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Term Paper on Rheumatoid Arthritis



Elizabeth Super
Dr. Malcolm Campbell
Biology 307: Immunology

Fig. 1 Structural representation of histamine. Histamine, or 2-(4-imidazolyl)-ethyl-amine, is a dibasic vasoactive amine that is located in most body tissues but is highly concentrated in the lungs, skin, and gastrointestinal tract. A single polypeptide chain protein, histamine is stored in mast cells and basophils (Metcalfe et al., 1997).

Permission to use this image requested from on 18 March 2003.

Overview of Histamine (Rang et al., 1995)
1. Histamine is a basic amine that is stored in mast cells and basophils.
2. Histamine is held by ionic forces within intracellular granules by macroheparin.
3. The interaction between allergen and IgE, bound to the surface of mast cells or
basophils by a surface receptor that binds the Fc fragment of IgE, leads to degranulation of these cells, with release of mediators, including histamine.
4. It acts on H1-, H2-, or H3-receptors on target cells to produce its effects.
5. Its main actions include stimulation of gastric secretion, contraction of most smooth
muscle (other than blood vessel smooth muscle), cardiac stimulation, vasodilation, and increased vascular permeability.
6. When injected intradermally, histamine causes the “triple response”, which includes
local vasodilation, wheal, and flare.
7. Histamine has two major pathophysiological roles, which include the stimulation of
gastric acid secretion, which is treated with H2-receptor antagonists, and the mediation of type 1 hypersensitivity reactions such as urticaria and hay fever, which is treated with H1-receptor antagonists.

Overview of Mast Cells and Basophils
Mast cells and basophils are the effector cells involved in the immediate hypersensitivity response (Bach, 1982). Found in tissues throughout the body, they are particularly associated with blood vessels and nerves and are in proximity to surfaces that border the external environment (Metcalfe et al, 1997). Both contain numerous osmophilic granules that contain heparin and other proteins that support mediators, including histamine, which alters cellular and vascular reactions. Secretion of mediators occurs by degranulation during which the contents of the granules are exocytosed. Degranulation is provoked by certain chemical agents, C3a and C5a (two complement components) binding to surface receptors, certain drugs, and the IgE system (Bach, 1982). Mast cells and basophils have receptors for IgE antibodies and can be activated to secrete mediators if IgE first binds to these receptors, followed by antigen binding to the Fab fragment of the fixed IgE molecules (Rang et al., 1995). Degranulation can lead to allergic reactions or anaphylactic shock, in extreme cases (Sompayrac, 1999).

Synthesis and Storage of Histamine
Histamine, or 2-(4-imidazolyl)-ethyl-amine, is a dibasic vasoactive amine that is located in most body tissues but is highly concentrated in the lungs, skin, and gastrointestinal tract. It is produced by the decarboxylation of histidine by histidine decarboxylase (Paul, 1984). This reaction takes place in the Golgi apparatus of mast cells and basophils (Metcalfe et al., 1997). A single polypeptide chain protein, histamine is then stored in mast cells and basophils, where it is localized primarily in the cytosol. In both mast cells and basophils, histamine is detained in intracellular granules complexed with an acidic protein and macroheparin that interact with the basic histamine by ionic forces (Rang et al., 1995). Approximately 3-8 pg histamine/cell is found in mast cells that are isolated from human lung, skin, lymphoid tissue, and the small intestine. Histamine dissociates from its complex by cation exchange with extracellular sodium at a neutral pH (Metcalfe et al., 1997). Therefore, it is readily available upon cell activation. The granules comprise up to 70% of the weight of a mast cell, so substantial extracellular histamine concentrations can be produced locally upon histamine release. Histamine is less potent than other mediators linked to acute hypersensitivity, so high local concentrations are required to produce significant effects in vivo (Paul, 1984).

