Aberrant humoral responses

Immunological tolerance is the process that normally prevents lymphocytes from reacting with self antigens. Under certain circumstances, immunological tolerance breaks down and autoimmune disease results. Humoral antibodies to self antigens on cell surfaces can lead to cell death by direct complement-mediated cell lysis, by ADCC or by opsonization. Antibodies directed against hormones or against cell surface receptors may interfere with cell function. One such example is the autoimmune disease...

Intestinal inflammation induced by exogenous agents

Trinitrobenzene sulfonic acid-induced colitis Administration of an enema containing trinitrobenzene sulfonic acid (TNBS) results in the development of colitis in animals studied. The colitis has the features of a delayed-type hypersensitivity response to TNBS. Variations are seen in the response amongst different strains of mice, and mice could potentially be used to define genes that control susceptibility of disease. These mice have responded well to drugs used in the treatment of IBD and...

Diagnosis and clinical characteristics

Most patients with X-linked hyper-IgM present in the first 2 years of life with recurrent sinopulmonary infections, while some patients have presented with Pneumocystis carinii pneumonia. Low or undetectable serum IgG, IgA and IgE levels with a normal or elevated IgM level in a boy suggests the diagnosis of X-linked hyper-IgM. The presence of a normal number of mature B cells in X-linked hyper-IgM differentiates it from X-linked agammaglobulinemia. Normal numbers of T cells and T cell subsets...

Structure of IgM

IgM, previously known as y-macroglobulin, exists as a variable size polymer of identical subunits. Each subunit (monomer) displays a molecular weight of 180 kDa and a sedimentation rate of 7.8 S. The IgM molecule possesses a double heterodimeric structure, consisting of two identical p heavy (H) (jjl2) and two identical k or light (L2) chains. In healthy humans, the predominant polymer is the pentamer ( x2, I.2)5, with a molecular weight of 970 kDa and a sedimentation rate of approximately 19...

Toward a comprehensive model for etiopathogenesis of rheumatoid arthritis

To date, no convincing evidence has been provided for a single infectious agent fulfilling Koch's postulates as an etiologic agent for rheumatoid arthritis. Nevertheless, some interesting observations have been made that correlate some pathogens with rheumatoid arthritis. This is the case, for example, with EBV. Patients with rheumatoid arthritis have increased titers of unusual antibodies to EBV, such as antirheumatoid arthritis nuclear antigens (anti-RANA). EBV antigens have been identified...

Spontaneous animal models with systemic autoimmune diseases

University of California at Davis (UCD) 200 strain as an animal model for progressive systemic sclerosis (SSc) - scleroderma SSc is a human disease that is classified among the autoimmune connective tissue diseases that also comprise systemic lupus erythematosus (SLE), dermatomyositis and polymyositis, rheumatoid arthritis and several others. While there are several well-established, spontaneously occurring animal models available for SLE, models for the other conditions in this group are...

Adverse effects of NSAIDs

Like the beneficial effects of NSAIDs, the adverse effects of these drugs can be largely attributed to their effects on prostaglandin synthesis. The most common detrimental effects of NSAIDs are ulceration in the gastrointestinal tract, renal damage, delayed labor and hypersensitivity reactions (often manifest as asthma). NSAIDs can cause gastric and duodenal ulceration and can exacerbate or delay the healing of pre-existing ulcers. Inhibition of prostaglandin synthesis in the upper...

Il8

Bioactiw lipids generation (t) (loukolrtenes and platelet Figure 4 In vitro biological activities of IL-8. causes a rapid (< 30 min) mobilization of bone marrow stem cells into the peripheral blood in mice and primates. Intradermal injection of IL-8 induces a rapid and concentration-dependent neutrophil infil tration and neutrophil-dependent plasma leakage at the injected sites. In addition to neutrophils, local injection of IL-8 at a lower dose induces lymphocyte migration to the injected...

Prostaglandin production

Prostaglandins are synthesized from arachidonic acid catalyzed by the enzyme cyclooxygenase. Prostaglandins, particularly the E series, have biologic properties that can enhance microvascular permeability with subsequent edema, vasodilatation and induction of pain. In IBD, there is in increased level of prostaglandin production. Elevated levels of prostaglandins are found in the stool, venous blood and rectal mucosa in IBD. Prostaglandin levels in IBD in mucosa, serum or rectal dialysates...

