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The E6 protein binds to and mediates the degradation of p53 and stimulates the expression of telomerase reverse transcriptase (TERT) antibiotics questions pharmacology effective azithrocine 100mg, the catalytic subunit of telomerase antibiotic qualities of garlic 100mg azithrocine fast delivery, which you will recall contributes to the immortalization of cells antibiotic eye drops cheap azithrocine 100mg with mastercard. E6 from highrisk HPV types has a higher affinity for p53 than E6 from Increased TERT telomerase expression HPV E6 p53 Inhibition of p53 Immortalization Increased cell proliferation Genomic instability HPV E7 p21 Inhibition of p21 Increased CDK4/cyclin D Inhibition of RB RB Oncogenic DNA Viruses As with RNA viruses antibiotic resistance ted ed buy generic azithrocine 500 mg line, several oncogenic DNA viruses that cause tumors in animals have been identified. The net effect of HPV E6 and E7 proteins is to immortalize cells and remove the restraints on cell proliferation. The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G1/S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. Finally, E7 proteins from high-risk HPVs (types 16, 18, and 31) also bind and presumably activate cyclins A and E. To summarize, high-risk HPV types express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis, and combat cellular senescence. The primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of HPV vaccines in preventing cervical cancer. For example, when human keratinocytes are transfected with DNA from HPV types 16, 18, or 31 in vitro, they are immortalized but do not form tumors. In addition to such genetic cofactors, HPV in all likelihood also acts in concert with environmental factors. These include cigarette smoking, coexisting microbial infections, dietary deficiencies, and hormonal changes, all of which have been implicated in the pathogenesis of cervical cancers. A high proportion of women infected with HPV clear the infection by immunologic mechanisms, but others do not because of acquired immune abnormalities, such as those that result from HIV infection, or for unknown reasons. As might be expected, women who are coinfected with high-risk HPV types and HIV have an elevated risk of cervical cancer. LMP-1 behaves like a constitutively active CD40 receptor, a key recipient of helper T-cell signals that stimulate B-cell growth (Chapter 6). LMP-1 activates the NF-B and JAK/STAT signaling pathways and promotes B-cell survival and proliferation, all of which occur autonomously. Thus, the virus "borrows" normal B-cell activation pathways to expand the pool of latently infected cells. Another EBV gene, EBNA-2, encodes a nuclear protein that mimics a constitutively active Notch receptor. EBNA-2 transactivates several host genes, including cyclin D and the SRC family of proto-oncogenes. In addition, the EBV genome contains a gene encoding a homologue of IL-10 (vIL-10) that was "borrowed" from the host genome. The EBV proteins that are required for B-cell immortalization and proliferation are highly immunogenic, and in normal individuals the EBV-driven polyclonal B-cell proliferation is readily controlled by a cytotoxic T-cell response. Depending on the timing and intensity of this response, the individual either remains asymptomatic or develops a self-limited episode of infectious mononucleosis (Chapter 8). If T-cell immunity is defective, however, EBV transformed B cells can produce a rapidly progressive, fatal lymphoma. Burkitt lymphoma is a neoplasm of B lymphocytes that is endemic in central Africa and New Guinea, areas where it is the most common tumor of childhood. The association between endemic Burkitt lymphoma and EBV is strong: More than 90% of endemic tumors carry the EBV genome. Although EBV is intimately involved in the causation of Burkitt lymphoma, several observations suggest that additional factors are involved. Most notably, Burkitt lymphoma cells do not express LMP-1, EBNA2, and other EBV proteins that drive B-cell growth and immortalization. Given these observations, how then does EBV contribute to the genesis of endemic Burkitt lymphoma In regions where Burkitt lymphoma is endemic, concomitant infections such as malaria impair immune competence, allowing sustained B-cell proliferation. Eventually, T-cell immunity directed against EBV antigens such as EBNA2 and LMP-1 eliminates most of the EBV-infected B cells, but a small number of cells downregulate expression of these immunogenic antigens. EBV, a member of the herpesvirus family, was the first virus linked to a human tumor, Burkitt lymphoma. Since its initial discovery 50 years ago, EBV has been implicated in the pathogenesis of a diverse collection of human tumors including various lymphomas, several carcinomas, and even rare sarcomas. The most