Introduction to Medical Immunology - part 6 ppt

Page 384 II. Clinical Manifestations The clinical expression of SLE varies among different patients. The kind of organ (vital versus nonvital) that becomes involved determines the seriousness and the overall prognosis of the disease. The average frequency of some main clinical manifestations of SLE that may be observed during the entire course of SLE is shown in Table 20.1 A. Diagnosis. The diagnosis is based on the verification that any four of the manifestations that are listed in Table 20.2 are present simultaneously or serially during a period of observation. Those manifestations are both clinical, indicating multisystemic involvement, and laboratory demonstration of autoantibodies. B. Course. Exacerbations and remissions, heralded by the appearance of new manifestations and worsening of preexisting symptoms, give the disease its fluctuating natural history. C. Overlap Syndrome. Occasionally, physicians observe clinical situations in which the differentiation between SLE and another connective tissue disease is difficult. In some patients, the distinction may be impossible, and they are classified as having an overlap syndrome. This syndrome represents the association of SLE with another disorder such as scleroderma or rheumatoid arthritis. III. Immunological Abnormalities in SLE A. Autoantibodies 1. The LE cell is a peculiar-looking polymorphonuclear leukocyte that has ingested nuclear material. It was possible to reproduce this phenomenon in vitro by incubating normal neutrophils with damaged leukocytes preincubated with sera obtained from SLE patients. Investigations concerning the Table 20.1 Main Clinical Manifestations of SLE Manifestation Patients (%) Musculoarticular 95 Renal disease 60 Pulmonary disease (pleurisy, pneumonitis) 60 Cutaneous disease (photosensitivity, alopecia, etc.) 80 Cardiac disease (pericarditis, endocarditis) 20 Fever of unknown origin 80 Gastrointestinal disease (hepatomegaly, ascites, etc.) 45 Hematological/reticuloendothelial (anemia, leukopenia, splenomegaly) 85 Neuropsychiatric (organic brain syndrome, seizures, peripheral neuropathy, etc.) 20 Page 385 Table 20.2 Diagnostic Features of Systemic Lupus Erythematosus a Facial erythema (butterfly rash) Discoid lupus Photosensitivity Oral or nasopharyngeal ulcers Arthritis without deformity Pleuritis or pericarditis Psychosis or convulsions Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia Heavy proteinuria, or cellular casts in the urinary sediment Positive anti-dsDNA or anti-Sm antibodies False positive syphilis serologies Antinuclear antibodies a Established by the American College of Rheumatologists. nature of this phenomenon led to the discovery that antibodies directed to nuclei could promote the formation of LE cells, and subsequently to the definition of a heterogeneous group of antinuclear antibodies. 2. Antinuclear antibodies (ANA). ANAs are detected by an indirect immunofluorescence assay using a variety of tissues and cell lines as substrates. A positive result is indicated by the observation of nuclear fluorescence after incubating the cells with the patient's serum, and, after thorough washing to remove unbound immunoglobulins, with an antihuman immunoglobulin serum. Four patterns of fluorescence can be seen, indicating different types of antinuclear antibodies (see Table 20.3). The test for antinuclear antibodies is not very specific, but is very sensitive. A negative result virtually excludes the diagnosis of SLE (95% of patients with SLE are ANA positive), while high titers are strongly suggestive of SLE but not confirmatory, since ANAs can be detected in other conditions including other systemic autoimmune/collagen diseases and chronic infections. Table 20.3 Immunofluorescence Patterns of Antinuclear Antibodies Pattern Antigen Disease association(s) Peripheral Double-stranded DNA SLE Homogeneous DNA-histone complexes SLE and other connective tissue diseases Speckled Non-DNA nuclear antigens Sm SLE ribonucleoprotein Mixed connective tissue disease, SLE, scleroderma, etc. SS-A, SS-B Sjögren's disease Nucleolar Nucleolus-specific RNA Scleroderma Page 386 3. Anti-DNA antibodies are the most important in SLE. They can react with single-stranded DNA (ssDNA) or with double-stranded DNA (dsDNA). Two-thirds of patients with SLE have circulating anti-DNA antibodies. a. Anti-ssDNA may be found in many diseases besides SLE. b. Anti-dsDNA antibodies are found almost exclusively in SLE (60–70% of the patients). They are most commonly detected by immunofluorescence, using as a substrate a noninfectious flagellate, Crithidia lucilliae, which has a kinetoplast packed with double-stranded DNA. This test is very specific, and the antibodies can be semiquantitated by titration of the serum (to determine the highest serum dilution associated with visible fluorescence of the kinetoplast after addition of a fluorescent-labeled anti-IgG antibody). c. Levels of serum anti-DNA antibodies may fluctuate with disease activity, but they are poor predictors of disease activity. 