Organ-Specific Systemic

Hashimoto thyroiditis Systemic lupus erythematosus

Autoimmune hemolytic anemia Rheumatoid arthritis

Autoimmune atrophic gastritis of pernicious anemia Sjögren syndrome

Multiple sclerosis Reiter syndrome

Autoimmune orchitis Inflammatory myopathies *

Goodpasture syndrome Systemic sclerosis (scleroderma) *

Autoimmune thrombocytopenia Polyarteritis nodosa *

Insulin-dependent diabetes mellitus

Myasthenia gravis

Graves disease

Primary biliary cirrhosis *

Autoimmune (chronic active) hepatitis *

Ulcerative colitis *

*The evidence supporting an autoimmune basis of these disorders is not strong.

autoimmunity are type I diabetes mellitus, in which the autoreactive T cells and antibodies are specific for b cells of the pancreatic islets, and multiple sclerosis, in which autoreactive T

cells react against central nervous system myelin. An example of systemic autoimmune disease is SLE, in which a diversity of antibodies directed against DNA, platelets, red cells, and

protein-phospholipid complexes result in widespread lesions throughout the body. In the middle of the spectrum falls Goodpasture syndrome, in which antibodies to basement membranes

of lung and kidney induce lesions in these organs.

It is obvious that autoimmunity results from the loss of self-tolerance, and the question arises as to how this happens. Before we look for answers to this question, we review the

mechanisms of immunologic tolerance to self-antigens.

Immunologic Tolerance

Immunologic tolerance is a state in which the individual is incapable of developing an immune response to a specific antigen. Self-tolerance refers to lack of responsiveness to an

individual's own antigens, and it underlies our ability to live in harmony with our cells and tissues. Several mechanisms, albeit not well understood, have been postulated to explain the

tolerant state. They can be broadly classified into two groups: central tolerance and peripheral tolerance.[37] [38] [39] [40] Each of these is considered briefly.

Central Tolerance.

This refers to death (deletion) of self-reactive T- and B-lymphocyte clones during their maturation in the central lymphoid organs (the thymus for T cells and the bone marrow for B cells).

Deletion of developing intrathymic T cells has been extensively investigated. Experiments with transgenic mice provide abundant evidence that T lymphocytes that bear receptors for selfantigens

undergo apoptosis within the thymus during the process of T-cell maturation. It

is proposed that many autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in

association with self-MHC molecules.[37] A protein called AIRE (autoimmune regulator) is thought to stimulate expression of many "peripheral" self-antigens in the thymus and is thus

critical for deletion of immature self-reactive T cells.[38] Mutations in the AIRE gene (either spontaneous in humans or created in knockout mice) are the cause of an autoimmune

polyendocrinopathy ( Chapter 24 ). The

Figure 6-27Schematic illustration of the mechanisms involved in central and peripheral tolerance. The principal mechanisms of tolerance in CD4+ T cells are shown. APC, antigenpresenting

cell.

Figure 6-28Pathogenesis of autoimmunity. Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers

(inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, activation of lymphocytes, and tissue injury.

Figure 6-29Role of infections in autoimmunity. 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).

TABLE 6-8-- 1997 Revised Criteria for Classification of Systemic Lupus Erythematosus

(Not Available)

Data from Tan EM, et al: The revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982; and Hochberg, MC: Updating the American College

of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, 1997.

mechanisms that maintain self-tolerance. Antibodies have been identified against an array of nuclear and cytoplasmic components of the cell that are neither organ nor species specific. In

addition, a third group of antibodies is directed against cell-surface antigens of blood cells. Apart from their value in the diagnosis and management of patients with SLE, these antibodies

are of major pathogenetic significance, as, for example, in the immune complex-mediated glomerulonephritis so typical of this disease.[56]

ANAs are directed against several nuclear antigens and can be grouped into four categories:[56] (1) antibodies to DNA, (2) antibodies to histones, (3) antibodies to nonhistone proteins

bound to RNA, and (4) antibodies to nucleolar antigens. Table 6-9 lists several ANAs and their association with SLE as well as with other autoimmune diseases to be discussed later.

