Curing Your Autoimmune Diseases Permanently
Autoimmune disorders comprise a large group of diseases caused by an immune reaction to a self (or auto) antigen. Self-reactive lymphocytes, both T cells and B cells, are largely eliminated during development, but some appear to persist in a mature state in peripheral lymphoid tissue, where they can be activated to cause autoimmunity. Mechanisms of activation of autoimmunity include Genetic predisposition to autoimmunity is also important, and the MHC (HLA) locus is the best defined risk factor for most such diseases. In general, the mechanism of antibody production requires both a genetic predisposition and then a trigger, presumably of environmental origin, since concordance for autoimmune disease is only about 30 50 in identical twins.
Myasthenia gravis is a condition of muscle weakness due to impaired neuromuscular transmission. other associated autoimmune diseases, in particular thyroid disease. A CT scan is required to assess the presence of an associated thymoma. Two variants of myasthenia gravis may be seen.
This autoimmune disease is the result of genetic environmental triggers. These patients demonstrate CD8-cell infiltration of the islet cells that likely are involved with subsequent P-cell destruction. A long prodrome is usually present from genetic predisposition to onset of disease. These patients may demonstrate various antibodies to islet antigens including insulin, glutamic acid decarboxylase, and tyrosine phosphotase 1A-2. Thus, a combination of markers rather than a single test should be used for predictive and diagnostic testing to enhance sensitivity without losing specificity.
Although it was speculated for some time that there might be a subset of regulatory T cells (TR), it was not until these cells could be identified by cell surface markers that definitive studies could be performed. In both mice and humans, the major population of TR is CD25+, CD4+. CD25 is the a-chain of the high affinity IL-2 receptor. TR have rearranged T cell receptors and are antigen specific many of them react with host antigens. Once activated, the TR secretes IL-10 and TGF-0 and suppresses the immune response nonspecifically. The importance of TR has been shown in mice and humans. Mice that are depleted of CD25+, CD4+ lymphocytes rapidly develop autoimmune disease and in humans genetic deficiency of Foxp3 transcription factor, which is downstream of CD25 signaling, is associated with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome).55 In normal subjects, lymphocytes reacting with self-antigens with high affinity are eliminated in the thymus....
More than one antibody may be present. Look at the reactions of the antibody with the cells on the panel. Are there differences among the reacting cells in temperature, suspending medium, or strength of reaction Do some cells hemolyze Are some reactions enhanced or destroyed with enzymes This may give an indication of the identity of one or more of the antibodies. Absorption and elution studies may be used to separate the antibodies. Type the subject's cells to determine their antigenic composition. Except in autoimmune diseases, antibodies are not present in the subject's serum if the antigens are on the RBCs. If the cells have a positive DAT, serums reacting by AGT cannot be used in the routine manner.
(CVID) is a non-inherited form of hypogammaglobulinaemia which usually appears in adult life. There is a generalized decrease in all immunoglobulins, presumably due to B-cell dysfunction. There may be multiple pathogenetic mechanisms, but the clinical features are similar to those of agammaglobulinaemia with proneness to infection and to autoimmune diseases. Additional features include chronic lung damage, lymphoid hyperplasia and giardia-induced diarrhoea.
Effector cells from inducing tumor regression. The almost 20 years of silence that followed this pioneer observation were mainly due to the absence of a marker that specifically identified such suppressor T cells. Subsequently, a CD4+ T-cell population similar to North's suppressor T cells was found involved in autoimmune manifestations. These cells were characterized by the expression of the surface marker CD25 and shown to be responsible for the control of autoimmunity. Indeed, removal of CD25-positive T cells led to autoimmune disease in several organs and reconstitution of the eliminated population reverted the pathological status (Powrie and Mason, 1990 Sakaguchi et al., 1985 Sugihara et al., 1988). This population was found to be anergic and suppressive in vitro and proposed to be responsible for autoimmunity induced by thymectomy 3 days postnatal, in accordance to the key role of thymus in central tolerance (Itoh et al., 1999). The knowledge acquired in the field of...
A testicular prosthesis can be inserted at the time of orchidec-tomy if the patient wishes. Testicular prostheses were previously manufactured using a solid shell containing a silicon gel core. Concerns were expressed in the early 1990s about such designs in breast prostheses, and a possible association with autoimmune diseases. No causal relationship has been established, although histological and serological evidence of silicone shedding has been identified 2,3 . Currently manufacturers employ either (solid) silicone elastomer or a saline filled silicone shell.