4. Antibodies to the DNA-histone complex are present in over 65% of patients with SLE. The use of enzyme- linked immunosorbent assays has permitted the identification of antibodies to all histone proteins including H1, H2A, H2B, H3, and H4. Antihistone antibodies are also present in patients with drug-induced SLE, most frequently associated with hydralazine and procainamide therapies. 5. Antibodies to nonhistone proteins have been studied intensely lately. The nonhistones against which antibodies have been described include: a. Anti-Sm. Antibodies to the Sm antigen are present in one-third of patients with SLE. Anti-Sm antibodies have not been found in other conditions. The antigenic determinant is on a protein that is conjugated to one of six different small nuclear RNAs (snRNA). b. Anti-U1-RNP. The antigenic epitope is on a protein conjugated to U1- RNA. Antibodies to this antigen are present in the majority of patients with SLE and in mixed connective tissue disease, which is included in the overlap syndromes. c. Anti-SS-A/Ro. These antibodies are present in one-third of patients with SLE and two-thirds of patients with Sjögren's syndrome (SS). Antibodies to the Ro antigen are frequently found in patients with SLE who are ANA-negative. Babies born to mothers with anti-Ro antibodies may have heart block, leukopenia, and/or skin rash. d. Anti-SS-B/La. The antigenic epitope recognized by this antibody is on a 43-kD protein conjugated to RNA. Antibodies to La antigen are present in about one-third of patients with SLE and in approximately one- half of the patients with Sjögren's syndrome. 6. Cross-reactive autoantibodies. Patients with SLE frequently have antiphospholipid antibodies and antibodies cross-reactive with cardiolipin. The anticardiolipin antibodies recognize a cryptic epitope on β 2 -glycoprotein I that is exposed after it binds to anionic phospholipids. B. The Pathogenic Role of Autoantibodies in SLE. Classically, it has been accepted that autoantibodies do not play the initiating role in the pathogenesis of SLE, but that they are likely to play either an important role as co-factors in the pathogenesis of the disease, or play a direct role in the pathogenesis of some of Page 387 the manifestations of the disease. This dogma, based on the belief that autoantibodies cannot enter living cells, has recently been challenged. Not only can anti-RNP, anti-DNA, and anti-Ro antibodies enter live cells, but also they can induce apoptosis. Thus, the concepts about the pathogenic role of autoantibodies are likely to change in the near future. 1. Anti-T-cell antibodies are believed to bind and eliminate certain regulatory subsets of T cells; as a consequence, the normal negative feedback circuits controlling B-cell activity may not be operational, explaining the uncontrolled production of autoantibodies by the B cells. 2. Antibodies against CR1 (complement receptor 1) and against the C3 convertase are occasionally detected. CR1 antibodies may block the receptor and interfere with the clearance of immune complexes. Antibodies to the C3 convertase, by stimulating its function, may contribute to increased C3 consumption. 3. Anti-red-cell antibodies and antiplatelet antibodies are the cause, respectively, of hemolytic anemia and thrombocytopenia. 4. Autoantibodies directed against central nervous system antigens may be detected in the serum and the cerebrospinal fluid of patients with SLE who have CNS involvement and have also been considered pathogenic. 5. Anti-DNA antibodies form immune complexes by reacting with DNA and are implicated in the pathogenesis of glomerulonephritis (see below). 