Role of prostaglandins in inflammation

The primary prostaglandins such as PGE2, as well as the breakdown products of prostacyclin and TxA2, have all been detected in elevated levels at sites of acute and chronic inflammation. The most abundant cyclo-oxygenase product is usually PGE2, but this depends on the nature and location of the inflammatory response. For example, in conditions where mast cell degranulation is central to the pathology, such as in systemic mastocytosis, PGD2 and its metabolites can be detected in high amounts in...

Immunological mechanisms as pathologic processes

The assumption is generally made that the immune response is protective. To appreciate the concept of immunologic mechanisms as pathologic processes, the paradigm of the immune system as a beneficial event has to be shifted completely. There are some situations where the actual lesion is a relatively localized interaction between cell-cell and cell-organism. Perhaps the classic example is that of the most commonly recognized form of Mycobacterium tuberculosis infection, where a relatively...

Group A streptococcus

Several immunologic diseases result from infection with S. pyogenes, the group A streptococcus. Acute glomerulonephritis, characterized by hematuria, proteinuria, hypertension and edema, may appear 6-14 days after infection caused by a limited number of group A streptococcal serotypes. Attack rates are related to the magnitude of the immune response, with high levels of antibodies to streptococcal cell membrane antigens being found in the serum of affected patients. Electron microscopic demon...

Superantigens in disease

Bacterial superantigens have been implicated as a causative agent in several acute pathological conditions, including food poisoning, toxic shock associated with staphylococcal sepsis, the toxic shock syndrome, scalded skin syndrome and scarlet fever. A common feature of these diseases is massive systemic immunoactivation, as reflected by high serum levels of TNFa, II.-1, IL-6 and IFNy. Associated toxic shock is likely, at least in part, to be due to excessive release of cytokines. SAgs are...

The hsp65 connection

In 1984 it became possible to study the complexities of AA using an etiologic agent of disease, a clone of T cells capable of adoptively transferring AA, called A2b. It was demonstrated that A2b recognized an MT antigen and an antigen in the proteoglycan moiety of joint cartilage. This supported the autoimmune theory AA was caused by antigen mimicry between MT and a joint antigen. The MT epitope recognized by clone A2b was later identified as the nine amino acids at positions 180-188 in the...

Ra

Further, passive transfer of transient arthritis is seen with the transfer of sera from arthritic mice or rats to naive animals. More profound is the ability of sera from a human with polyarthritis to induce arthritis similar to CIA in mice. As with the passive transfer of murine antibodies against CII, this arthritis is also transient in nature. This is in sharp contrast to CIA where chronic arthritis develops, culminating in joint destruction. Thus, autoantibodies do play a role in the...

Human Ir genes

A number of studies have demonstrated HLA associations with the immune response to different antigens. While it is more difficult to formally demonstrate Ir genes in humans, it is clear that the human MHC gene products function in an analogous manner to the mouse. One example where Ir gene effects in humans most likely play a role is the association of HLA alleles with autoimmune diseases such as ankylosing spondylitis associated with HLA-B27. and rheumatoid arthritis and juvenile onset...

Nonspecific immune suppression

Even 'nonspecific' immune suppression comes in degrees of specificity. One popular target is activated T cells. It could be predicted that activated T cells would be enriched for cells involved in the autoimmune process. However this prediction may not be useful, as there is evidence that many activated T cells are involved in the endogenous immunoregul-ation which diminishes the immune responses to auto and other antigens. Activation antigens that have been used as the target for immune...

Therapeutic effects

For many years the only clinical use of plasmapheresis was to alleviate the hyperviscosity syndrome of Waldenstrom's macroglobulinemia. In 1976 three articles in the Lancet detailed its use in Goodpasture's syndrome, systemic lupus erythematosus and myasthenia gravis. Since then reports of its use in over 180 different conditions have appeared. In most of these diseases plasmapheresis has been shown to be ineffective or to offer no clear benefit over conventional treatment. In 1981 a report...

Consequences of autoimmunity

Autoimmunity is defined as an immune response leading to reaction with self antigen, i.e. any molecule that is a normal body constituent of the animal mounting the response. Self reactivity can arise either through the triggering of receptors directly by autoantigen or by virtue of cross-reaction between foreign and self antigens. Topographic similarity of B cell epitopes or sequence homologies of linear T cell epitopes may lead to such cross-reactions and it is highly unlikely that the immune...

