What type of hypersensitivity is rheumatoid arthritis

The rash persists for 7 to 10 days each time, and it seems to largely go away on its own. Lately, the rashes have also begun to appear on her cheeks and above her eyes on either side of her forehead. In Adaptive Specific Host Defenses , we discussed the mechanisms by which adaptive immune defenses, both humoral and cellular, protect us from infectious diseases.

However, these same protective immune defenses can also be responsible for undesirable reactions called hypersensitivity reactions. Hypersensitivity reactions are classified by their immune mechanism. When a presensitized individual is exposed to an allergen , it can lead to a rapid immune response that occurs almost immediately.

Such a response is called an allergy and is classified as a type I hypersensitivity. Allergens may be seemingly harmless substances such as animal dander, molds, or pollen. Allergens may also be substances considered innately more hazardous, such as insect venom or therapeutic drugs.

Food intolerances can also yield allergic reactions as individuals become sensitized to foods such as peanuts or shellfish. Figure 1. For susceptible individuals, a first exposure to an allergen activates a strong T H 2 cell response. Cytokines interleukin IL -4 and IL from the T H 2 cells activate B cells specific to the same allergen, resulting in clonal proliferation, differentiation into plasma cells, and antibody-class switch from production of IgM to production of IgE.

The fragment crystallizable Fc regions of the IgE antibodies bind to specific receptors on the surface of mast cells throughout the body. It is estimated that each mast cell can bind up to , IgE molecules, with each IgE molecule having two allergen-specific fragment antigen-binding Fab sites available for binding allergen on subsequent exposures.

By the time this occurs, the allergen is often no longer present and there is no allergic reaction, but the mast cells are primed for a subsequent exposure and the individual is sensitized to the allergen. On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules. Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation , a reaction in which the contents of the granules in the mast cell are released into the extracellular environment.

Preformed components that are released from granules include histamine , serotonin , and bradykinin. The activated mast cells also release newly formed lipid mediators leukotrienes and prostaglandins from membrane arachadonic acid metabolism and cytokines such as tumor necrosis factor. The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I hypersensitivity reactions. Histamine stimulates mucus secretion in nasal passages and tear formation from lacrimal glands, promoting the runny nose and watery eyes of allergies.

Interaction of histamine with nerve endings causes itching and sneezing. The vasodilation caused by several of the mediators can result in hives, headaches, angioedema swelling that often affects the lips, throat, and tongue , and hypotension low blood pressure.

Bronchiole constriction caused by some of the chemical mediators leads to wheezing, dyspnea difficulty breathing , coughing, and, in more severe cases, cyanosis bluish color to the skin or mucous membranes. Vomiting can result from stimulation of the vomiting center in the cerebellum by histamine and serotonin. Histamine can also cause relaxation of intestinal smooth muscles and diarrhea. Figure 2. On first exposure to an allergen in a susceptible individual, antigen-presenting cells process and present allergen epitopes with major histocompatibility complex MHC II to T helper cells.

B cells also process and present the same allergen epitope to TH2 cells, which release cytokines IL-4 and IL to stimulate proliferation and differentiation into IgE-secreting plasma cells. The IgE molecules bind to mast cells with their Fc region, sensitizing the mast cells for activation with subsequent exposure to the allergen. With each subsequent exposure, the allergen cross-links IgE molecules on the mast cells, activating the mast cells and causing the release of preformed chemical mediators from granules degranulation , as well as newly formed chemical mediators that collectively cause the signs and symptoms of type I hypersensitivity reactions.

Type I hypersensitivity reactions can be either localized or systemic. Localized type I hypersensitivity reactions include hay fever rhinitis , hives, and asthma. Systemic type I hypersensitivity reactions are referred to as anaphylaxis or anaphylactic shock. Although anaphylaxis shares many symptoms common with the localized type I hypersensitivity reactions, the swelling of the tongue and trachea, blockage of airways, dangerous drop in blood pressure, and development of shock can make anaphylaxis especially severe and life-threatening.