Release of Histamine
Mast cells release histamine during inflammatory or allergic reactions. When exposed to allergens, humans produce IgE antibodies that are directed against the allergen. Mast cells have receptors that can bind to the Fc region of IgE antibodies (Sompayrac, 1999). IgE binds with high affinity and high specificity. No conformational changes of the receptor occur when IgE binds. Binding of monomeric IgE to the Fc receptor does not cause mast cell activation and degranulation; initial exposure to an allergen causes large numbers of IgE antibodies to attach to mast cells surfaces without activating them (Metcalfe et al., 1997). Upon second exposure to an allergen, the IgE molecules bound to the mast cell surface can bind to allergen. The allergen causes crosslinking of the IgE molecules on the cell surface, which clusters the Fc receptors. This clustering stimulates a signal transduction that causes the mast cell to ‘degranulate’, or dump their granules into the tissues (Sompayrac, 1999).

Ishizaka and Ishizaka established that at least two specific IgE molecules, complexed with allergen, were required to induce skin reactions in man. Therefore, the important step in mast cell activation appears to be the crosslinking of IgE molecules, which causes the clustering of Fc receptors. This step also appears necessary because the bridging of receptors forms hydrophilic channels that allow calcium levels to increase intracellularly, which triggers mediator release. It has also been established that IgE acts as an anchor for antigen and helps to amplify the transduction signal generated by the bridging due to antigen-binding (Froese, 1980).

Histamine’s small size, low molecular weight, and diffusability cause it to disperse from local sites, which limits its effect to a small period of time (Paul, 1984). Specific receptors on target cells mediate the biological activities of histamine (Metcalfe et al., 1997). Extracellular histamine is rapidly metabolized, by enzymes present in leukocytes, to metabolites that are excreted in the urine (Paul, 1984).

Fig. 2 Degranulation of a Mast Cell. Mast cells detain histamine in intracellular granules. Binding of IgE to cell surface receptors on a mast cell primes the cell to respond to allergen. Introduction of allergen and its subsequent binding to IgE induces crosslinking of IgE and clustering of Fc receptors. Clustering initiates a signal transduction event that stimulates the mast cell to degranulate, or release the contents of its granules. Mediators, such as histamine, which is represented by the tan circle, are released from granules and can bind to specific receptors to carry out their actions (Sompayrac, 1999).

Permission to use this image requested from on 18 March 2003.

Histamine Receptors
Histamine acts by binding to receptors on target cells, and different cells types express different receptor types. Upon binding to target cell receptors, histamine causes intracellular events, such as phosphatidylinositol breakdown to IP3 and DAG, which lead to different effects in different cell types (Abbas et al., 1994). Three main types of histamine receptors – H1, H2, and H3 – have been identified and were distinguished by the actions of agonist and antagonist drugs on each receptor type. Pyrilamine, cimetidine, and thioperamide are selective antagonists at H1-, H2-, and H3-receptors, respectively. Dimaprit and (R)a-methyl histamine are selective agonists for H2- and H3-receptors, respectively. No selective agonists have been identified for H1-receptors. Histamine H1 antagonists (commonly called antihistamines) and H2 antagonists have clinical uses, but those acting at H3 receptors are currently utilized as research tools (Rang et al., 1995). Antihistamines inhibit the wheal and flare response caused by intradermal allergens or anti-IgE antibodies (Abbas et al., 1994).

H1-receptors are located in human bronchial muscle and are linked to transduction systems that cause increased intracellular Ca2+, which leads to muscle contraction. H2-receptors are located in acid-secreting stomach cells and in the heart. Stimulation leads to gastric acid secretion and increased atrial rate. This receptor type is linked to transduction systems involved in activation of adenylate cyclase and increased production of cyclic AMP. H3-receptors are related to neural tissue and are found at presynaptic sites; stimulation causes the inhibition of neurotransmitter release (Rang et al., 1995).