If the patient has sustained other major life-threatening injuries at the time of trauma, then replantation of digits may need to be postponed or even cancelled. Certain diseases that can adversely affect peripheral circulation, such as diabetes mellitus, some autoimmune diseases, collagen vascular diseases or atherosclerosis, among others, may also produce a condition which contraindicates replantation.
Functionality of antigen-specific CTL was observed. In a chronic-infection mouse model of LCMV, one highly invasive lab-derived LCMV clone will cause prolonged infection with detectable viremia in blood and multiple peripheral organs. PD-1 was dramatically upregulated on CTL in response to the viral infection, and its expression was maintained during chronic infection, while B7-H1 is persistently expressed on spleen cells. These infected mice have not only a significant decrease in the number of antigen-specific memory CD8 T-cell population, but also a functional impairment of their remaining memory T cells. Interestingly, blockade of B7-H1 PD-1 pathway by monoclonal antibodies against B7-H1 or PD-1 increased proliferation of several virus-specific CTL clones, restored CTL function and reduced viral burden (Barber et al.,2006). More importantly, persistent upregulation of PD-1 is also observed on HIV, HCV and HBV viral-specific CTLs in chronically infected patients and correlates with...
Hyoscine n-butylbromide (Buscopan) is an anticholinergic agent that has been used as a muscle relaxant for the barium enema examination as well as for CT and MR colonography in Europe. It has not received approval for use in the USA. Buscopan has a different mechanism of action than glucagon and is less expensive. Hypotonia of the colon is induced by its action on the postganglionic parasympathetic receptors in smooth muscle. Contraindications to the use of anticholinergic agents include glaucoma, severe prostatic hyperplasia, unstable heart disease, bowel obstruction or ileus, and myasthenia gravis. Anticholinergics can cause side effects such as tachycardia, dry mouth, acute urinary retention, and acute gastric dilatation.
3-There is a disease, myasthenia gravis, precisely located at these junctions. The action potentials are not efficiently transmitted through the gap (also called cleft) and the net result is a weak muscular contraction (thus, the etymology of the term is well explained, from Greek, myo, muscle, asthenia, weakness, gravis, serious). The usual cause is an acquired im-munological abnormality, but some cases result from genetic abnormalities. The prevalence of myasthenia gravis in the United States is estimated at 14 100,000 population. Patients with myasthenia gravis come to the physician complaining of muscle weakness. The course of disease is variable but usually progressive. After 15 to 20 years, weakness often becomes fixed and the most severely involved muscles are frequently atrophied. The normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages. ACh diffuses across the synaptic cleft and binds to receptors on the muscle...
Neutralization of Treg suppression was first attempted in tumor-bearing mice by means of the anti-CD25 monoclonal antibody (PC61). The administration of this antibody resulted in the production of generalized autoimmune disease similar to that observed in mice thymectomized at day 3 of age, which cannot develop natural Treg (Taguchi and Takahashi, 1996). It was initially observed that PC61 administration resulted in the disappearance of CD25+ cells, as detected by staining with a different clone of anti-CD25 antibody (7D4) (Onizuka et al., 1999). The depletion of CD25+ T cells resulted in enhancement of immune reactivity and impairment of tumor growth in several tumor models, thus definitively confirming the central role of Treg in anti-tumor immunity (reviewed by Zou, 2006).
The answer is b. (Rowland, pp 721-726.) Myasthenia gravis is a disease or, more accurately, a collection of diseases in which autoimmune damage occurs at the neuromuscular junction. The postsynaptic membrane is damaged in myasthenia gravis, and the acetylcholine receptor is the principal site of damage. A relative acetylcholine deficiency develops at the synapse because receptors are blocked or inefficient. Symptoms of myasthenia gravis range from slight ocular motor weakness to ventilatory failure. 329. The answer is d. (Rowland, p 723.) More than 90 of patients with myasthenia gravis have some type of ocular motor weakness. This ranges from ophthalmoplegia to lid ptosis. Patients usually notice the lid weakness or complain of blurred vision as one of the first symptoms. More severe disease includes limb weakness, difficulty with swallowing, and respiratory difficulties. Patients usually report fatigue that increases as the day progresses. 343. The answer is e. (Rowland, p 713.)...