In fact, death can occur within minutes of onset of signs and symptoms. Late-phase reactions in type I hypersensitivities may develop 4—12 hours after the early phase and are mediated by eosinophils , neutrophils , and lymphocytes that have been recruited by chemotactic factors released from mast cells.

Activation of these recruited cells leads to the release of more chemical mediators that cause tissue damage and late-phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge. Individuals who possess genes for maladaptive traits, such as intense type I hypersensitivity reactions to otherwise harmless components of the environment, would be expected to suffer reduced reproductive success.

With this kind of evolutionary selective pressure, such traits would not be expected to persist in a population. This suggests that type I hypersensitivities may have an adaptive function. There is evidence that the IgE produced during type I hypersensitivity reactions is actually meant to counter helminth infections.

In addition, there is evidence that helminth infections at a young age reduce the likelihood of type I hypersensitivities to innocuous substances later in life. Thus it may be that allergies are an unfortunate consequence of strong selection in the mammalian lineage or earlier for a defense against parasitic worms.

In most modern societies, good hygiene is associated with regular bathing, and good health with cleanliness. But some recent studies suggest that the association between health and clean living may be a faulty one.

Some go so far as to suggest that children should be encouraged to play in the dirt—or even eat dirt [3] —for the benefit of their health. This recommendation is based on the so-called hygiene hypothesis , which proposes that childhood exposure to antigens from a diverse range of microbes leads to a better-functioning immune system later in life.

The hygiene hypothesis was first suggested in by David Strachan, [4] who observed an inverse relationship between the number of older children in a family and the incidence of hay fever. Although hay fever in children had increased dramatically during the midth century, incidence was significantly lower in families with more children. Strachan proposed that the lower incidence of allergies in large families could be linked to infections acquired from older siblings, suggesting that these infections made children less susceptible to allergies.

Strachan also argued that trends toward smaller families and a greater emphasis on cleanliness in the 20th century had decreased exposure to pathogens and thus led to higher overall rates of allergies, asthma, and other immune disorders.

Other researchers have observed an inverse relationship between the incidence of immune disorders and infectious diseases that are now rare in industrialized countries but still common in less industrialized countries. The lack of early challenges to the immune system by organisms with which humans and their ancestors evolved may result in failures in immune system functioning later in life.

Immune reactions categorized as type II hypersensitivities , or cytotoxic hypersensitivities , are mediated by IgG and IgM antibodies binding to cell-surface antigens or matrix-associated antigens on basement membranes. These antibodies can either activate complement , resulting in an inflammatory response and lysis of the targeted cells, or they can be involved in antibody-dependent cell-mediated cytotoxicity ADCC with cytotoxic T cells.

In some cases, the antigen may be a self-antigen, in which case the reaction would also be described as an autoimmune disease. Autoimmune diseases are described in Autoimmune Disorders. In other cases, antibodies may bind to naturally occurring, but exogenous, cell-surface molecules such as antigens associated with blood typing found on red blood cells RBCs. This leads to the coating of the RBCs by antibodies, activation of the complement cascade, and complement-mediated lysis of RBCs, as well as opsonization of RBCs for phagocytosis.

These type II hypersensitivity reactions, which will be discussed in greater detail, are summarized in the table Common Type II Hypersensitivities. Immunohematology is the study of blood and blood-forming tissue in relation to the immune response. Antibody-initiated responses against blood cells are type II hypersensitivities, thus falling into the field of immunohematology. For students first learning about immunohematology, understanding the immunological mechanisms involved is made even more challenging by the complex nomenclature system used to identify different blood-group antigens , often called blood types.

The first blood-group antigens either used alphabetical names or were named for the first person known to produce antibodies to the red blood cell antigen e. However, in , the International Society of Blood Transfusion ISBT Working Party on Terminology created a standard for blood-group terminology in an attempt to more consistently identify newly discovered blood group antigens.

