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The history of autoimmune disease and animal models (part two)

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The Autoimmune disease models

1. Childhood Asthma

Asthma is a chronic airway inflammatory disease. Due to the persistence of this chronic inflammatory reaction, the airway is highly reactive, and the symptoms recur when exposed to the cause. The study of the pathogenesis of asthma has evolved from the theory of sputum to the theory of chronic inflammation of the airways, and has now developed into a parallel theory of smooth muscle dysfunction and airway inflammation. Clinical treatment can also be done by repeated treatment, with emphasis on anti-inflammatory and relief of smooth muscle spasm. In the 1950s, non-selective adrenaline was used as an antispasmodic agent to treat asthma. In 1956, a selective strong short-acting β2 agonist (Short Acting Beta 2 Agonist SABA) was introduced. In 1971, a β2 agonist (Long Acting Beta2 Agonist LABA) came out. Oral glucocorticoids were used in the 1960s to antagonize airway inflammation, which is effective but has many side effects. In 1972, beclomethasone dipropionate (BDP) was successfully developed. In the 1980s, budesonide (BUD) and fluticasone propionate (FP) were developed. By analogy, these inhaled corticosteroids have a stronger anti-inflammatory effect on the airway, and their side effects are significantly reduced.

When children are stimulated by allergens, cold air or other incentives, they often first manifest as symptoms of upper respiratory tract allergy, such as itchy eyes, itchy nose, sneezing, etc. Because infants and young children are difficult to express itching, their symptoms often only express as blinking, blowing nose, etc, and further manifest as itching, dry cough and expectoration. These symptoms usually last for hours or days before the onset of asthma. Sudden onset of wheezing is a major feature of childhood asthma. The wheezing symptoms of asthma in children vary greatly depending on the severity of asthma. Children may have high-pitched wheezing that can be heard without a stethoscope or at a distance. Due to frequent breathing or difficulty breathing, asthma symptoms in infants and young children can be expressed as mouth breathing and nose flapping, and many children may be accompanied by a cough. Under normal circumstances, dry cough will appear at the beginning of the disease. When the seizure subsides, a white mucus-like phlegm will be coughed out. In severe cases, the symptoms of asthma can be expressed as irritability, purpura, pale, and cold sweat. Physical examination revealed an increase in heart rate and wheezing in both lungs. Symptoms of heart failure may be further aggravated with jugular vein engorgement, edema, middle lung, small blisters, and enlarged liver. Signs of emphysema can be seen in children with chronic asthma, such as barrel chest and chest percussion. In the remission period, children with asthma may have no symptoms or signs, have no effect on activities, or only manifest as symptoms of allergic rhinitis and pharyngitis. A small number of children may have chest discomfort, with or without wheezing in the lungs.

Specific immunoassay is an important indicator for evaluating allergic conditions in children with asthma. Most children's asthma is associated with allergies, and allergies can increase the persistence and severity of asthma. The original test is very important for guiding allergen immunotherapy and preventing asthma attacks. The skin prick test is the most basic test method to help clinicians find allergens and assist clinicians in the diagnosis of asthma. Skin tests are usually carried out using a variety of common inhaled allergens, including indoor dust, cockroaches, pollen, fungi, animal skins, and silk. Usually, the above-mentioned allergen immersion liquid is diluted into a skin test solution in a certain ratio, and a skin pricking needle is used for percutaneous test on the forearm palm side, and 0.01% of histamine phosphate and physiological saline are used as controls to eliminate false negatives and false positives. Antihistamines, corticosteroids and other drugs should be discontinued before the skin test. This method is safe, simple fast, economical, and has been popularized and applied internationally, and it is painless, so it is very suitable for children. The specific IgE (sIgE) assay is one of the most important detection methods for in vitro diagnosis of allergies when the asthmatic children are allergic to an allergen, and the sIgE assay for the allergen is performed in vivo. The classical detection method is Radioallergosorbent test (RAST), which is a CAP method. There are two reporting methods for the CAP system to detect sIgE results. The method is sensitive, specific, accurate and absolutely safe, avoiding the severe side effects that may be induced by skin tests or systemic responses (very few SPT), and the test is not subject to operator proficiency, medication, and skin conditions (such as severe skin disease, skin scratches). The detection of total serum IgE has been widely used as a screening test for the diagnosis of allergies for many years. However, in addition to allergic diseases, many factors such as race, gender, age, parasitic infection and seasonality can affect IgE levels in serum. In addition, the total IgE level of serum in 20-30% of allergic patients is normal, or even lower than normal level. And the total IgE is not specific, because allergic reaction is not determined by the body, but by the specific IgE corresponding to the allergen. Therefore, the detection of total IgE by serum alone is not perfect for judging the allergic condition of children with asthma, nor does it indicate which allergen is allergic. However, IgE and IgG can be used as indicators to evaluate the efficacy of specific immunotherapy. If the treatment is effective, the former decreases and the latter increases. The Phadiatop screening test is to embed more than 90% of the common allergens in the air in the same CAP and measure them using the CAP system. For example, one or several sIgE phadiatops in serum indicate an allergic reaction, but a negative result can’t exclude allergies because phadiatop only includes common but not all inhaled allergens, and the types of allergens are regional.

2. Mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is a heterogeneous group of chronic, autoimmune subepithelial blistering diseases which predominantly affects the mucous membranes and occasionally involves the skin. In vivo, MMP is characterized by linear deposition of IgG, IgA, or C3 along the epithelial basement membrane zone. Although the oral and ocular mucosae are the most common sites affected, the nasopharynx, esophagus, larynx and anogenital region may also be involved. This disorder results in mucosal and/or skin blistering, ulceration, and subsequent scarring. The severity and distribution of the disease is highly variable from mild cases involving only oral mucosa to severe cases involving the eye, genital and esophageal mucosa. The disease may be implicated in the larynx or esophagus, causing stenosis, and may even be life-threatening. Since the consequences of this disease can be severe and limited therapeutic options are available once scarring is developed, early diagnosis of this disease is critical. However, as the disease is rare and the early symptoms are non-specific, MMP is often unrecognized in the early inflammatory stage. Other nomenclatures for MMP include cicatricial pemphigoid, oral pemphigoid, ocular cicatricial pemphigoid (OCP), ocular pemphigoid, and benign mucous membrane pemphigoid. Autoantibodies to one or several autoantigens in the mucosal or epithelial BMZ have been identified in MMP patients. The association of MMP with human leukocyte antigen (HLA) major histocompatibility class II HLA-DQB1*0301 has been demonstrated. The cause is usually unknown, but there are some reports say that MMP can be triggered by medications such as methyldopa, clonidine and D-penicillamine.

The pathogenesis of MMP is complex. MMP has been found to be heterogeneous and involves several different antigens. The pathogenicity of autoantibodies in MMP has been demonstrated in vivo and in vitro.   

Circulating IgG and/or IgA autoantibodies against components of the basement membrane zone found in MMP patients’ serum indicate that MMP is mediated by a humoral immune response. Loss of immunologic tolerance to structural proteins in the BMZ results in development of MMP antibodies. By using immunoblotting and immunoprecipitation techniques, a variety of autoantigens including the bullous pemphigoid antigen 1 (BPAg1) (a 230-kDa protein, BP230), the bullous pemphigoid antigen 2 (BPAg2) (a 180-kDa protein, BP180), integrin subunits α6/β4, laminin-332 (also called epiligrin and laminin-5), laminin-6, and collagen type I have been identified. BPAg1 is an intracellular protein, whereas BPAg2 and α6/β4 integrins are transmembrane proteins. The most frequently targeted autoantigen in MMP is BPAg2. Laminin-5 is thought to be the major ligand between the transmembrane proteins and the anchoring filaments. Anchoring fibrils, composed of type VII collagen, are located deeper in the lamina densa. These autoantigens are not exclusive to MMP. Although BPAg2 is more common, autoantibodies to both BPAg1 and BPAg2 can be present in BP, and autoantibodies against type VII collagen are also found in epidermolysis bullosa acquisita.

An antibody-induced complement-mediated process results in epithelial detachment. Passive transfer studies in newborn mice have shown that antibodies to BPAg2 induce subepidermal blisters by an inflammatory mechanism. This interaction triggers immunologic events that result in the expression of inflammatory mediators that induce migration of lymphocytes, eosinophils, neutrophils, and mast cells to the BMZ. The separation of epithelium from the underlying tissue within the BMZ results from either direct cytotoxic action or the effect of lysosomal proteolytic enzymes. Passive transfer of antibodies against laminin 5 induced non-inflammatory subepidermal blisters, indicating that anti-laminin 5 IgG is pathogenic, although the mechanism is not clear. Anti-α6 antibody produced separation of epithelium from basement membrane. Fibroblasts can also be activated by the process of producing inflammatory cytokines such as transforming growth factor beta (TGF-β), which is known to induce fibrosis. The collagen produced may lead to scarring. Several studies have shown a predominance of CD4+ T cell and Langerhans cell infiltrates in the conjunctiva of MMP patients, indicating the involvement of cellular immunity in the pathogenesis of MMP. The presence of Th17 lymphocytes in conjunctival biopsies was significantly increased in patients with OCP.

MMP can affect multiple mucosal sites, occasionally involve the skin. It is a chronic, progressive disease that most frequently involves the oral mucosa (85% of patients), followed by ocular conjunctiva (65%), nasal mucosa (20–40%), skin (25–30%), anogenital area and/or pharynx (20%), larynx (5–15%), and esophagus (5–15%). Lesions occurring at any site may heal with scarring. There is a great variability in the presentation and severity among patients with both localized and extensive involvement. Localized disease can progress to extensive disease. Those who have the disease affecting only the oral mucosa and/or the skin with less tendency of scarring and with minimal clinical significance are defined as “low-risk” MMP patients. On the contrary, “high-risk” patients are those who have disease occurring in any of the following sites: ocular, nasopharyngeal, esophageal, laryngeal, and genital mucosa. Despite medical treatment of MMP, the high likelihood of scar formation at these sites is associated with a poor prognosis. The ocular involvement can result in blindness, scarring of the laryngeal mucosa can result in sudden asphyxiation, scarring of the esophagus can influence food taking, and scarring of the anogenital mucosa can seriously affect the patients’ daily activities.

To be continued in Part Three…


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