For tumor-associated differentiation antigens that are also expressed on normal tissues, T-cell tolerance should be mediated through the central and peripheral pathways that normally operate to prevent autoimmunity. Thus, the majority of self-reactive T cells undergo negative selection during development in the thymus, where immature T cells expressing high-avidity TCRs that recognize MHC-self-peptide complexes presented by thymic antigen-presenting cells (APCs) undergo apoptosis (Kappler et al., 1987 Kisielow et al., 1988 Sebzda et al., 1994 Surh and Sprent, 1994). Subsequently, mature T cells specific for parenchymal self-antigens that are not presented in the thymus can be subjected to a variety of peripheral tolerance mechanisms such as deletion (Jones et al., 1990), functional inactivation (also referred to as anergy Schwartz, 2003) or suppression by regulatory T cells (Sakaguchi, 2000 Shevach, 2001). the deletion of developing cognate T cells (Anderson et al., 2002). Although...
One way to compensate for their lack of immunogenicity is to combine the purified subunits with more immunogenic adducts or administer them with newer adjuvants. A complex of the recombinant immunogen and recombinant complement C3dg is an appealing adduct because of its potential to recruit not only the B cell receptor, but also the CD21 CD19 complex, which potentiates the B cell response. Newer and more potent adjuvants include MF59, which is a lipid-detergent mixture containing squalene F127, a copolymer that can be mixed with the immunogen and other immunomodulators at a cool temperature and, when injected, the mixture gels at body temperature providing a solid phase depot of immunoreac-tants and the use of unmethylated CpG DNA, which is able to directly Toll-like receptor 9, which in humans is primarily expressed on B cells and plasmacytoid dendritic cells.64,65 Although the development of new adjuvants is a burgeoning field, acceptance of this technology for human use has lagged...
(pollen, animal hair, chemicals, etc.) and to unwanted cells or cell products arising within the body from cancer or autoimmune diseases. The immune system comprises (1) cellular defence mechanisms mediated by several types of leucocytes and (2) humoral defence mechanisms mediated by soluble proteins, so-called
Interest in vaccine adjuvants is growing rapidly for several reasons. First, dozens of new vaccine candidates have emerged over the past decade for prevention or treatment of infectious diseases, cancer, fertility, and allergic and autoimmune diseases. Many of these candidates require adjuvants. Second, vaccines have become commercially more profitable in the past few years. Third, the Children's Vaccine Initiative (CVI) initiated in 1990 has helped to energize political and public health interest in vaccine adjuvants by establishing ambitious goals for enhancing present vaccines and for developing new ones (11). Fourth, refinements in the fields of analytical biochemistry, macro-molecular purification, recombinant technology, and improved understanding
The most common congenital immunodeficiency. Diarrhea is usually caused by Giardia lamblia recurrent sinopulmonary infections are caused by 5. pneumoniae, H. influenzae, or S. aureus associated with an increased incidence of allergies and autoimmune diseases. Selective IgA deficiency may be due to a specific defect in isotype switching. P-209
Main therapeutic anticholinesterases. They permit the accumulation of acetylcholine at neuromuscular junctions and autonomic synapses. They also give rise to muscarinic effects of salivation, sweating, abdominal cramps, diarrhoea, bradycardia and even asystole. Their use and that of edrophonium is discussed in the section on myasthenia gravis
VKH syndrome is a bilateral, granulomatous panuveitis associated with poliosis, vitiligo, and alopecia with both central nervous system and auditory manifestations 61 . This inflammatory syndrome is considered to be a T-cell-medi-ated autoimmune disorder against a melano-cytic antigen. Typical histopathological features, seen in the early phases of VKH, are a granulomatous T-cell inflammation that primarily involves the choroid, with similar milder inflammatory infiltration in the iris and ciliary body. The retina is preserved except at sites of Dalen-Fuchs nodules, aggregations of proliferating retinal pigment epithelial cells admixed with a few inflammatory cells. Damage of RPE cells is detected by fluorescein angiography as multiple pinpoint areas of leakage at the level of RPE. Disruption of RPE cells is confirmed through electron microscopic examination, by showing M ller cell processes with attachment to Bruch's membrane. Disappearance of choroidal melanocytes, phagocytosis of...