6. Anticardiolipin antibodies cause false positives in serological tests for syphilis, seen frequently in SLE patients. They are also associated with miscarriages, thrombophlebitis and thrombocytopenia, and various central nervous system manifestations because of vascular thrombosis. The constellation of these symptoms is known as antiphospholipid syndrome and, although it was first recognized in lupus patients, the majority of the cases do not fulfill the diagnostic criteria for SLE. Anticardiolipin antibodies are detected in up to 8% of the normal population. C. The Diagnostic Value of Autoantibodies. Some autoantibodies may not be linked with any specific clinical manifestations but are very useful as disease markers. For example, Anti-dsDNA and anti-Sm antibodies are diagnostic of SLE. Most other autoantibodies are present in more than one clinical disease or syndrome. However, even if many of the patients share some common immunological abnormalities, particularly the presence of antinuclear antibodies or of rheumatoid factor, specific disorders can usually be individualized by the presence of a specific set of autoantibodies, as illustrated diagrammatically in Figure 20.1. D. Immune Complexes in SLE 1. Marked elevations in the levels of circulating immune complexes can be detected in patients with SLE sera during acute episodes of the disease by a variety of techniques (see Chap. 25). Since patients with active SLE have high levels of free circulating DNA and most have also anti-DNA antibodies, DNA-anti-DNA IC are likely to be formed either in circulation or in collagen-rich tissues and structures such as the glomerular basement membrane, which have affinity for DNA. 2. Besides the fact that immune complexes are formed at increased rates in Page 388 Figure 20.1 Diagrammatic representation of the different types of autoantibodies detected in SLE and related diseases. The percentages refer to the positivity rate in the disease to which the arrows point. Note that (1) antihistone antibodies are frequently found as the only serological abnormality in cases of SLE-like syndromes, and (2) anticentromere antibodies are characteristically associated to the “CREST” syndrome (associated of calcinosis, Raynaud's syndrome, scleroderma involving the skin and the esophagus, and telangiectasia). patients with SLE, the clearance rate of circulating immune complexes is decreased. Several factors seem to contribute to the impaired clearance of immune complexes: a. Immune complexes are cleared by the Fc-receptor-bearing cells of the reticuloendothelial system. This function has been found to be decreased in patients with SLE. b. Immune complexes are transported to the reticuloendothelial system by red blood cells that bind them through their CR1 (as noted earlier, IC often have adsorbed complement components and split products, including C3b, which reacts with CR1), and patients with SLE have decreased numbers of CR1, a fact that may compromise the clearance of immune complexes. c. Immune complexes are partially solubilized as a consequence of complement activation, a process that contributes to their inactivation and clearance. Individuals with C4 deficiency develop a disease with clinical features resembling those of SLE. This observation may be explained by the fact that immune complexes are cleared at slower rates in C4-deficient individuals, perhaps due to the role of C4 fragments in the solubilization and clearance of circulating immune complexes. 2. The pathogenic role of immune complexes is suggested by a variety of observations: Page 389 a. Rising levels of anti-DNA antibodies in conjunction with falling serum C3 levels (reflecting consumption by antigen-antibody complexes) are good predictors of an oncoming flare of lupus nephritis. b. Patients with IgG1 and IgG3 (complement fixing) anti-DNA antibodies develop lupus nephritis more frequently than those patients in whom anti-DNA antibodies are of other isotypes. c. There is ample evidence for complement activation via the classic and the alternative pathway in patients with active nephritis. Circulating levels of C3 and C4 are usually decreased, whereas plasma levels of complement breakdown products such as C3a, C3d, and Bb are increased. C1q, C3b, and complement split products such as C3d, C3b, and C3c can be detected on circulating immune complexes. 