Histamine produces many of the effects of inflammation and hypersensitivity, including vasodilation, edema, increased vascular permeability, and smooth muscle contraction (Rang et al., 1995). Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction – a runny nose and watery eyes (Sompayrac, 1999). It is thought to be a major mediator of the acute inflammatory response, although histamine H1 antagonists have little effect on acute inflammation (Rang et al., 1995).

Gastric Secretion: The most important action of histamine, in a clinical sense, is its stimulation of gastric acid secretion by acting on H2-receptors. It is implicated in the formation of peptic ulcers (Rang et al., 1995).

Smooth Muscle Effects: Histamine causes contraction of the smooth muscle of the ileum, bronchi and bronchioles, and uterus by acting on H1-receptors. It may be involved in increased peristalsis associated with food allergies (Abbas et al., 1994). Histamine-induced bronchiolar constriction has been implicated in the first phase of bronchial asthma (Rang et al., 1995). In asthmatics, histamine was found to increase airway smooth muscle tone and cause mucosal edema and glandular secretion, resulting in the narrowing of the airways and limited air flow. In nonasthmatics, bronchial activity to histamine was limited, most likely due to fewer H1-receptors in airway smooth muscle (Goldie, 1990).

Cardiovascular Effects: Acting on H1-receptors, histamine causes the dilation of blood vessels; it induces endothelial cells to synthesize vascular smooth muscle relaxants, including prostacyclin and nitric oxide, which cause vasodilation (Abbas et al., 1994). Acting on H2-receptors, it increases heart rate and cardiac output. When injected intradermally, histamine leads to reddening of the skin, wheal, and flare, called the “triple response”. Vasodilation of small arterioles and precapillary sphincters causes reddening, while increased permeability of postcapillary venules causes the wheal; both these effects are implicated in activation of H1-receptors. Histamine does not increase capillary permeability. Histamine also induces an “axon reflex”, which leads to stimulation of sensory nerve fibers and the release of a vasodilator mediator; this causes the flare (Rang et al., 1995).

Itching: If histamine is injected into the skin, it causes itching, due to stimulation of sensory nerve endings (Rang et al., 1995).

Effects on Nasal Mucosa: Allergens can bind to IgE-loaded mast cells in the nasal mucosa, which leads to three clinical responses: sneezing results from histamine-associated sensory neural stimulation; hypersecretion from glandular tissue occurs; nasal mucosal congestion results due to vascular engorgement associated with vasodilation and increased capillary permeability (Monroe et al., 1997).

Role of Histamine in the Immune Response
Histamine was originally considered to be a mediator involved in the immediate hypersensitivity response. It has also been shown to affect leukocyte function and migration. It is involved in inhibition of lectin- or antigen-induced proliferation of T cells, release of lymphokines from T cells, the induction of cytotoxic T cells, cytolysis by mature cytotoxic T cells, B cell differentiation, lysosomal enzyme release in neutophils, IgE-mediated histamine release from basophils, and in chemokinetic effects on neutophils and eosinophils (Gallin et al., 1980). These actions can be blocked by H2 antagonists. Many of these effects on leukocyte function are inhibitory and can be seen as anti-inflammatory actions, which can limit antibody hypersensitivity. However, H1 effects of histamine on blood vessels and skin are proinflammatory and occur during hypersensitivity reactions. It has been proposed that histamine initially promotes and later inhibits immune responses (Paul, 1984).