The HLA system has been associated with disease for over 30 years, but the precise role of HLA molecules in disease pathogenesis is not well established 16 . While microbial pathogens may play a more direct role than currently appreciated even in diseases we now consider due to autoimmunity, it is likely that in many cases HLA associated uveitis is at least in part an autoimmune process resulting from loss of tolerance to self antigens. While a discussion of the proposed mechanisms of loss of tolerance is beyond the scope of this chapter, several observations are pertinent. Despite the known role of HLA molecules in antigen presentation and the establishment and maintenance of tolerance there is no direct evidence that antigen presentation by the HLA molecule is critical to disease pathogenesis. It may be that presentation of ocular peptides in the thymus plays a role in the susceptibility to uveitis. In one study that did suggest that the HLA molecule itself was critical, a mouse...
Effector T cells are often characterized as either T-helper cell type i or type 2 (Thi or Th2) by their selective patterns of cytokine secretion. Classically, the Th2 phenotype is observed in allergy or in conferring protection from autoimmune diseases whereas the Thi phenotype has been linked to numerous autoimmune diseases Dynamic changes in lymphocyte subsets are observed through immunohistopathological studies of EAU involved eyes 9 . Early stages of S-Ag induced EAU is associated with an early T-helper phenotype. In contrast, T-suppressor cell abundance is very low during the initial inflammatory phases (less than 20 of the total T lymphocytes),but continually increases in the recovery phase (50-67 of the total T lymphocytes). These changes in the ratios between T-helper and T-suppressor cells during the different stages of EAU likely reflect the kinetics and regulation of the inflammatory response in autoimmune diseases.
Another group at increased risk are patients with autoimmune disease, particularly collagen vascular diseases requiring intensive immuno-suppression. CMV may develop with any im-munosuppressive, including cyclosporine or tacrolymus, but is particularly associated with the use of cyclophosphamide, which has a generalized action on T and B cells. Patients who are lymphopenic, with low CD4 and or CD8 counts, are at particular risk. While there is often a temporal relationship to recent cy-clophosphamide use, this is not always the case as patients may develop an active retinitis even months later 12 . These patients usually present with a generalized reduction of their cellular immunity sometimes related to the use of other medications such as antiviral agents.
In some cases, the study of tolerance to self has been greatly aided by animal models of spontaneous or experimentally induced autoimmunity. With transgenic technology, it is possible to engineer antigens that are well defined in terms of three-dimensional structure and T-cell subset responses for microinjection. Furthermore, expression of the introduced gene can be targeted to tissues that are readily accessible for histological analysis, and in some cases, timing of expression can be controlled. of great importance, since many of the major failures of tolerance to self (i.e., autoimmune disease) are owing to immune responses to these parenchymal self' antigens.
Since many human and mouse tumor antigens are expressed on both tumors and the normal tissues from which they derive (i.e., differentiation antigens, e.g., tyrosinase (Wolfel et al., 1994), TRP2 (Wang et al., 1996) and Pmel-17 gp100 (Cox et al., 1994)), it is likely that the pathways which tolerize the T-cell repertoire to tissue-specific self-antigens in order to avoid autoimmunity also negatively impact the ability of these same T-cell specificities to mediate tumor immunity. To model the impact of pre-existing T-cell tolerance to differentiation antigens on tumor vaccine efficacy, Hu et al. developed a transgenic mouse model in which the Friend murine leukemia virus envelope protein (env) was expressed under the control of a lymphoid-specific promoter. Env-specific T cells were tolerant in these animals as demonstrated by their failure to expand following vaccination with
A molecule constitutively expressed by Treg and associated to their function is CTLA-4. The blockade of CTLA-4 does not result in Treg depletion, but in their expansion in lymph nodes (Quezada et al., 2006) nevertheless, in some instances, it inhibits their suppressive function. In the model of inflammatory bowel disease, Treg suppression of colitogenic T cells is inhibited by CTLA-4 blockade. Since such inhibition is lost in the case CTLA-4 knock-out Treg are targeted, the experiment indicates that Treg-associated CTLA-4 was responsible for immuno-suppression in the gut (Read et al., 2006). Conversely, when used as adjuvant in cancer immunotherapy, CTLA-4 blockade has been shown to improve the immune response even in mice previously depleted of Treg (Sutmuller et al., 2001). In line with this evidence, Allison's group has recently demonstrated that CTLA-4 blockade, in conjunction with GM-CSF-based vaccination, modifies the intratumor balance between Treg and T effectors, restoring...