3. It is believed that tissue-fixed immune complexes cause inflammatory changes secondary to complement activation. Glomerulonephritis, cutaneous vasculitis, arthritis, and some of the neurological manifestations of SLE are fully explainable by the local consequences of immune complex formation or deposition. It is unclear whether tissue-fixed IC results mostly from the deposition of circulating IC or from formation of antigen-antibody complexes in situ. a. Glomerulonephritis. Immunofluorescence studies indicate that the capillary tufts of renal glomeruli in patients with lupus nephritis contain deposits of immunoglobulins and complement. Elution studies have shown that DNA and anti-DNA antibodies are present in these deposits, confirming that they correspond to antigen-antibody complexes. The deposition of IC in the glomerular basement membrane can be explained in three different ways: i. Deposition of soluble, circulating IC (as discussed in Chap. 25) ii. Formation of immune complexes in situ. DNA has affinity to glomerular basement membranes and, once immobilized, may react with circulating anti-DNA antibodies to form antigen-antibody complexes. iii. Cross-reaction of anti-DNA antibodies with collagen and cytoskeleton proteins. Currently, in situ formation of DNA-anti- DNA antibodies appears as the most likely initiating event, but regardless of how they are formed, IC in the basement membrane are considered nephritogenic because they can activate complement and cause inflammation. b. Deposition in the dermo-epidermal junction. In SLE patients, immune complex deposits have also been noted on the dermo-epidermal junction of both inflamed skin and normal skin, appearing as a fluorescent “band” when a skin biopsy is studied by immunofluorescence with antisera to immunoglobulins and complement components (band test). IV. Pathogenesis of SLE A. General Considerations. At the present time, we believe that multiple factors contribute to the pathogenesis of SLE. Environmental, hormonal, genetic, and Page 390 immunoregulatory factors are involved in the expression of the disease. The various etiological factors contribute differentially to the expression of the disease in individual patients. B. Insights from Animal Models. The understanding of the pathogenic mechanisms underlying the progression of SLE has been helped by the discovery of spontaneously occurring disease in mice which resembles SLE in many respects. During the inbreeding of mice strains, it was observed that the F1 (first generation) hybrids obtained by mating white and black mice from New Zealand [(NZB × NZW)F1] spontaneously developed a systemic autoimmune disease involving a variety of organs and systems. Throughout the course of their disease, the mice develop hypergammaglobulinemia, reflecting a state of hyperactivation of the humoral immune system. The animals have a variety of autoantibodies and manifestations of autoimmune disease and immune complex disease similar to those seen in humans with SLE. As the disease progresses, they develop nephritis and lymphoproliferative disorders and die. C. Genetic Factors in Murine and Human SLE 1. Genetic determinants of disease in NZB mice. The importance of genetic factors is underlined by the observation that the parental NZB mice have a mild form of the disease manifested by autoimmune hemolytic anemia, but that the introduction of the NZW genetic background made the disease accelerate and worsen. Genetic linkage studies and microsatellite gene marker analysis indicate that many of the immunological abnormalities are under multigenic control, one gene(s) controlling the animal's ability to produce anti-DNA antibodies, another the presence of anti -erythrocyte antibodies, and still other genes controlling high levels of IgM production and lymphocytic proliferation. 2. Genetic determinants of disease in MRL mice. Two other mouse strains that develop an SLE-like disease spontaneously have been identified: MRL lpr/lpr and MRL gld. The first strain has a defect in the FAS gene, whereas the second has a defect in the FAS ligand gene. The products of these two genes are responsible for the programmed cell death of cells also known as apoptosis, which is critical for the control of undesirable immune responses. Similar abnormalities have not been clearly established in humans. 3. Genetic factors in human SLE. Several pieces of evidence indicate that genetic factors also play a role in the pathogenesis of human SLE. a. Presence of serum anti-DNA and anti-T- cell antibodies as well as cellular abnormalities in healthy relatives of SLE patients. b. Moderate degree of concordance among monozygotic twins. The fact that the clinical concordance between twins is only moderate strongly indicates that genetic factors alone may not lead to the expression of the disease and that other factors are needed. The genes that could play a role, probably in synergy with environmental factors, have not been identified. c. Current evidence indicates that in humans, as in mice, these genes are probably linked to the MHC. For example, the HLA-DR2 haplotype is overrepresented in patients with SLE. Also, as mentioned before, an SLE-like disease