The study of histamine-receptor antagonists began nearly seventy years ago. In 1937, Bovet and Staub discovered the first H1-receptor antagonist, which marked the first generation of antihistamines to treat allergic diseases. Although widespread in use, major CNS adverse effects, such as sedation and performance deficits, and their anticholinergic activities caused doubt about their effectiveness. A second generation of antihistamines was quickly developed that showed fewer sedating side effects. The number of second-generation antihistamines has grown rapidly, and their efficacies can be compared by injecting histamine epicutaneously and viewing which antihistamines block the wheal (swelling) and flare (vasodilation) response. Antihistamines suppress the histamine-induced wheal and flare response by blocking the binding of histamine to its receptors on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells. They effectively exert competitive antagonism of histamine for H1-receptors. Itching and sneezing are suppressed by antihistamine blockade of H1-receptors on nasal sensory nerves. Therefore, antihistamine therapy represents a major therapeutic option (Monroe et al., 1997). Antihistamines are used to treat allergies, motion sickness, certain types of headaches, Crohn's disease, acute multiple sclerosis, and some stomach secretory conditions. Antihistamines, which are well absorbed from the gut and are metabolized primarily in the liver, act over a period of about 4-6 hours. They are available as OTC drugs or as prescription drugs. The following are a list of common antihistamines available in the United States (Altruis, 2002):
Azatadine (Optimine®)
Carbinoxamine/Pseudoephedrine (Cardec®)
Cetirizine (Zyrtec®)
Cyproheptadine (Periactin®)
Dexchlorpheniramine (Polaramine®, Dexchlor ER®)
Fexofenadine (Allegra®)
Loratadine (Claritin®)
Promethazine (Phenergan®)
Tripelennamine (Pelamine®, Triplen®)

Histamine Deficiency
Histamine stimulates the production of digestive enzymes and gastric acid, which aid in protein and fat digestion. A histamine deficiency can cause the body to become more dependent on carbohydrates, which are used to synthesize cholesterol. Therefore, increased carbohydrates and impaired fat metabolism can lead to high total cholesterol levels. Histamine also stimulates the production of melatonin, which is necessary for fat metabolism, in the pineal gland. A histamine deficiency leads to lower levels of melatonin and decreased fat metabolism in the brain, which can cause stress on the body. Whereas histamine is a stress regulator, a deficiency in histamine leading to stress actually increases the body’s need for histamine; this contributes to even greater worsening of symptoms (Prokarin, 2003). Studies have shown that histamine deficiency leads to poor folic acid status (Kamsteeg, 2003). Interestingly, patients with multiple sclerosis are deficient in histamine; in MS, the myelin sheath that insulates nerves of the CNS and spinal cord is destroyed, and nerve fibers “short circuit”. Histamine, which stimulates repair by increasing the production of myelin, is greatly reduced in MS patients. Various histamine patches and replacement therapies have been developed due to this information (Berger, 2000).

Type 1 Hypersensitivity: Immediate and Anaphylactic
Immediate hypersensitivity, commonly known as an allergic reaction, is the result of an innocuous substance (ie. grass pollen, dead house-dust mites, certain foods, or drugs) coming into contact with respiratory or gastrointestinal mucosa (Rang, et al., 1995). Non-allergic individuals produce mainly TH1 cells and low levels of IgG antibodies and respond weakly to these allergens. Atopic, or allergic, individuals produce mostly TH2 cells and large quantities of IgE antibodies that bind to receptors on mast cells (Spiegelberg, 1989). This overproduction of IgE antibodies in response to otherwise innocuous antigens is responsible for allergic reactions. The release of mediators, such as histamine, can cause a number of effects localized to the nose (hay fever), bronchial tree (initial phase of asthma), skin (urticaria), or gastrointestinal tract. A generalized reaction to mediator release leads to anaphylactic shock (Rang et al., 1995).

Anaphylaxis was studied in the early 1900’s when a French physician, Charles Richet, intended to test how much Portuguese Man of War toxic was required to kill a dog. Although he was able to determine the lethal dose, many of the dogs, which were not given the lethal dose, survived the experiments. Richet injected the dogs a second time to determine whether they had become immune to the effects of the first dose. Although he proposed that the first dose would provide protection (prophylaxis) against the second injection, all of the dogs died. These opposite effects were termed “anaphylaxis”. Later studies showed that anaphylaxis is caused by the massive degranulation of mast cells and subsequent high levels of histamine release into the tissues. Blood volume is reduced so severely that the heart can no longer pump efficiently; at the same time, smooth muscle contraction around the trachea can cause suffocation (Sompayrac, 1999).

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