New antigens are now given a number and assigned to a blood-group system, collection, or series. However, even with this effort, blood-group nomenclature is still inconsistent. The recognition that individuals have different blood types was first described by Karl Landsteiner — in the early s, based on his observation that serum from one person could cause a clumping of RBCs from another.

These studies led Landsteiner to the identification of four distinct blood types. The functions of these antigens are unknown, but some have been associated with normal biochemical functions of the cell. Furthermore, ABO blood types are inherited as alleles one from each parent , and they display patterns of dominant and codominant inheritance. The alleles for A and B blood types are codominant to each other, and both are dominant over blood type O.

It is important to note that the RBCs of all four ABO blood types share a common protein receptor molecule, and it is the addition of specific carbohydrates to the protein receptors that determines A, B, and AB blood types.

The genes that are inherited for the A, B, and AB blood types encode enzymes that add the carbohydrate component to the protein receptor. Individuals with O blood type still have the protein receptor but lack the enzymes that would add carbohydrates that would make their red blood cell type A, B, or AB.

Isohemagglutinins are produced within the first few weeks after birth and persist throughout life. These antibodies are produced in response to exposure to environmental antigens from food and microorganisms. A person with type A blood has A antigens on the surface of their RBCs and will produce anti-B antibodies to environmental antigens that resemble the carbohydrate component of B antigens.

A person with type B blood has B antigens on the surface of their RBCs and will produce anti-A antibodies to environmental antigens that are similar to the carbohydrate component of A antigens. A patient may require a blood transfusion because they lack sufficient RBCs anemia or because they have experienced significant loss of blood volume through trauma or disease.

Although the blood transfusion is given to help the patient, it is essential that the patient receive a transfusion with matching ABO blood type. A transfusion with an incompatible ABO blood type may lead to a strong, potentially lethal type II hypersensitivity cytotoxic response called hemolytic transfusion reaction HTR. For instance, if a person with type B blood receives a transfusion of type A blood, their anti-A antibodies will bind to and agglutinate the transfused RBCs.

In addition, activation of the classical complement cascade will lead to a strong inflammatory response, and the complement membrane attack complex MAC will mediate massive hemolysis of the transfused RBCs.

The debris from damaged and destroyed RBCs can occlude blood vessels in the alveoli of the lungs and the glomeruli of the kidneys. Within 1 to 24 hours of an incompatible transfusion, the patient experiences fever, chills, pruritus itching , urticaria hives , dyspnea, hemoglobinuria hemoglobin in the urine , and hypotension low blood pressure.

In the most serious reactions, dangerously low blood pressure can lead to shock, multi-organ failure, and death of the patient. Hospitals, medical centers, and associated clinical laboratories typically use hemovigilance systems to minimize the risk of HTRs due to clerical error. Hemovigilance systems are procedures that track transfusion information from the donor source and blood products obtained to the follow-up of recipient patients. Hemovigilance systems used in many countries identify HTRs and their outcomes through mandatory reporting e.

For example, if an HTR is found to be the result of laboratory or clerical error, additional blood products collected from the donor at that time can be located and labeled correctly to avoid additional HTRs.

As a result of these measures, HTR-associated deaths in the United States occur in about one per 2 million transfused units. Figure 4. Blood from a type A donor is administered to a patient with type B blood.

The anti-A isohemagglutinin IgM antibodies in the recipient bind to and agglutinate the incoming donor type A red blood cells. The bound anti-A antibodies activate the classical complement cascade, resulting in destruction of the donor red blood cells.

Cytotoxic reactions involve the binding of both IgM and IgG antibodies to antigens bound to cells. The antigen—antibody binding results in the activation of the complement cascade and in the destruction of the cell to which the antigen is bound.

C Type III hypersensitivity. Immunocomplexes are formed when the antigens bind to the antibodies. They are usually removed from the process by phagocytosis.