common EBV-associated tumors are lymphomas derived from B cells and nasopharyngeal carcinoma; other EBV-associated neoplasms are discussed elsewhere in this book. The manner in which EBV causes B-cell tumors such as Burkitt lymphoma is complex and incompletely understood, but best appreciated by considering its effects on normal B cells. EBV has surface glycoproteins that recognize and bind the complement receptor CD21, allowing the virus to attach to and infect B cells. Viral infection of B cells is latent; that is, there is no viral replication, and the cells are not killed. However, EBV proteins are expressed in latently infected B cells that allow the cells to grow indefinitely (immortalization). The molecular basis of B-cell growth and immortalization is complex, but as with other viruses it involves the "hijacking" of several normal signaling pathways. Thus although sporadic Burkitt lymphomas are triggered by mechanisms other than EBV, they appear to develop through similar oncogenic pathways.
Local invasion of tumor cells may damage or destroy vital structures and is a prerequisite for distant spread antimicrobial hand soap buy cheap azithrocine 250mg on-line. Studies in mice and humans reveal that although many of these locally invasive cells enter the bloodstream each day antibiotics for dogs for bladder infection order azithrocine 250mg line, very few produce metastases antimicrobial wound cleanser generic 100mg azithrocine otc. For cancer cells to emerge from a primary mass herbal antibiotics for dogs order 250 mg azithrocine, enter blood vessels or lymphatics, and produce a secondary growth at a distant site, they must go through a series of Figure 7. At each point in this sequence, the breakaway cells must overcome the challenges of avoiding immune defenses (discussed later) and adapting to a microenvironment. The complexity of this series of events may explain why individual "metastasis genes" have not been found; it may be that the "metastatic phenotype" requires the Molecular basis of cancer: role of genetic and epigenetic alterations accumulate complementary genetic and epigenetic alterations that collectively promote the metastatic cascade. This set of "skills" may be present only in rare cells, or might even require a collaboration between subclones, with each providing some needed function. This latter idea implies that successful metastases may arise from cells that migrate as cohesive groups, for which there is some evidence. In the discussion that follows, the metastatic cascade is divided into two phases: (1) invasion of the ECM and (2) vascular dissemination, tissue homing, and colonization. Throughout, we touch on some of the proposed molecular mechanisms that underlie the process. As discussed in Chapter 1, tissue compartments are separated from each other by two types of ECM, basement membrane and interstitial connective tissue, each made up of different combinations of collagens, glycoproteins, and proteoglycans. To metastasize, carcinoma cells must breach the underlying basement membrane, traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane. This process is repeated in reverse when tumor cells extravasate at a distant site. Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps. Normal epithelial cells are tightly glued to each other and to the ECM by a variety of adhesion molecules. As discussed earlier, E-cadherins are transmembrane glycoproteins that mediate the homotypic adhesion of epithelial cells, serving both to hold the cells together and to relay signals between cells. In several epithelial tumors including certain adenocarcinomas of the stomach and breast, E-cadherin function is lost due to pathogenic mutations, and in many other epithelial cancers it is hypothesized that E-cadherin expression is silenced, at least transiently, through a process called epithelial-mesenchymal transition (EMT). It is postulated that EMThis integral to the metastasis of carcinomas, particularly breast and prostate cancers. Degradation of the basement membrane and interstitial connective tissue is the second step in invasion. Tumor cells may accomplish this by secreting proteolytic enzymes or by inducing stromal cells. Tumor cells detach from each other because of reduced adhesiveness and attract inflammatory cells. Proteases secreted from tumor cells and inflammatory cells degrade the basement membrane. Binding of tumor cells to proteolytically generated binding sites and tumor cell migration follow. Many different proteases such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator are overexpressed in tumors and have been implicated in tumor cell invasion. It is easy to imagine that as tumors evolve over time, they come to be dominated by cancer cells that are most effective at co-opting the complex, ever-changing tumor microenvironment to serve their