Clinical aspects

The major clinical use of IL-2 to date has involved tumor immunology. The potential for IL-2 as a cancer treatment is based on activation of cells which are cytotoxic for the tumor, and some success has been obtained with renal cell carcinoma and metastatic melanoma. However the use of II.-2 is limited by various side-effects. To circumvent these difficulties lymphokine-activated killer (LAK) cells as well as tumor-infiltrating lymphocytes (TILs) have been tested after in vitro activation by...

Selective immunosuppression

Tolerance in its classical definition depends on knowing the antigenic epitopes to be recognized, and hence a major drawback of studies in human and experimental autoimmunity is our lack of understanding of the important epitopes. Nevertheless there are a variety of experimental approaches which are finding their way into human application, at least to the clinical trial stage. A major objective is to ensure that in established disease, with an ongoing immune response, the therapeutic strategy...

Primate Nonhuman Immune System

Todd M Allen and David I Watkins, Wisconsin Regional Primate Research Center and Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USA Nonhuman primates have been widely used as animal models for human diseases. Simian immunodeficiency virus (SIV) infection of rhesus macaques provides an excellent model for human immunodeficiency virus (HIV) infections of humans. Similarly, experimental autoimmune encephalomyelitis (EAE) induction in macaques and...

Immunodeficiency and radiation sensitivity

Many immunodeficient states have been associated with increased radiation sensitivity. Ataxia telangiectasia (AT) is associated with an increased sensitivity of T cells to the cytotoxic effect of ionizing radiation, with defective cell-mediated immunity, and with nervous system disorders. The gene responsible for this disorder (the Atm gene) has recently been identified as being important in the regulation of cell division. Lymphocytes from patients with AT do not exhibit normal cell cycle...

Type III hypersensitivity

Antibodies binding to equivalent amounts of soluble antigens give rise to immune complex formation. The antigens involved in inducing the pathogenic immune response can be either foreign or self, and the antibodies either IgG or IgM. When complexes are formed, they usually activate complement and then bind to C3b receptors on erythrocytes. The erythrocytes are then responsible for removing complexes from the plasma and transporting them to the sinusoids of the liver and spleen, where they are...

Info

The second locus in the series, RT2, was originally designated AgC, and by linkage similarities involving serum esterase loci appears to be homologous to the mouse Ea-1 locus. RT3 is a blood group locus that was formerly designated AgD. The histocompatibility loci RT4 and RT5 were previously designated H-2 and H-5, respectively and unfortunately most of the common inbred strains have not been characterized for these loci. The RT6 antigens (formerly designated ART-2, AgF, Pta and RT LY-2) are...

TGF0 and experimental autoimmune diseases

The influence of TGFp on EAE as a prototype of organ-specific CD4+ T cell-mediated autoimmune disease has been extensively studied. TGFp strongly inhibits in vitro activation of T cells from Lewis rats with EAE. During recovery from EAE, CD4+ spleen cells produce TGFp and thereby regulate both the production of IFNy and the encephalitogenicity of effector cells. Systemic administration of TGFp reduces the incidence and severity of EAE induced in the SJL mouse, without generalized...

Thyroidspecific antigens Thyroglobulin

Thyroglobulin autoantibodies can be demonstrated by several procedures, such as precipitation in agar, IIF, indirect hemagglutination of cells coated with thyroglobulin, RIA and ELISA. At present, hemagglutination is the most commonly employed technique for the detection of antibodies against thyroglobulin. The ELISA is increasingly used for the measurement of antibodies to thyroglobulin and will additionally detect antibodies that are nonagglutinating. Thyroglobulin antibodies are found in...

Ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis, characterized by exacerbations and remissions, affecting primarily the axial skeleton and the sacroiliac joints. In 1973 it was demonstrated by two independent groups that the class I major histocompatibility complex (MHC) molecule HLA-B27 was present in over 90 of patients with AS, while its frequency in the general Caucasian population was of the order of 8 . Clearly the HLA-B27 molecule was somehow involved in the development...

Stress proteins as target antigens

Heat shock proteins have been shown to be among the dominant antigens recognized by both the regulatory (helper T lymphocytes) and effector (B lymphocytes and cytotoxic T cells (CTLs)) arms of the adaptive immune system for a variety of pathogenic infections and experimentally induced immune reactions. B cell responses In mice, immunization with a mycobacterial lysate elicits antibody responses to only a limited number of Mycobacterium tubercu losis or M. leprae antigens, including hsp70,...