However, the deposition of these immunocomplexes in the tissues or in the vascular endothelium can produce a tissue aggression mediated by immunocomplexes. D Type IV hypersensitivity. These types of reactions are not mediated by antibodies. Delayed hypersensitivity reactions are mediated primarily by T lymphocytes cell-mediated immunity. Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies.

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by APC, such as a DCs, macrophage, or B-cell [ ].

IL-5 plays a role in eosinophil development, recruitment and activation. IL-9 plays a regulatory role in mast cells activation. For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present peptides from it, bound to the MHC-II molecules found on B cell surfaces, to the antigen receptors on Th2 cells. Type I reactions are immediate hypersensitivity reactions involving IgE-mediated release of histamine and other mediators from mast cells and basophils Figure 3A.

Examples include anaphylaxis and allergic rhino conjunctivitis [ ]. Type II or cytotoxic hypersensitivity [ ] depends on the abnormal production of IgG or IgM directed against tissue antigens or a normal reaction to foreign antigens expressed on host cells. There are three main mechanisms of injury in type II reactions: 1 activation of complement followed by complement-mediated lysis or phagocytosis and removal by leukocytes; the IgG or IgM antibody can complex with antigens on the surface of cells or extracellular matrix and this complex then may activate complement.

An example is antibody produced against acetylcholine receptors in myasthenia gravis resulting in increased turnover of the receptor at motor end-plates and subsequent muscular weakness or drug-induced hemolytic anemia [ , ].

Drug-induced immune hemolytic anemia DIIHA is rare, and required to provide the optimal serological tests to confirm the diagnosis. The drugs most frequently associated with DIIHA at this time are cefotetan, ceftriaxone and piperacillin. DIIHA is attributed most commonly to drug-dependent antibodies that can only be detected in the presence of drug. The drug affects the immune system, causing production of red blood cell RBC autoantibodies; the clinical and laboratory findings are identical to autoimmune hemolytic anemia AIHA , other than the remission associated with discontinuing the drug.

The most acceptable one involves drugs like penicillin that covalently binds to proteins e. The most controversial is the so-called immune complex mechanism, which has been revised to suggest that most drugs are capable of binding to RBC membrane proteins, but not covalently like penicillins.

The combined membrane plus drug can create an immunogen; the antibodies formed can be IgM or IgG and often activate complement, leading to acute intravascular lysis and sometimes renal failure; fatalities are more common in this group.

Type III reactions immune-complex reactions involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation.

An example is serum sickness. Type III hypersensitivity is caused by circulating immunocomplexes and is typified by serum sickness a drug reaction in which multimeric drug-antibody aggregates form in solution. Preformed immunocomplexes deposit in various vascular beds and cause injury at these sites. Multimeric antigen-antibody complexes are efficient activators of the complement cascade through its classical pathway. The vascular beds in which immunocomplexes are deposited are determined in part by the physical nature of the complexes their aggregate size, charge, hydrophobicity, etc.

Typical sites of injury are kidney, skin, and mucous membranes. Type III hypersensitivity is common in systemic lupus erythematosus SLE and underlies most of the pathophysiology of this chronic autoimmune disease. Some inflammatory reactions may blend features of type II and III hypersensitivity with the formation of immunocomplexes in situ [ ]. Type IV reactions delayed hypersensitivity reactions and cell-mediated immunity are mediated by T cells rather than by antibodies Figure 3D.

An example is contact dermatitis from poison ivy or nickel allergy, tuberculosis, leprosy and sarcoidosis. In tuberculosis, cellular hypersensitivity, the delayed type of allergy, may be defined as an immunological state in which lymphocytes and macrophages are directly or indirectly sensitive to tuberculin, activate macrophages [ ], and can passively transfer delayed hypersensitivity to the normal host [ ].

