IMMUNOPATHOLOGY I: AUTOIMMUNITY, AUTOANTIBODIES, AND AUTOIMMUNE DISEASE

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I. INTRODUCTION
II. CONCEPTS OF TOLERANCE
III. AUTOIMMUNITY AND AUTOIMMUNE DISEASE
IV. METHODS FOR THE DETECTION OF ANTINUCLEAR ANTIBODIES AND TISSUE DEPOSITION OF IMMUNE COMPLEXES
V. SYSTEMIC LUPUS ERYTHEMATOSUS
VI. KEY CONCEPTS
VII. IMMUNOPATHOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS

READING ASSIGNMENTS:

• Autoimmune Disorders, pp. 195-215
• Immunodeficiency Disorders, pp. 215-231
• Transplantation and Transplant Rejection, pp. 190-195

OBJECTIVES:

1. Familiarize yourself with the clinical, laboratory, and pathological features of the multisystemic autoimmune diseases discussed in class.
   
   
2. Develop an understanding of the mechanisms resulting in autoimmunity, including the role of abnormal immune regulation and the importance of immune complexes as mediators of tissue injury.
   
   
3. Understand the general classification of immunodeficiency disorders.
   
   
4. Obtain a general understanding of the development of immunity, including the tissue distribution and morphology of the immune "system".
   
   
5. Familiarize yourself with the clinical and laboratory features of selected immunodeficiency disorders; consider the implications for prognosis and therapy once you have established the diagnosis.
   
   
6. Familiarize yourself with the pathogenesis of transplant rejection, particularly the rejection of renal allografts.
   
   
7. Gain a general appreciation of the morphological characteristics of immune disorders.

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I. INTRODUCTION

II. CONCEPTS OF TOLERANCE

• Self-Recognition as a Normal Phenomenon
  
  
• Mechanisms of Tolerance
  
  
  • Clonal deletion or anergy
  • Sequestration of antigen
  • Suppression of the immune response by cellular and humoral mechanisms

III. AUTOIMMUNITY AND AUTOIMMUNE DISEASE

• Examples of "normal" Autoantibodies
  
  
• Classification of Autoimmune Disease
  
  
  • Organ-specific diseases
  • Multisystemic autoimmune diseases-characteristics
    • Unknown etiology
    • Many organ systems affected
    • B cell hyperactivity
    • Autoantibody formation, especially antinuclear antibodies
    • Overlap syndromes
    • Genetic predisposition
    • Increased frequency in women of child bearing age
    • Tissue injury caused by immune mechanisms, often autoantibodies or Immune complexes
      
      
      
• Specific Multisystemic Autoimmune Diseases
  
  
  • Systemic lupus erythematosus (SLE)
  • Progressive systemic sclerosis (a.k.a. scleroderma)
  • Rheumatoid arthritis
  • Sjogren's syndrome
  • Mixed connective tissue disease

IV. METHODS FOR THE DETECTION OF ANTINUCLEAR ANTIBODIES AND TISSUE DEPOSITION OF IMMUNE COMPLEXES

• Direct immunofluorescence on tissues to detect immune complexes
  
  
• Indirect immunofluorescence to detect antinuclear antibodies
  
  
  • Patterns of immunofluorescence observed with antinuclear antibodies
    • Diffuse pattern- anti-histone antibodies
    • Rim pattern- anti-doublestranded DNA
    • Speckled pattern- antibodies against non-histone proteins
    • Nucleolar pattern- antibodies against proteins associated with nucleolar RNA
    • Centromere pattern- antibodies directed against proteins in the kinetochore.
  • The significance of elevated titers of antinuclear antibodies

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V. SYSTEMIC LUPUS ERYTHEMATOSUS

A prototype of multisystemic autoimmune diseases

• Clinical Features of SLE
  
  
  • Criteria of the American Rheumatism Association
  • Frequency of various symptoms and signs
  • SLE as a multisystemic autoimmune disease
    
    
    
• Immunopathological Features of SLE
  
  
  • Skin manifestations of SLE
  • Renal manifestations of SLE
    
    
    
• Laboratory Tests for the Diagnosis of SLE
  
  
  • Antinuclear antibodies as a screening technique
  • Anti-double stranded DNA antibodies
  • Other autoantibodies in SLE
  • Serum complement levels
    
    
• Treatment and Prognosis
  
  
• The Pathogenesis of SLE
  
  
  • Etiological considerations
  • Genetic aspects
  • Disturbed B cell activity as the central problem in SLE

VI. KEY CONCEPTS

• Self-recognition is central to the functions of the normal immune response
  
  
• The multisystemic autoimmune diseases are related, but distinctive clinical entities characterized by B cell hyperactivity, formation of antinuclear antibodies, predisposing genetic factors, increased frequency in women of child bearing age, overlap syndromes, and tissue injury mediated by immune mechanisms, especially immune complexes.
  
