibition of

TH1 lymphocytes

Tumor necrosis factor

Increases endothelial ICAM-1 expression

Interleukin-5

Activates eosinophils and basophils

Interleukin-3

Activates esoinophils and basophils,

growth factor for mast cells

Granulocyte-monocyte

Activates eosinophils and basophils,

colony-stimulating factor

growth factor for mast cells

Select chemokines

Neutrophil, eosinophil and basophil

chemotaxis, Enhance mast cell and

basophil mediator release

The importance of specific IgE in the development of allergic rhinitis is confirmed by nasal challenge with allergen in subjects with specific IgE, correlation of symptoms with the level of allergen exposure, the predictive value of specific IgE in determining response to specific allergen immunotherapy, evidence of mast cell degranulation with allergen contact, and the improvement of allergic rhinitis with anti-IgE monoclonal therapy. Local production of IgE, which would not be recognized by blood or skin tests, and non-

  1. 1. Mechanisms of allergic reaction: Allergen is processed and presented to T-cells via dendritic cells or macrophages or B-cells. The T-cell response is regulated by a network of regulatory T-cells and by the concentrations of a variety of cytokines secreted by cells involved in the immune response. In allergy-prone subjects (atopic subjects), the tendency to produce IgE specific for the allergen is increased. The IgE is made by B-cells, which transform into plasma cells. The IgE is bound to mast cells and basophils via a high-affinity receptor for IgE. Upon subsequent exposure to allergen, the mast cells degranulate and release chemical mediators responsible for the early-phase reaction and recruit inflammatory cells, which are largely responsible for the late-phase reaction. The dashed arrow indicates that some of the mediators released or created by the mast cell during degranulation, particularly leukotrienes and kinins, contribute to the late-phase reaction. Itching, sneezing, and watery rhinorrhea are the predominnt symptoms in the early-phase reaction, whereas congestion and mucoid nasal discharge or rhinorrhea are the predominant symptoms in the late-phase reaction. (From Fineman S. In: Lieberman PL, Blaiss MS, eds. Atlas of Allergic Diseases. Philadelphia: Lippincott Williams & Wilkins; 2002:113.)
  2. 1. Mechanisms of allergic reaction: Allergen is processed and presented to T-cells via dendritic cells or macrophages or B-cells. The T-cell response is regulated by a network of regulatory T-cells and by the concentrations of a variety of cytokines secreted by cells involved in the immune response. In allergy-prone subjects (atopic subjects), the tendency to produce IgE specific for the allergen is increased. The IgE is made by B-cells, which transform into plasma cells. The IgE is bound to mast cells and basophils via a high-affinity receptor for IgE. Upon subsequent exposure to allergen, the mast cells degranulate and release chemical mediators responsible for the early-phase reaction and recruit inflammatory cells, which are largely responsible for the late-phase reaction. The dashed arrow indicates that some of the mediators released or created by the mast cell during degranulation, particularly leukotrienes and kinins, contribute to the late-phase reaction. Itching, sneezing, and watery rhinorrhea are the predominnt symptoms in the early-phase reaction, whereas congestion and mucoid nasal discharge or rhinorrhea are the predominant symptoms in the late-phase reaction. (From Fineman S. In: Lieberman PL, Blaiss MS, eds. Atlas of Allergic Diseases. Philadelphia: Lippincott Williams & Wilkins; 2002:113.)

IgE mechanisms of mast cell degranulation are hypotheses offered to explain allergic-like rhinitis in subjects without measurable specific IgE.

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