Vogt-Koyanagi-Harada (VKH) disease is a bilateral, granulomatous panuveitis with exudative retinal detachments associated with systemic manifestations such as meningeal signs and cutaneous signs (poliosis, alopecia, vitiligo) and dysacusis 6 . There is now enough evidence to indicate that the disease is caused by an autoimmune process against melanocytes or an antigen present in these cells, namely tyrosinase or tyrosinase related protein 7 . As for most of these autoimmune diseases an infectious event due to one or several different commonly occurring pathogens probably triggers the reaction in susceptible individuals 7 . The disease is more prevalent in Asians,in particular Japanese 8,9 , in Hispanics and native Americans, but can occur in any individual of any race. A genetic predisposition to the disease that can be suspected as an association with class II human leucocyte antigens (HLA) has been established, mainly HLA-DR4 locus for Japanese 10 , and HLA-A31 and HLA-B55 for...
Botox is administered by injection with a small needle directly into the muscles to be treated. The most common side effect is bruising from the needle. Another risk is unintended paralysis of nearby muscles because of diversion of the toxin from the site of injection. The most common example of this problem is drooping of the eyelid after injection of frown muscles. Patients who are pregnant or nursing should not receive Botox, not should patients with myasthenia gravis, a neurological disease that may be worsened by treatment.
The -308 G A polymorphism, termed TNF2, is strongly linked to HLA aplotype A1-B8-DR3 (3). This linkage is of interest because it has been reported that individuals with this aplotype produce high levels of TNFa and are more susceptible to a wide spectrum of autoimmune diseases. Studies with the TNFa promoter linked to a reporter gene have shown that the TNF2 allele leads to an increased tissue-specific constitutive and inducible expression, both in vitro and in vivo, compared to the wild-type TNF1 allele (7,8,10,12,13).
From an immunological perspective, androgen levels are inversely related to disease severity in certain autoimmunity models (Fox, 1992 Roubinian et al., 1978), and androgen ablation can reverse the decline in thymic output associated with aging (Sutherland et al., 2005) as well as enhance peripheral T-cell responsiveness (Roden et al., 2004 Viselli et al., 1995). Since androgen ablation is a standard therapy for advanced prostate cancer, many clinical trials utilizing T cell-based therapies will likely involve patients who have already undergone or who will be scheduled to undergo androgen ablation. Thus, understanding the effects of androgen ablation
Coloboma is a defect of the lid that can range from a small indentation to a large cleft, which can lead to ulceration from excessive drying. Coloboma can also extend to the iris, lens, retina, and choroid. They are associated with chromosomal disorders and malformation syndromes. Epicanthal folds are folds of skin on the nasal side of the eye. Usually more prominent at birth and receding with time, they are responsible for pseudostrabismus by making the eyes appear closer together. Ptosis, or drooping of the upper eyelid, is the most common anomaly of the eyelid. It is usually an isolated finding but can be seen in systemic disorders such as botulism and myasthenia gravis.
Primary biliary cirrhosis is an autoimmune disease. It is thus also associated with other autoimmune diseases, particularly scleroderma, CREST syndrome, Sjogren's syndrome and renal tubular acidosis. There is a genetic predisposition because of the association with the HLA-DR8 haplotype.
Major excitatory transmitters include Substance P, acetylcholine, and excitatory amino acids major inhibitory transmitters include GABA, enkephalin, and glycine. Disruption of neurotransmitter function can lead to different diseases of the nervous system. One such example involves the role of acetylcholine at the neuromuscular junction. When antibodies are formed against the acetylcholine receptor at the neuromuscular junction, transmission is disrupted and the autoimmune disease called myasthenia gravis occurs. This disorder includes symptoms such as weakness and fatigue of the muscles.
EAU is an animal model of posterior uveitis, which can be induced in genetically susceptible animal species by immunization with uveito-genic retinal antigens or by the adoptive transfer of antigen-specific T cells 6 . The EAU course is characterized by photoreceptor damage, vasculitis, choroiditis and vitritis, serous retinal detachment and retinal folding. EAU histopathology strikingly resembles lesions of ocular sarcoidosis,Vogt-Koyanagi-Harada (VKH) syndrome, sympathetic ophthalmia, Behcet's disease, and birdshot retinochoroidopathy, a group of non-infectious uveitis syndromes in humans that have a suspected autoimmune aetiology. EAU also serves as an animal model for organ-specific, T-lymphocyte-mediated autoimmunity.