develops frequently in individuals with C4A deficiency (C4A genes are located in chromosome 6, in close proximity to Page 391 the MHC genes). At present, lack of one of the C4A genes represents the highest single genetic predisposing factor for the development of SLE in humans. D. Immune Response Abnormalities in SLE 1. B-cell abnormalities. Increased numbers of B cells and plasma cells are detected in the bone marrow and peripheral lymphoid tissues secreting immunoglobulins spontaneously. The number of these cells correlates with disease activity. a. In murine lupus, the B cells responsible for the production of anti-DNA antibodies express the CD5+ marker, which has been suggested to identify activated B cells. However, in humans, anti-DNA antibodies are secreted by both CD5+ and CD5- B cells. b. In addition, only a limited number of light- and heavy-chain genes are used, demonstrating that the autoantibody response involves only a few of all B-cell clones available. Furthermore, the changes appearing in their sequence over time strongly suggest that they undergo affinity maturation, a process that requires T- cell help. It also suggests that the response is driven by a few antigens. c. Immunosuppressive drug treatment of both murine and human lupus causes clinical improvement associated with decreased B-cell activity. d. Any infection that induces B-cell activation is likely to cause a clinical relapse in patients with inactive SLE. 2. T-cell abnormalities. From our knowledge of the biology of the immune response, it can be assumed that the production of high titers of IgG anti -dsDNA antibodies in patients with SLE must depend upon excessive T-cell help and/or insufficient control by suppressor T cells. a. In both human and murine lupus, a new subset of CD3+ cells that express neither CD4 nor CD8 has been found to provide help to autologous B cells synthesizing anti-DNA antibodies. b. The finding of anti-T-cell antibodies in the serum of (NZB × NZW)F1 mice and in the sera of humans with SLE raised the possibility that another factor contributing to the inordinate B-cell activity associated with the development of autoimmunity could be the deletion of a specific subset of regulatory cells. Obviously, defective suppressor T-cell function may further enhance the helper T-cell-mediated B-cell over-activity. c. In humans, the anti-T-cell antibodies are also responsible for the lymphopenia that is frequently seen in patients with SLE. This lymphopenia is often associated with findings suggestive of a generalized depression of cell-mediated immunity, such as decreased lymphokine production (IL-1 and IL-2) and lack of reactivity (anergy) both in vivo and in vitro to common recall antigens, particularly during active phases of human SLE. The impairment of cell-mediated immunity may explain the increased risk of severe opportunistic infections in patients with SLE. d. Extensive deletions in the T-cell repertoire have been found in NZW mice, in which the C β 2 and D β 2 genes of the T-cell antigen receptor are missing. These deletions could be associated with a faulty establishment of tolerance to self-MHC during intrathymic ontogeny. Page 392 e. In humans, restriction fragment length polymorphism studies of the constant region of the TcR demonstrated an association between TcR α chain polymorphism and SLE and TcR β chain polymorphism and production of anti-Ro antibodies. More recently, sequence information of the TCR chains of pathogenic human T-cell clones demonstrated bias in the T-cell repertoire selection process, whose meaning is still to be defined. The immune response is thus “oligoclonal” in both T and B compartments. D. Nonimmune Factors Influencing the Course of SLE 1. Hormonal effects. The expression of the genetic and immunological abnormalities characteristic of murine lupus like disease is influenced by female sex hormones. a. In (NZB × NZW)F1 mice, the disease is more severe females. Administration of estrogens aggravates the evolution of the disease, which is only seen in castrated male mice and not in complete males. b. The extent of the hormonal involvement in human SLE cannot be proven so directly, but the large (9:1 female:male ratio) female predominance as well as the influence of puberty and pregnancies at the onset of the disease, or the severity of the disease's manifestations, indicates that sex hormones play a role in the modulation of the disease. 