Lymphocytes, when exposed to tuberculin merely produce a toxic or irritating product affecting macrophages, whether they sensitize macrophages to tuberculin [ ]. In tuberculosis, delayed hypersensitivity is both beneficial and detrimental. In low concentrations, tuberculin stimulates the development of immunity in macrophages. Therefore, the presence of hypersensitivity is an asset in preventing pulmonary tuberculosis for only small units of one to three bacilli that reach the alveolar spaces where the infections begins.

In high concentrations, tuberculin kills macrophages and thus is responsible for the liquefaction of caseous foci. This process results in tremendous extracellular multiplication of tubercle bacilli followed by their spread throughout the bronchial tree and to the other people [ ]. Despite the various immunological mechanisms to maintain tolerance to itself, there are certain individuals who develop autoimmunity.

In , the idea was postulated that the T and B cells specific for antigens coming from infecting pathogens, also generate a cross reaction against autoantigens even though the pathogens are eliminated. This type of response is initiated by low affinity T cells that have escaped the central tolerance. In addition, there is a genetic component capable of initiating and causing a persistence of autoimmunity and, therefore, trigger an autoimmune disease. However, epigenetic factors also play an important role in their development.

They have been classified as a specific organism or systemic, with the genetic susceptibility in the alleles of class I and class II molecules, a large part of the cause of the occurrence of autoimmune diseases such as systemic lupus erythematosus and type I diabetes mellitus [ 90 ].

Thus, the appearance of polymorphisms in more than 50 genes, among which a small number has been identified that affect the expression of molecules involved in the general activation of T cells, causes a high susceptibility to type I diabetes. In the case of the presentation of systemic autoimmune diseases, genetic susceptibility occurs in the general activation of B lymphocytes, affecting the signaling and survival receptors, which allows the autoreactive B cells of higher affinity to escape from the negative selection.

Also, the genetic deletion of certain TLRs, such as TLR-9, increases the susceptibility to manifest autoimmune diseases. Depositions of antigen-antibody complexes in tissues, such as kidney, have been an important factor in the manifestation of autoimmune diseases. This is due to the variation in certain genes such as those responsible for synthesizing the components of the complement and its receptors, which can initiate autoimmune pathologies.

Another important factor that triggers autoimmunity is the loss of certain immunoregulatory mechanisms. Such is the case of a chronic stimulation of the TCR, by a persistent antigenic exposure that can deregulate the immune response through adaptive tolerance mechanisms. A loss of the anergy of autoreactive T lymphocytes, a failure in cell death by apoptosis of autoreactive T cells, the loss of suppression of these cells due to T regs lymphocytes, polyclonal activation of autoreactive T lymphocytes, may also occur among other mechanisms that can trigger autoimmunity [ ].

Finally, autoimmune diseases can affect a specific cell type, several cells or the entire organism. Its initiation will depend on the pathways by which the immunological tolerance is altered, being of great importance the genetic predisposition that certain individuals present.

Autoimmune diseases are a consequence of an immune reaction against an autoantigen. They can affect a single organ or cell type; however, they are usually also systemic, as is the case of the onset of rheumatoid arthritis or systemic lupus erythematosus. Systemic lupus erythematosus SLE is a rare disease with a prevalence of 3.

It is a multisystemic autoimmune disorder characterized by extended immunological dysregulation, formation of autoantibodies and immune complexes, resulting in inflammation and potential damage to a wide variety of organs. The clinical manifestation presented is nonspecific, such as the appearance of fever, fatigue, anorexia, alopecia and arthralgias. Symptoms such as generalized inflammation, including lymphadenopathy and hepatosplenomegaly, may manifest during the onset of SLE.

However, the hallmark of this disease is the appearance of a butterfly-shaped malar rash. This condition can affect any organ of the system and its diagnosis is given through clinical manifestations and laboratory tests. The indicated treatment is according to the activity of the disease and its severity, as well as the organs affected by the SLE. The immunopathogenesis of this disease is mediated by the recruitment of autoreactive T cells and excessive plasma levels of proinflammatory cytokines.

In addition, dendritic cells and subpopulations of T cells such as Th1, Th17 and regulatory T cells are significantly altered in function and number.