  
• Antinuclear antibodies are useful tests to screen for multisystemic autoimmune diseases.
  
  
• SLE is a prototype multisystemic autoimmune disease in which tissue injury is often caused by immune complex deposits.
  
  
• Anti-double stranded DNA antibodies are diagnostically specific for SLE.
  
  
• The immune complexes deposited in tissues in SLE are composed of DNA: anti-DNA complexes.
  
  
• Immunosuppressive drugs, such as steroids or cyclophosphamide, can be used to treat SLE.
  
  
• The fundamental abnormality in SLE is disturbed regulation of B cell activity, but the pathogenetic mechanisms responsible for this problem are unknown.

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VII. IMMUNOPATHOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS

• Clinical Features
  
  
  • Systemic lupus erythematosus (SLE) is a multisystem disease of unknown etiology in which the deposition of immune complexes in various tissues plays a key role. The overall frequency of SLE is estimated to be about 1 case per 2000 population. SLE is unusually common in young women (9 females:1 male). The age distribution is broad (5-67 in one series), but most cases occur in the second and third decades. There is no definite racial or ethnic predilection. The criteria for diagnosis established by the American Rheumatism Association (ARA) are listed in Table 1.

• When 4 criteria are met, the diagnosis of SLE can be assigned with 96% sensitivity and specificity. However, some patients with SLE will not fulfill these requirements the first time they are seen by a physician. Therefore, the criteria are principally used as guidelines to diagnosis and as standards for entering patients into clinical studies. The most frequently encountered abnormalities are listed in Table 2.

This list is not all inclusive, but emphasizes the protein manifestations of SLE.

• Similar abnormalities can be found in other diseases, particularly in other connective tissue disorders closely related to SLE. Therefore, the laboratory evaluation of suspected SLE cases is essential to accurate diagnosis.
  
  
• Pathology
  
  
  • The tissue pathology in SLE is well described in most standard textbooks. A summary of the most common lesions is given in Table 3.

• These abnormalities are due in large part to the deposition of immune complexes in vessel walls or in perivascular connective tissue. The most damaging complexes are of intermediate size (1.0-1.5 million daltons) and usually contain IgG and DNA. In tissues most deposits will also contain complement with tissue damage resulting from the inflammatory reaction provoked by activated complement factors. Although anti-DNA antibodies are of great importance in the pathogenesis of SLE, other autoantibodies are formed which contribute to the complex clinical manifestations of the disease. For example, anti-red cell antibodies are responsible for the Coomb's positive hemolytic anemia in SLE, anti-lymphocyte antibodies contribute to the leukopenia, and anti-platelet antibodies result in thrombocytopenia. Antibodies that interfere with coagulation tests ("lupus anticoagulants") have been described that are associated with an increased risk of spontaneous abortion. Anti-neuronal antibodies may contribute to CNS damage.
• Although the lesions in SLE are diverse, a principal cause of morbidity and mortality is lupus nephritis. In order to predict the prognosis of lupus nephritis it is useful to subdivide the renal pathology into five groups as indicated in Table 4.
• Glomerular immune complexes consisting mainly of IgG, DNA, and complement are found in every glomerulus. The frequency of subendothelial deposits in glomerular capillaries observed by immunofluorescence or electron microscopy correlates well with prognosis. Massive subendothelial deposits cause the "wireloop" capillaries visible by light microscopy. Moreover, immune complexes deposited in capillaries of the cardiac valves, skin, synovium, choroid plexus, and the adventitia of the splenic penicillary arteries are partially responsible for the lesions observed in these location.

• Laboratory Tests: Numerous laboratory tests are available which have diagnostic significance in SLE. Examples include antinuclear antibodies (ANA) detected by immunofluorescence, the LE cell preparation, anti-native DNA antibodies detected by radioimmunoassay or immunofluorescence and direct fluorescence of sun-exposed skin. The ANA test is widely used for screening purposes. Virtually all SLE patients will have a positive result at some time during their course. At the time of first admission 95% will have a positive ANA test. Both the titer of the antinuclear antibodies and the pattern of fluorescence observed provide useful information. In this hospital a titer of 1:80 or greater is diagnostically significant. Table 5 summarizes much information concerning the diagnostic sensitivity and specificity of the ANA test.

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• The reason for the variety of patterns observed is that the autoantibodies produced in SLE are heterogeneous with regard to their antigen specificity. The antibody specificities responsible for each pattern are given in Table 6.
  