2. Environmental factors a. Sunlight exposure was the first environmental factor influencing the clinical evolution of human SLE to be identified. Exposure to sunlight may precede the clinical expression of the disease or disease relapse. This could be related to the fact that the Langerhans cells of the skin and keratinocytes release significant amounts of interleukin-1 upon exposure to UV light, and could thus represent the initial stimulus tipping off a precarious balance of the immune system. b. Infections also seem to play a role. The normal immune response to bacterial and viral infections may spin off into a state of B-cell hyperactivity, triggering a relapse. c. Drugs, particularly those with DNA binding ability, such as hydantoin, isoniazide, and hydralazine, can cause a drug-induced lupus-like syndrome. i. These drugs are known to cause DNA hypomethylation. Because hypomethylated genes are transcribed at higher rates, it is theoretically possible that they cause SLE by increasing the transcription rate of genes that are involved in the expression of the disease. ii. Antinuclear antibodies appear in 15 to 70% of patients treated with any of these drugs for several weeks. These antinuclear antibodies belong, in most cases, to the IgM class and react with histones. Only when the antibodies switch from IgM to IgG does the patient become symptomatic. These antinuclear antibodies usually disappear after termination of the treatment. iii. Patients with drug-induced SLE usually have a milder disease, without significant vital organ involvement. Page 393 Case Revisited • The patient's fatigue could just be a reflection of a systemic inflammatory disease, but could also be due to anemia. Hemolytic anemia is not infrequent in SLE. Seizures and other neurological symptoms may be due either to the deposition of immune complexes in CNS tissues or to the binding of antineuronal autoantibodies, with or without complement activation, the effect of infiltrating autoreactive T cells, and to the effects of neurotoxins (such as quinolinic acid) released by activated immune cells. • Patients with SLE often develop antiphospholipid antibodies. Although the exact pathogenic sequence is not known, these antibodies interfere with clotting factors causing vascular thrombosis usually without vasculitis. • The pathogenesis of skin lesions is likely to involve several factors. Deposition of IC at the dermoepidermal junction is likely to play a role, but not the only one, since this deposition can be observed in normal skin. Exposure to sunlight is likely to play a significant role as well, perhaps because the Langerhans cells and keratinocytes of the skin release significant amounts of interleukin-1 upon exposure to UV light, and could thus add an additional trigger to a local inflammatory reaction involving both the effects of UV exposure and the effects of IC deposition. • In this patient, several complications would cause concern: autoimmune hemolytic anemia may be extremely difficult to treat, and the progression of her CNS involvement would also raise considerable therapeutic problems. In addition, deterioration of the kidney function, due to the development of lupus nephritis, is always a major concern in any patient with SLE. • This patient presented with several clinical features typical of SLE: facial erythema, arthritis, seizures, and possible anemia. The detection of autoantibodies such as those directed against dsDNA or the Sm antigen would be confirmatory, but even if only nonspecific antinuclear antibodies were detected, a diagnosis of SLE should still be entertained. To evaluate the cause of some of the most striking symptoms of this patient, a complete blood count should be performed and, if anemia is present, Coombs tests should be ordered. Other important tests to be ordered included X-rays of the hands, rheumatoid factor, anticardiolipin and antiphospholipid antibodies, serum creatinine, and urine protein (to evaluate kidney function). • One of the most difficult questions to answer is what triggers the onset of an autoimmune disease. This patient fits in the age and sex group in which SLE is more prevalent. Other than hormonal influences, it is likely that this patient carries a genetic predisposition to develop SLE (although the precise marker and nature of such predisposition are not yet clearly identified). Most unclear of all is what is the initial stimulus. An infection leading to cross-reactive autoimmunity is a very appealing hypothesis, but we have no clue about the nature of such infection. [...]