The answers are 153-b, 154-b. The thymus is composed of two lobes, which are frequently asymmetrical. With increasing age it atrophies and is replaced by fat with streaky or nodular densities. Cystic transformation can occur along the developmental pathway of the thy-mopharyngeal duct, and in patients with Hodgkin's lymphoma, persistence of these cysts can be seen due to thymic involution. These cysts can persist or even enlarge after radiation treatment or chemotherapy. Rebound thymic hyperplasia is seen in children, where a period of stress associated with thymic involution is followed by regrowth or overgrowth of the gland. However, despite an abnormal increase, the gland maintains its normal arrowhead configuration. Thymomas are neoplasms of the thymic epithelial cells with cystic degeneration and calcification. They are seen in adults, usually in the fifth decade of life. About 40 of adults with thymomas have myasthenia gravis and 15 of patients with myasthenia gravis...
27 Piredda L, Amendola A, Colizzi V, Davies PJA, Farrace MG, Fraziano M, Gentile V, Uray I, Piacentini M, Fesus L Lack of 'tissue' transglutaminase protein cross-linking leads to leakage of macromolecules from dying cells Relationship to development of autoimmunity in MRL lpr lpr mice. Cell Death Differ 1997 4 463-472.
In addition, the authors found no evidence for autoimmunity in the transgenic mice that they created (24), and the disease state can be induced by targeting a variety of genes to the (3-islet cells. Despite these cautious notes, the transgenic technology still provides one of the best, if not the only model at present to study many complex biological systems.
As detailed above, tumors often exploit T-cell peripheral tolerization pathways that normally operate to prevent autoimmunity, to delete or inactivate tumor-reactive T cells. Understanding how these tolerance pathways operate under normal conditions will undoubtedly provide key insights into how tolerance might be mitigated in order to allow tumor vaccines to more effectively prime tumor-reactive effector T-cell responses. It is also becoming apparent that standard treatments for certain cancers can not only impact disease progression, but also influence the functional capacity of tumor-reactive T cells. For instance, chemotherapeutic drugs such as Cytoxan can deplete T cells however, when administered in the proper sequence they can actually augment certain T cell-based anti-tumor modalities. Additionally, androgen ablation therapy for prostate cancer can induce a state of minimal residual disease that leads to a reduction in the level of tolerizing prostate tumor antigen and hence...
LS is a lymphocyte-mediated inflammatory disease characterized by pallor and scarring. It is commoner in females and can affect any age but the majority of patients are either prepubertal or menopausal (21-26). The etiology is unknown, but there is evidence to support that LS is an autoimmune disorder, and in females it may be associated with other autoimmune disorders such as vitiligo in children and thyroid disease in older women.
The kidney reacts to the various inflammatory conditions with similar sonographic changes. It can be entirely normal in early pyelonephritis or glomerulonephritis. Later, edema causes an enlargement and interstitial infiltration an increased parenchymal echogenicity with accentuated demarcation of the parenchyma (29) relative to the hypoechoic pyramids (30) (Fig. 39.3). This is referred to as punched-out medullary pyramids ' In comparison with the adjacent hepatic or splenic parenchyma (9), the renal parenchyma appears more echogenic (Fig. 39.3) than the parenchyma of the normal kidney (Fig. 38.2). Interstitial nephritis can be caused by chronic glomerulonephritis, diabetic nephropathy, urate nephropathy (hyperuricemia as manifestation of gout or increased nucleic acid turnover), amyloidosis or autoimmune disease, but the etiology cannot be deduced from the increased parenchymal echogenicity.
The answer is c. (Holmes, 3 e, p 489.) Lyme disease (caused by Borrelia burgdorferi, a spirochete) has been associated with false-positive treponemal FTA-ABS (Fluorescent Treponemal Antibody Absorption) tests which are designed for the diagnosis of Treponema pallidum infections (i.e., syphilis). The nontreponemal test is often negative in this disease. Other conditions associated with false-positive treponemal tests include yaws, pinta, leptospirosis, and lupus. Biological false-positive nontreponemal tests VDRL (Venereal Disease Research Laboratory), and RPR (Rapid Plasma Reagin) are classified as acute (reverting back to negative in six months) or chronic. Acute reactions can occur with recent immunization, mononucleosis, viral pneumonia, tuberculosis, malaria, and a variety of viral diseases. Chronic reactions can occur in users of intravenous drugs, with aging, and in autoimmune diseases, such as systemic lupus erythematosus. A positive nontreponemal test must always be...