  
• The LE cell phenomenon was first described by Hargraves in 1948 in the bone marrow of two patients with SLE. This phenomenon was later reproduced in vitro using a source of normal neutrophils and SLE serum. The test as currently performed uses viable neutrophils to phagocytize nuclei which have reacted with IgG anti-nuclear antibodies. The reaction is complement-dependent. The antibody responsible for the LE cell phenomenon is directed against DNP. This antibody also produces the diffuse pattern observed by immunofluorescence. The LE cell preparation is positive in about two-thirds of patients with SLE. It is also positive in many patients with Sjogren's syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease, chronic active hepatitis, and drug-induced lupus syndrome. Thus, this test is less useful for screening purposes than the ANA by immunofluorescence, but may have value as a marker for connective tissue disorders in general.
  
  
• The test most widely used to establish the specific diagnosis of SLE measures antibodies against native double-stranded DNA. This test is positive in about 80% of SLE patients with very few false positive results. Virtually all patients with lupus nephritis have elevated anti-DNA antibody titers. These antibody titers rise and fall as the disease activity waxes and wanes and are useful indicators of the therapeutic response. Other laboratory tests such as serum complement levels and circulating immune complexes are also of value in assessing disease activity. Recently, an important family of antibodies has been found in SLE called phospholipid antibodies (sometimes referred to as "lupus anticoagulants"). These antibodies, which are not restricted to SLE patients, have been associated with an increased risk of spontaneous abortion, thrombosis, and thrombocytopenia. The syndromes associated with these antibodies have been termed antiphospholipid antibody syndromes.
  
  
• Many additional antibodies have been discovered in SLE sera which improve diagnostic specificity or identify subsets of patients whose clinical findings and prognosis differ. These include anti-Ro (first described in the sera of a Vermont patient), anti-La, and anti-Sm antibodies. These will be mentioned only in passing. Although we speak of these antibodies as if their specificities were different, monoclonal antibodies produced by fusing lymphocytes from patients with SLE and nonsecretory myeloma cells react with many different substrates such as cardiolipin, DNA, and circulating coagulation factors. Appropriately spaced phosphodiester linkages may be the determinant common to each of these "autoantigens".
  
  
• Prognosis: Long term survival has improved substantially in recent years. The estimated 10 year survival in one large series reported recently was over 90%. This may reflect the recognition of milder disease concomitant with improved diagnostic techniques and greater physician awareness of the symptoms and signs of SLE. However, improved management using corticosteroids, cytotoxic drugs, and judicious antibiotic therapy has also contributed to the more favorable prognosis.
  
  
  • For certain patients with SLE the prognosis is less optimistic. This is particularly true for the subgroup of patients with the diffuse proliferative variant of lupus nephritis. Approximately 10%-20% of these patients will develop end-stage renal disease and some will die from uremia or infection. Other common causes of death in SLE include CNS involvement, malignancy, and myocardial infarction. The latter two causes of death are becoming increasingly frequent as patients with SLE survive longer. The explanation for their increased frequency in SLE compared with normal individuals of comparable age and sex is not known.
    
    
• Etiology and Pathogenesis: The etiology of SLE is unknown, but studies in humans and experimental models have provided a wealth of information regarding pathogenesis. The fundamental abnormality in SLE is B cell hyperactivity. Although abnormalities in T cell immunoregulation may contribute to disturbed B cell responsiveness, T cell dysfunction is not an invariant feature of the disease. Genetic factors exert a modest influence on disease expression. Concordant disease occurs in about 15% of first degree relatives. Although many genes acting in concert are necessary for the development of SLE, genes controlled by the major histocompatibility region (HLA) are probably of importance in shaping the autoantibody repertoire, influencing the development of the specific antibodies found in individual SLE patients, including those that contribute directly to disease manifestations. Since concordant SLE in genetically-identical monozygotic twins occurs in less than 50% of twin pairs (compared to 3% in dizygotic twins) environmental factors must also be important in disease expression. In view of the fact that 3 distinct murine models of SLE exist and that individual patients exhibit remarkable heterogeneity in symptoms, signs, and disease progression, it is reasonable to suppose that the pathogenetic factors influencing disease expression are heterogeneous, also. In this sense, SLE is a disease syndrome with diverse pathogenic factors resulting in variations in disease expression from patient to patient.

Further Reading:

1. Arnett FC, et al: Systemic lupus erythematosus: Current state of the genetic hypothesis. Semin Arthritis Reum. 14: 24, 1984.

2. Balow JE: Lupus as a renal disease. Hosp Practice 23:111, 1988.

3. Eisenberg GM: Antiphospholipid antibody syndrome: The reality and implications. Hosp. Practice. June 15, 1992, pp. 119-131.

4. Mills JA. Systemic lupus erythematosus. NEJM 330:871, 1994.

5. Steinberg A: The treatment of lupus nephritis. Kidney Intl 30:69, 1986.

6. von Mohlen CA; Tan EM. Autoautoibodies in the diagnosis of systemic rheumatic diseases. Seminars Arthritis Rheumatism 24:323, 1995.

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