... basis of autoimmunity: Part I Mechanisms of aberrant self-recognition Immunol Today, 16: 90–98, 1995; Part II Genetic predisposition Immunol Today, 16: 150–159, 1995 Tsokos, G.C (moderator) Pathogenesis of Systemic Lupus Erythematosus A Symposium-in-Writing Clin Immunol Immunopath., 63 :3, 1992 Wallace, D (ed.) Systemic Lupus Erythematosus and Sjögren's Syndrome Curr Opin Rheumatol., 8:393–445, 19 96 Page... elimination of antibody-coated neutrophils III Autoantibodies in Rheumatoid Arthritis A Rheumatoid Factor and Anti-Immunoglobulin Antibodies The serological hallmark of rheumatoid arthritis is the detection of rheumatoid factor (RF) and other anti-immunoglobulin antibodies By definition, classic RF is an IgM antibody to autologous IgG The more encompassing designation of anti-immunoglobulin (Ig) antibodies... synovium discussed above found these two cytokines at levels high enough to deliver such stimulatory signals to monocytes and fibroblasts VI A Summary Overview of the Pathogenesis of Rheumatoid Arthritis A Predisposing Factors Two important types of factors seem to have a strong impact in the development of rheumatoid arthritis 1 Genetic factors The link to HLA-DR4, and particularly with subtypes Dw4 and Dw14,... in the inflammatory lesion This is a significant finding, because activated dendritic cells release a variety of proinflammatory lymphokines, such as IL-1 iii Another prominent role of GM-CSF is to be a very strong inducer of the expression of MHC-II molecules (stronger than interferon-γ) Increased MHC-II expression is believed to be an important factor leading to the development of autoimmune responses,... precursors of RF-producing B cells Their frequency is surprisingly high in mice where it is relatively easy to induce the production of RF in high titers after polyclonal B-cell stimulation Human bone marrow B lymphocytes can also be stimulated to differentiate into RF-producing plasmablasts by mitogenic stimulation with PWM or by infection with Epstein-Barr virus ii Tolerance to self-IgG must be ensured... occurrence of anti-ssDNA in RA and in many Page 4 06 other connective tissue diseases is unknown, but these antibodies may represent an indicator of immune abnormalities due to the persistence of abnormal B-lymphocyte clones that have escaped the repression exerted by normal tolerogenic mechanisms and are able to produce autoantibodies of various types IV Genetic Factors in Rheumatoid Arthritis A HLA-Associations... antibodies to red cells, causing immune hemolytic anemia, appear later in the evolution of the disease Bibliography Alarcon-Segovia D., Ruiz-Arguelles A., Llorerente L Broken dogma, penetration of autoantibodies into living cells Immunol Today, 17: 163 – 164 , 19 96 Boumpas, D.T., Fessler, B.J., Austin, H.A III, Balow, J.E., Klippel, J.H., Lockshin, M.D Systemic lupus erythematosus: emerging concepts Part 1:... different V-region genes Page 403 2 Methods used for the detection of rheumatoid factor Rheumatoid factor and anti-Ig antibodies can be detected in the serum of affected patients by a variety of techniques a The Rose-Waaler test is a passive hemagglutination test that uses sheep or human erythrocytes coated with anti-erythrocyte antibodies as indicators The agglutination of the IgG-coated red cells to titers... systemic lupus erythematosus are: A Associated with the formation of mixed cryoglobulins B Frequently associated with hemolytic anemia C Predictors of the development of inflammatory complications D Rarely associated with high titers of antinuclear factor E Suggestive of a drug-induced etiology Questions 20.2–20.3 refer to the following case history: A 28-year-old woman has a history of weight loss,... thritis persist indefinitely, reflecting their origin as part of an autoimmune response d Infection-associated RF bind to IgG molecules whose configuration has been altered as a consequence of binding to exogenous antigens The resulting RF-IgG-Ag complexes are large and quickly cleared from circulation The adsorption of IgG to latex particles seems to induce a similar conformational alteration of the IgG . Antibodies to the DNA-histone complex are present in over 65 % of patients with SLE. The use of enzyme- linked immunosorbent assays has permitted the identification of antibodies to all histone proteins. protein that is conjugated to one of six different small nuclear RNAs (snRNA). b. Anti-U1-RNP. The antigenic epitope is on a protein conjugated to U 1- RNA. Antibodies to this antigen are present. ANA-negative. Babies born to mothers with anti-Ro antibodies may have heart block, leukopenia, and/or skin rash. d. Anti-SS-B/La. The antigenic epitope recognized by this antibody is on a 43-kD