Phenytoin, sulfonamides, barbiturates, and allopurinol. Finger pressure in the vicinity of a lesion in EM major leads to a sheetlike removal of the epidermis (Nikolsky sign). Pemphigus vulgaris is a chronic, bullous, autoimmune disease usually seen in middle-aged adults. The Nikolsky sign is positive in pemphigus vulgaris. Secondary syphilis appears 2 to 6 mo after primary infection and consists of round to oval maculopapular lesions 0.5 to 1.0 cm in diameter. The eruptions typically involve the palms and soles. Secondary syphilis lesions that are flat and soft with a predilection for the mouth, perineum, and perianal areas are called condylomata lata. The skin lesions of systemic lupus erythematosus (SLE) range from the classic butterfly malar rash to the discoid plaques of chronic cutaneous lupus erythe-matosus (CCLE). Urticaria is characterized by pruritic wheals typically lasting several hours.
In immunodeficiency, infections are characterized by increased frequency, unusual severity, a prolonged course or persistence of infection, and at times unusual organisms. Some common clinical manifestations that may be seen in immunodeficiency are recurrent sinopulmonary infections, failure to thrive, persistent thrush, diarrhea, and malabsorption. Associated conditions may include skin lesions such as eczema and pyoderma. Patients may have autoimmune disease and hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia. Patients may also have hepatosplenomegaly.
Be difficult to monitor with a baseline elevated aPTT. Acquired dysfibrinogenemia is seen with liver disease, multiple myeloma, Waldenstrom's macroglobulinemia, and autoimmune diseases the end result of all of these conditions is altered polymerization or delayed fibrinopeptide release.
Capability of fibroblasts to present antigen to T-helper lymphocytes may result in an increased susceptibility to autoimmunity and a loss of self-tolerance. Increased HLA-DR expression in necrotizing scleritis also supports the role of altered immune function in these patients 12,13,16 .
Exactly how ocular surface inflammation in LKC arises is not completely understood. Clearly, systemic autoimmune disease, such as Sjogren's syndrome, or androgen deficiency predispose some classes of patients, and desiccating environmental stress appears to be an important trigger. Consistent with this, human corneal epithelial cells respond to a hyperosmolar environment (as would result from desiccation of the tear film) by activating a cascade of stress associated protein kinases, which in turn activate transcriptional regulators of inflammatory cytokine and MMP production. Inflammatory mediators produced by ocular surface epithelial cells could initiate or contribute to an inflammatory cascade leading to dysfunction of other components of the lacrimal functional unit, for example, tear-secreting glands. Cytokines from ocular surface epithelial cells could also affect proliferation, differentiation, or apoptosis of other epithelial cells. Finally, the proinflammatory cytokines...
Cells polarized towards a Th1 phenotype secrete interleukin-2 (IL-2) and interferon-g (IFNg), which are thought to be primarily responsible for cell-mediated inflammatory reactions, de-layed-type hypersensitivity (DTH), and tissue injury in autoimmune diseases (Fig. 8.2). In contrast, Th2 cells produce IL-4, IL-5, IL-6, IL-9 and IL-10 and are efficient promoters of antibody responses. The imbalance between these two types of response is considered to be involved in the pathogenesis of autoimmune disease. Both susceptible as well as resistant animal strains initially mount a balanced Th0 type response to the uveitopathogenic antigen 16 . However, EAU susceptibility is characterized by polarization of the early Th0 response toward Th1 in susceptible strains and Th2 in resistant strains. Since cy-tokine production may play a critical role in the mechanism of human uveitis and biologic agents that interfere with cytokine action are becoming available as potential therapeutic agents, it is...
Although the aetiology and pathogenesis of Be-hcet's disease remains unknown, HLA typing of affected individuals revealed a strong association with HLA-B*5i 44, 45 . HLA-B*5i was detected in 50-80 of patients with Behcet's disease in many ethnic populations from the Middle East to Japan, including Turkish, Greek, Italian, French, Tunisian, Saudi Arabian, Israeli, Chinese, Korean, and Japanese, as compared to its presence in only i0-20 of unaffected controls. Studies using HLA-B*5i transgenic mice demonstrate immune dysregulation characterized by a heightened neutrophil response with increased production of superoxide, therefore supporting a possible role in immune patho-genesis 46 . However, uveitis and more specifically the typical lesions observed in Behcet's disease are not observed in these transgenic animals. It is likely that HLA-5i in combination with other genetic and environmental factors may predispose to ocular inflammatory and systemic autoimmune diseases.