Mechanisms controlling autoimmunity

Cell Bypass Theory

Because pathogenic autoimmunity is the exception rather than the rule, mechanisms must exist which normally prevent the development of autoimmune disease. In this respect the immune system is able to distinguish self from nonself and, ultimately, becomes 'tolerant' towards most self antigens. However, as alluded to above, many of the tolerance mechanisms controlling autoimmunity may be less concerned with repression of all self reactive lymphocytes than with preventing the development of...

Clinical features Table

Patients with CVI present with recurrent bacterial infections of the respiratory tract, such as sinusitis, otitis media, bronchitis and pneumonia. The most common etiologic agents are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. The onset of these abnormally frequent infections may occur at any age but most patients do not come to medical attention until the second or third decade. This is in contrast to X-linked agammaglobulinemia, where recurrent...

Campath1 Antigen Cd52

Geoff Hale, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK The CD52 antigen of human lymphocytes was first defined with monoclonal antibodies isolated in the Department of Pathology, University of Cambridge. It is a lipid-anchored glycoprotein, unusual in having an extremely small peptide component. CD52 antibodies are remarkably lytic, killing cells in vitro with human complement, and also in vivo, probably by other mechanisms. They have many possible applications for...

Spondyloarthropathy

The spondyloarthropathies are a group of arthritides which share common features and include ankylos ing spondylitis, reactive arthritis including Reiter's syndrome , enteropathic arthritis the arthritis associated with inflammatory bowel disease , psoriatic arthritis and unclassified spondyloarthropathy. The shared features include arthritis of the axial skeleton and particularly the sacroiliac joints, peripheral arthritis and enthesitis the inflammation of the transitional tissue between...

Arthus Reaction

Paul G Hellewell, Applied Pharmacology, Imperial College School of Medicine at the National Heart and Lung Institute, London, UK Adriano G Rossi, Respiratory Medicine Unit, Department of Medicine, Rayne Laboratory, Edinburgh, UK The Arthus reaction was first described by Maurice Arthus as an acute inflammatory response induced in rabbit skin by a local injection of horse serum in rabbits sensitized by previous injections of the same substance. Although the reaction described originally could...

Further reading

Berczi I, Baragar FD, Chalmers IM, Keystone EC, Nagy E and Warrington RJ 1993 Hormones in self tolerance and autoimmunity a role in pathogenesis of rheumatoid arthritis Autoimmunity 16 45-56. Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S and Richardson B 1988 Hydralazine and procaina- mide inhibit T cell DNA methylation and induce auto-reactivity. Journal of Immunology 140 2197-2200. Hala K, Malin G, Dietrich H et al 1996 Analysis of the initiation period of spontaneous autoimmune...

Examples of determinant spreading

Determinant spreading during the course of experimental autoimmune encephalomyelitis The term, determinant spreading, was first applied by Lehmann and colleagues to the phenomenon observed in experimental autoimmune encephalomyelitis EAE , a model of human multiple sclerosis MS . EAE is an inflammatory demyelinating disease of the central nervous system mediated by CD4 T cells specific for myelin autoantigens. liAF can be induced in susceptible mouse strains by immunization with myelin basic...

Polyclonal Hypergammaglobulinemia Causes

Figure 1 Serum protein electrophoresis. On the left is a normal pattern. Note the gamma globulin band is wide and the densito-metric tracing is broad-based. On the right is a monoclonal gammopathy pattern. The gamma region contains a narrow band and the densitometric tracing shows a tall narrow spike' cause of the IgE increase is not known. Hyper-IgD syndrome has also been described. These patients may present with constitutional symptoms including fever and headaches, and they may have...

Effects of IL13 on monocytes and endothelial cells

The effects of IL-13 on monocytes macrophages and endothelial cells are similar to those of IL-4. IL-1 modulates the phenotype of both human and murine monocytes macrophages and it inhibits production of proinflammatory cytokines, chemokines and nitric-oxide by these cells. IL-13 inhibits synthesis of IL-la, IL-1 p, IL-6, IL-12, tumor necrosis factor a TNE-a and the chemokines IL-8, macrophage inflammatory protein MlP-la and MIP-1 3 by monocytes. In addition, it enhances production of the IL-1...

Breakdown of autotolerance

The ability to tolerate autologous antigens, a central feature of the adaptive immune system, is guaranteed in redundant ways at the level of both the B and T lymphocyte system. It is thought to be the result of negative selection within the central lymphoid organs, i.e. bone marrow and thymus, where sensitive stages of developing B slgM1 slgD or T CD44 CD 8' cell clones are eliminated by apoptosis due to high-affinity binding to autologous antigens. Autoreactive cell clones that escape these...