malignant purposes. For example, MMP-9, a gelatinase that cleaves type IV collagen found within the epithelial and vascular basement membrane, also stimulates the release of VEGF from ECM-sequestered pools and generates collagen and proteoglycan cleavage products with chemotactic, angiogenic, and growth-promoting effects. Benign tumors of the breast, colon, and stomach have little MMP-9 activity, whereas their malignant counterparts overexpress this enzyme. Concurrently the concentrations of metalloproteinase inhibitors are also reduced in many cancers, further tilting the balance toward tissue degradation. The third step in invasion involves changes in how tumor cells attach to ECM proteins. Tumor cells demonstrate complex changes in the expression of integrins, which you will recall are transmembrane proteins that participate in adhesion of cells to other cells and to ECM (Chapter 3). In normal epithelial cells, integrins that bind basement membrane laminin and collagens are strictly restricted to the basal aspect of the cell; these receptors help to maintain the cells in a resting, polarized state. Loss of adhesion in normal cells leads to induction of apoptosis, but free tumor cells are resistant to this form of cell death (termed anoikis, meaning without a home), in part because of expression of other integrins that mitigate the loss of adhesion to ECM, apparently by transmitting signals that promote cell survival. Additionally, the matrix itself is modified in ways that promote invasion and metastasis. For example, cleavage of the basement membrane proteins collagen IV and laminin by MMP-2 or MMP-9 generates novel sites that bind to receptors on tumor cells and stimulate migration. Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis. Migration is a multistep process that involves many families of receptors and several signaling pathways that eventually impinge on the actin cytoskeleton. Cells must attach to the matrix at their leading edge, detach from the matrix at their trailing edge, and contract the actin cytoskeleton to ratchet forward. Such movement seems to be stimulated and directed by several types of factors, which likely vary among different types of tumors. Throughout this phase of the process, tumor cells interact not only with ECM but also with several types of stromal cells, including innate and adaptive immune cells, fibroblasts, and endothelial cells.
Tuberculosis flourishes wherever there is poverty antibiotic resistance horizontal gene transfer purchase azithrocine pills in toronto, crowding antibiotic resistance washington post purchase azithrocine toronto, and chronic debilitating illness infection 6 weeks after surgery trusted 250mg azithrocine. In the United States 9999 bacteria cheap azithrocine line, tuberculosis is mainly a disease of older adults, immigrants from high-burden countries, those living in crowded settings (prisons, homeless shelters, long-term care), and people with AIDS. Certain disease states also increase the risk: diabetes, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression. Infection refers to the presence of bacteria in the body, which may be symptomatic (active disease) or not (latent infection). Most infections are acquired by person-to-person transmission of airborne organisms from an active case to a susceptible host. In most healthy people primary tuberculosis is asymptomatic, although it may cause fever and pleural effusion. Generally, the only evidence of infection, if any remains, is a tiny, fibrocalcific pulmonary nodule at the site of the infection. If immune defenses are lowered, the infection may be reactivated, producing communicable and potentially life-threatening disease. These T cells control the host response to the bacteria and also result in development of pathologic lesions, such as caseating granulomas and cavitation. The development of resistance to the organism is accompanied by the appearance of a positive tuberculin test. AIDS is the greatest risk factor for progression to active disease, due to the loss of immunologic control of the organism. Other forms of immunosuppression, including glucocorticoids, TNF inhibitors, and transplants (solid organ and stem cell) also carry increased risk, as do renal failure and malnutrition. Rare inherited mutations that interfere with the Th1 response, such as loss of the IL-12 receptor 1 protein, result in increased susceptibility to severe tuberculosis and even symptomatic infection with normally avirulent (so-called "atypical") mycobacteria, such as the Mycobacterium avium complex (MAC), discussed later, or with the attenuated BCG vaccine strain. As previously mentioned, this group of genetic disorders is called Mendelian susceptibility to mycobacterial disease. This immune response, although largely effective, comes at the cost of accompanying tissue destruction. Reactivation of the infection or re-exposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as T-cell immunity and resistance are correlated, so, too, the loss of T-cell immunity (indicated by tuberculin negativity in a previously tuberculin-positive individual) may be an ominous sign that resistance to the organism has faded. Clinical Features Clinical tuberculosis is separated into two important types that differ in pathophysiology: primary tuberculosis, which occurs with the first infection, and secondary tuberculosis, which occurs in an individual who has been previously infected by M. Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore unsensitized person. In most people, the primary infection is contained, but in others, primary tuberculosis is progressive. Lymphatic and hematogenous dissemination following primary infection may result in the development of tuberculous meningitis and miliary tuberculosis (discussed later). Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host. It may follow shortly after primary tuberculosis, but more commonly it appears months to years after the initial infection, usually when host resistance is weakened. It most commonly stems from reactivation of a latent infection, but may also result from exogenous reinfection in the face of waning host immunity or when a large inoculum of virulent bacilli overwhelms the host immune system. Reactivation is more common in low-prevalence areas, and reinfection plays an important role in regions of high contagion. Secondary pulmonary tuberculosis classically involves the apex of the upper lobes of one or both lungs. Because of the preexistence of hypersensitivity, the bacilli elicit a prompt and marked tissue response that tends to wall off the focus of infection. As a result, the regional lymph nodes are less prominently involved early in secondary disease than they are in primary tuberculosis. Indeed, cavitation is almost inevitable in neglected secondary tuberculosis, and erosion of the cavities into an airway is an important source of infection because the person now coughs sputum that contains bacteria. Systemic symptoms, probably related to cytokines released by activated macrophages. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. Some degree of hemoptysis is present in about one-half of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the infection to the pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved. Multidrug resistance is now seen more commonly than it was in past years; hence, all newly diagnosed cases in the United States are treated with at least four drugs, unless the susceptibility of the bacterium from the source case is known. The prognosis is generally good if infections are localized to the lungs, except when they are caused by drug-resistant strains or occur in debilitated individuals. Acid-fast smears and cultures of the sputum of patients suspected of having tuberculosis should be performed.
On a molar basis bacteria dies at what temperature purchase azithrocine overnight delivery, they are several thousand times more active than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction virus new jersey order on line azithrocine. This is the most abundant mediator produced in mast cells by the cyclooxygenase pathway antibiotics for acne medication discount 250 mg azithrocine with visa. PAF (Chapter 3) is a lipid mediator produced by some mast cell populations that is not derived from arachidonic acid antibiotic macrobid order azithrocine 500 mg mastercard. It causes platelet aggregation, histamine release, bronchospasm, increased vascular permeability, and vasodilation. On activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. Mediators contained within mast cell granules are the first to be released and can be divided into three categories: Vasoactive amines. Histamine causes intense smooth muscle contraction, increases vascular permeability, and stimulates mucus secretion by nasal, bronchial, and gastric glands. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement. Mast cell activation is associated with activation of phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. Mast cells are sources of many cytokines, which may play an important role at several stages of immediate hypersensitivity reactions. The cytokines include: TNF, IL-1, and chemokines, which promote leukocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the Th2 response; and numerous others. The mediators produced by mast cells are responsible for most of the manifestations of immediate hypersensitivity reactions. Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and trigger the intense immediate reactions characterized by edema, mucus secretion, and smooth muscle spasm; others, exemplified by cytokines, including chemokines, set the stage for the late-phase response by recruiting additional leukocytes. Not only do these inflammatory cells release additional waves of mediators (including cytokines), but they also cause epithelial cell damage. Epithelial cells themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as chemokines. Late-Phase Reaction In the late-phase reaction, leukocytes are recruited that amplify and sustain the inflammatory response without additional exposure to the triggering antigen. Eosinophils are often an abundant leukocyte population in these reactions. They are recruited to sites of immediate hypersensitivity by chemokines, such as eotaxin, and others that may be produced by epithelial cells, Th2 cells, and mast cells. Upon activation, eosinophils liberate proteolytic enzymes as well as two unique proteins called major basic protein and eosinophil cationic protein, which damage tissues. Eosniophils contain crystals called Charcot-Leyden crystals composed of the protein galectin-10, which are sometimes released into the extracellular space and can be detected in the sputum of patients with asthma. These crystals promote inflammation and enhance Th2 responses, so they may contribute to allergic reactions. It is now believed that the late-phase reaction is a major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma. Clinical Syndrome Anaphylaxis (may be caused by drugs, bee sting, food) Bronchial asthma Clinical and Pathologic Manifestations Fall in blood pressure (shock) caused by vascular dilation; airway obstruction due to laryngeal edema Airway obstruction caused by bronchial smooth muscle hyperactivity; inflammation and tissue injury caused by late-phase reaction Increased mucus secretion; inflammation of upper airways, sinuses Increased peristalsis due to contraction of intestinal muscles Development of Allergies Susceptibility to immediate hypersensitivity reactions is genetically determined. The basis of familial predisposition is not clear, but studies in patients with asthma reveal linkage to polymorphisms in several genes encoding cytokines with important roles in allergic reaction, including the genes for the cytokines IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. How the diseaseassociated polymorphisms influence the development of allergies is not known. Linkage has also been noted to polymorphisms lying within the HLA genes located on chromosome 6, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens. Exposure to environmental pollutants, which is common in industrialized societies, is an important predisposing factor for allergy. For example, dogs and cats diverged from humans about 95 million years ago and are genetically distant from humans compared with chimpanzees, which diverged only about 4 to 5 million years ago and are >95% identical to humans genetically; yet dogs and cats, who live in the same environment as humans, develop allergies, and chimps do not. This observation suggests that environmental factors may be more important in the development of allergic disease than genetics. Viral infections of the airways are triggers for bronchial asthma, an allergic disease affecting the lungs (Chapter 15). It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by non-antigenic stimuli such as temperature extremes and exercise, and do not involve Th2 cells or IgE; such reactions are sometimes called nonatopic allergy. It is believed that in these cases mast cells are abnormally sensitive to activation by various nonimmune stimuli. The incidence of many allergic diseases has increased in high income countries, as populations have urbanized and exposure to the natural environment has diminished. These observations have led to an idea, sometimes called the hygiene hypothesis, that early childhood and even prenatal exposure to microbial antigens "educates" the immune system in such a way that subsequent pathologic responses against common environmental allergens are prevented. Thus, paradoxically, improved hygiene in early childhood may increase allergies later in life.
In addition antibiotic infusion purchase azithrocine 100 mg overnight delivery, B cells express an Fc receptor that recognizes IgG antibodies bound to antigens and switches off further antibody production (a normal negative-feedback mechanism) antibiotics for uti in adults purchase azithrocine online now. Knockout of this receptor results in autoimmunity xifaxan antibiotic ibs purchase azithrocine american express, presumably because the B cells can no longer be controlled antibiotics for uti leukocytes purchase azithrocine without prescription. These examples provide valuable information about pathways of self-tolerance and immune regulation, but the diseases caused by these single-gene mutations are rare, and mutations in these genes are not the cause of most common autoimmune disorders. Role of Infections and Other