Experimental DNA vaccines have been produced for a number of viruses, including HIV-1, SARS coronavirus, West Nile virus and foot and mouth disease virus trials have been carried out in mice, pigs, horses and humans. Before any DNA vaccine goes into clinical use some important questions about safety must be answered. There must be confidence that injection of the DNA will not trigger an anti-DNA autoimmune disease, and that the DNA will not create cancer-causing mutations by insertion into host genomes.
Myelin formation is produced in the peripheral nervous system by numerous Schwann cells, while a similar function in the central nervous system is carried out by an oligodendrocyte, which can wrap itself around numbers of neurons. Myelination in the nervous system allows for rapid conduction of action potentials by a process of saltatory conduction, in which the signals skip along openings in the myelin called nodes of Ranvier. Neurons that are myelinated (e.g., the pyramidal tracts and dorsal column-medial lemniscal system) are rapidly conducting, whereas those that are poorly or nonmyelinated (e.g., certain pain-afferent fibers to the spinal cord) are slowly conducting. Damage to such myelinated neurons typically disrupts the transmission of neural signals and is frequently seen in autoimmune diseases such as multiple sclerosis, in which sensory and motor functions are severely compromised.
Type I DM is has a very strong correlation with an autoimmune etiology. It is more common in persons with other autoimmune diseases, and there is an association with certain HLAs. Islet cell antibodies are present in most newly diagnosed patients. IDDM also tends to run in families. Preceding viral infections may serve as a trigger.
Like cyclophosphamide, chlorambucil is an alkylating nitrogen mustard derivative. It interferes with DNA replication, transcription and RNA translation, resulting in cytotoxicity. Chlor-ambucil is readily resorbed after oral administration and metabolized in the liver to the active substance phenylacetic acid mustard. The major excretion route of this and other metabolites is through the kidney. Chlorambucil is used for the treatment of malignancies as well as autoimmune diseases with vasculitic complications 13 its immunosuppressive effect is primarily mediated through inhibition of B cells.
Dry eye disease can arise in a number of different ways. For example, Sjogren's syndrome, a systemic autoimmune disease, probably initiates dry eye by autoimmune-mediated inflammation of the lacrimal glands, causing altered tear volume and composition (including proin-flammatory cytokines), in turn leading to inflammation of ocular surface tissues. In another example, disease of the meibomian glands, which secrete the lipid layer protecting the tear film, may initially impact tear composition by allowing excess evaporation, later causing ocular surface inflammation, which can impact neural control of the lacrimal glands. Intercon-nectedness within the lacrimal functional unit means that the varied causes of dry eye disease all eventually manifest an unstable, proinflam-matory tear film, which leads to inflammation of the ocular surface (Fig. 2.2), including apop-tosis of epithelial cells within the main and accessory lacrimal glands and the conjunctiva, and chronic firing of ocular...
Cyclosporine inhibits T cells by interfering with intracellular signalling pathways. After antigen recognition of the T cell, the T-cell receptor CD3 complex on the cell surface is activated and induces a cascade of intracellular signalling pathways, finally upregulating transcription of inflammatory cytokines like IL-2, -3, -4, IFN-g and expression of IL-2 receptor 43 . Cyclosporine as well as tacrolimus inhibit this signalling and therefore inhibit activation of T cells after antigen recognition. Due to their mode of action these drugs act on the afferent, antigen-specific arm of the immune response and only indirectly on the efferent effector mechanisms, explaining the late onset of immunosuppression in autoimmune diseases after initiation of treatment. Recently it was shown for uveitis patients that cyclosporine is capable of downregulating a pathogenic Th1-type immune response with correlation to clinical disease activity 20 . Since the first description of the use of...
Type 1 diabetes affects approximately 1 in 200 Americans, with a sibling recurrence risk of about 6 . It is an example of an autoimmune disease (see Immunology Lecture Notes), in which self-reactive T cells infiltrate the pancreas to destroy insulin-producing islet cells. Mutations in the class II major histocompatibility locus (MHC) region are estimated to contribute about one third of the risk of developing type 1 diabetes. Mutations in or near the insulin gene itself are responsible for another 10 15 of the risk. Autoimmunity
Primary muscle diseases such as muscular dystrophy, myasthenia gravis, and traumatic muscle injury are diagnosed by electromyography. Muscular disorders associated with diseases such as Guillain-Barre syndrome, diabetic neuropathy, and rabies are detected with EMG.
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