However, the fundamental immunological dysfunction in the appearance of SLE is the loss of tolerance to nuclear antigens. There are defects that promote the presentation of autoantigens and the response to apoptotic residues in an immunogenic form; also, those faults that affect the signaling of the T or B cells, which causes the autoreactive abnormal stimulation of the lymphocytes; as well as those defects that promote the survival of autoreactive lymphocytes.

Therefore, the loss of immunological tolerance is a factor that causes the presentation of systemic lupus erythematosus [ ].

Rheumatoid arthritis RA is a chronic inflammatory multisystem disease characterized by destructive synovitis, in which all joints can be affected, mainly the small joints of the hands and feet. RA is a chronic progressive disease that results in decreased functional capacity and quality of life.

It can manifest in individuals with genetic predisposition; however, it is of unknown etiology. It affects 0. The diagnosis of RA occurs through the presentation of clinical manifestations, such as the onset of arthritis of at least 3 joints and morning stiffness of more than 30 minutes, as well as an exacerbated joint inflammation with the presence of pain.

Likewise, blood concentrations of C-reactive protein and rheumatoid factor are evaluated, which will be elevated depending on the inflammatory activity of the RA. Another determinant with a high probability for the diagnosis of the disease is the evaluation of anti-CCP antibodies. The immunopathogenesis of RA results from the loss of immunological tolerance, with the consequence of an elevated secretion of proinflammatory cytokines such as IL-6, which is found in some patients, in high quantities in synovial fluid.

In addition, the formations of autoantibodies that attack the joints of the entire organism are among the main causes of the presentation of RA [ ]. The immune system is characterized by a network of complex mechanisms whose main objective is to protect the body.

For this reason, it is very important to know how our immune system works and how these pathologies originate. Currently, anaphylactic shock and skin reactions are the most frequent hypersensitivity reactions affecting organs and tissues.

There are several mechanisms and factors involved which triggers hypersensitivity reactions. On the other hand, although autoimmune diseases are relatively common and our current knowledge about the mechanisms involved in their pathogenesis is very limited.

Thanks to the authors who collaborated in the writing of this chapter: Dr. Flor Pamela Castro, Dra. Thanks for the financial support for chapter publication. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers.

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Downloaded: Abstract The immune response is known as a physiological mechanism to protect the body, providing defense to different systems that compose it and allowing its proper functioning. Keywords innate immune response adaptive immune response histocompatibility immune tolerance hypersensitivity diseases autoimmune diseases.

Introduction The immune system is characterized by both innate and adaptive immune responses. Immune innate system cells The cells of the innate immune system have several functions that are essential for the defense of the organism.

Macrophages Macrophages function as cells that capture and degrade agents that are not recognized as belonging to the organism, in addition to being antigen-presenting cells; therefore, they are essential in both types of immunity innate and adaptive [ 9 ]. In type III hypersensitivity, soluble antibodies bind to antigens to form immune complexes in the blood.

These complexes travel through the blood stream and get deposited in various organs. Hence this can occur in many parts of the body. Generally, common sites of deposition include:. One example of a Type III hypersensitivity is serum sickness, a condition that may develop when a patient is injected with a large amount of antitoxin that was produced in an animal. The image below is that of serum sickness:. The cases of different diseases vary widely.

Certain diseases can be common, such as rheumatoid arthritis. Diseases such as systemic lupus erythematosus can have the figure of 1. Note that systemic lupus erythromatosus is a disease of mixed hypersensitivity — type II and III hypersensitivity reaction occur in this disease. Depending on the manifestations of different type III hypersensitivity diseases, there are different risk factors as well. There are some gender differences between diseases of type II hypersensitivity.

Some diseases are more common in women such as rheumatoid arthritis. As different diseases are included in type III hypersensitivity, ethnicity and geographical location can have impact on the disease cases. Type III hypersensitivity reaction is induced by antigen-antibody complexes.