Environmental Factors Autoimmune reactions may be triggered by infections. Two mechanisms have been postulated to explain the link between infections and autoimmunity. If these cells are presenting self antigens, the result may be a breakdown of anergy and activation of T cells specific for the self antigens. Second, some microbes may express antigens that share amino acid sequences with self antigens. Immune responses against the microbial antigens may result in the activation of self-reactive lymphocytes. A clear example of such mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis (Chapter 12). More subtle molecular mimicry may be involved in classic autoimmune diseases as well. Some viruses, such as EBV and HIV, cause polyclonal B-cell activation, which may result in production of autoantibodies. The tissue injury that is common in infections may release and structurally modify A. Induction of costimulators on APCs Microbe Activation of APC Self antigen APC presents self antigen APC expresses costimulatory molecules Self-reactive T cell B7 CD28 Self tissue Autoimmunity B. Molecular mimicry Microbe Activation of T cells Self tissue Autoimmunity Microbial Self-reactive T cell that also antigen recognizes microbial peptide APC presents microbial peptide that resembles self antigen Figure 6. Infections may promote activation of self-reactive lymphocytes by inducing the expression of costimulators (A), or microbial antigens may mimic self antigens and activate self-reactive lymphocytes as a cross-reaction (B). The underlying mechanisms are not understood but may involve the effects of hormones and currently unknown genes on the X chromosome. One reason for the chronicity is that the immune system contains many intrinsic amplification loops that allow small numbers of antigen-specific lymphocytes to accomplish the task of eradicating complex infections. When the response is inappropriately directed against self tissues, the same amplification mechanisms exacerbate and prolong the injury. Another reason for the persistence and progression of autoimmune disease is the phenomenon of epitope spreading, in which an immune response against one self antigen causes tissue damage, releasing other antigens, and resulting in the activation of lymphocytes that recognize these newly encountered epitopes. Some of these diseases are caused by autoantibodies, whose formation may be associated with dysregulated germinal center reactions. Most chronic inflammatory diseases are caused by abnormal and excessive Th1 and Th17 responses; examples of these diseases include psoriasis, multiple sclerosis, and some types of inflammatory bowel disease. With this background, we can proceed to a discussion of specific autoimmune diseases. The systemic diseases tend to involve blood vessels and connective tissues, and therefore, they are often called collagen vascular diseases or connective tissue diseases. Our focus here is on selected systemic autoimmune diseases; organ-specific disorders are covered in relevant chapters. Systemic Lupus Erythematosus (SLE) SLE is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues. The disease may be acute or insidious in its onset, and is typically a chronic, remitting and relapsing, often febrile, illness. Injury to the skin, joints, kidney, and serosal membranes is most prominent, but virtually any organ in the body may be affected. Because of this, the disease is very heterogeneous, and any patient may present with any number of clinical features. In recognition of this, the American College of Rheumatology has established a complex set of criteria for this disorder, which is helpful for clinicians and for the assessment of patients in clinical trials (Table 6. SLE is a fairly common disease, with a prevalence that may be as high as 1 in 2500 in certain populations. Similar to many autoimmune diseases, SLE predominantly affects women, with a frequency of 1 in 700 among women of childbearing age and a female-to-male ratio of 9: 1 in the reproductive age group of 17 to 55 years. By comparison, the female-to-male ratio is only 2: 1 for disease developing during childhood or after 65 years of age. The prevalence of the disease is twofold to threefold higher in blacks and Hispanics than in whites. Although SLE most often presents in the twenties and thirties, it may manifest at any age, even in early childhood. Spectrum of Autoantibodies in Systemic Lupus Erythematosus the hallmark of SLE is the production of autoantibodies, several of which (antibodies to double-stranded DNA and the so-called Smith [Sm] antigen) are virtually diagnostic. These and other autoantibodies are pathogenic, either by forming immune complexes or by attacking their target cells. The levels of these autoantibodies in the blood are also helpful for the diagnosis and management of patients with SLE.