Several techniques are used to detect ANAs. Clinically the most commonly used method is indirect immunofluorescence, which detects a variety of nuclear antigens, including DNA,

RNA, and proteins (collectively called generic ANAs). The pattern of nuclear fluorescence suggests the type of antibody present in the patient's serum. Four basic patterns are recognized:

• Homogeneous or diffuse nuclear staining usually reflects antibodies to chromatin, histones and, occasionally, double-stranded DNA.

• Rim or peripheral staining patterns are most commonly indicative of antibodies to double-stranded DNA.

• Speckled pattern refers to the presence of uniform or variable-sized speckles. This is one of the most commonly observed patterns of fluorescence and therefore the least specific.

It reflects the presence of antibodies to non-DNA nuclear constituents. Examples include Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens ( Table 6-9 ).

• Nucleolar pattern refers to the presence of a few discrete spots of fluorescence within the nucleus and represents antibodies to nucleolar RNA. This pattern is reported most often

in patients with systemic sclerosis.

The fluorescence patterns are not absolutely specific for the type of antibody, and because many autoantibodies may be present, combinations of patterns are frequent. The

immunofluorescence test for ANA is positive in virtually every patient with SLE; hence this test is sensitive, but it is not specific because patients with other autoimmune diseases also

frequently score positive (see Table 6-9 ). Furthermore, approximately 5% to 15% of normal individuals have low titers of these antibodies. The incidence increases with age.

Detection of antibodies to specific nuclear antigens requires specialized techniques. Of the numerous nuclear antigen-antibody systems,[57] some that are clinically useful are listed in Table

6-9 . Antibodies to double-stranded DNA and the so-called Smith (Sm) antigen are virtually diagnostic of SLE.

There is some, albeit imperfect, correlation between the presence or absence of certain ANAs and clinical manifestations. For example, high titers of double-stranded DNA antibodies are

usually associated with active renal disease. Conversely the risk of nephritis is low if anti-SS-B antibodies are present.[56]

TABLE 6-9-- Antinuclear Antibodies in Various Autoimmune Diseases

Disease, % Positive

Nature of Antigen Antibody System SLE

Drug-Induced

LE

Systemic

Sclerosis—

Diffuse

Limited

Scleroderma—

CREST Sjögren Syndrome

Inflammatory

Myopathies

Many nuclear antigens (DNA,

RNA, proteins)

Generic ANA (indirect IF) >95 >95 70–90 70–90 50–80 40–60

Native DNA Anti-double-stranded DNA

<5 <5 <5 <5 <5

Histones Antihistone 50–70

<5 <5 <5 <5

Core proteins of small nuclear

ribonucleoprotein particles (Smith

antigen)

Anti-Sm

<5 <5 <5 <5 <5

Ribonucleoprotein (U1RNP) Nuclear RNP 30–40 <5 15 10 <5 <5

RNP SS-A(Ro) 30–50 <5 <5 <5

RNP SS-B(La) 10–15 <5 <5 <5 <5

DNA topoisomerase I Scl-70 <5 <5

10–18 <5 <5

Centromeric proteins Anticentromere <5 <5 22–36

<5 <5

Histidyl-t-RNA synthetase Jo-1 <5 <5 <5 <5 <5

Boxed entries indicate high correlation.

SLE, systemic lupus erythematosus; LE, lupus erythematosus; ANA, antinuclear antibodies; RNP, ribonucleoprotein.

In addition to ANAs, lupus patients have a host of other autoantibodies. Some are directed against elements of the blood, such as red cells, platelets, and lymphocytes; others are directed

against proteins complexed to phospholipids. In recent years, there has been much interest in these so-called antiphospholipid antibodies. [58] They are present in 40% to 50% of lupus

patients. Although initially believed to be directed against anionic phospholipids, they are actually directed against epitopes of plasma proteins that are revealed when the proteins are

complexed to phospholipids. A variety of protein substrates have been implicated, including prothrombin, annexin V, b2 -glycoprotein I, protein S, and protein C.[59] Antibodies against the

phospholipid-b2 -glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis. Some of

these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. Therefore, these antibodies are sometimes referred to as lupus anticoagulant. Despite having a

circulating anticoagulant that delays clotting in vitro, these patients have complications associated with a hypercoagulable state.[60] They have venous and arterial thromboses, which may

be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. This constellation of clinical features, in association with lupus, is referred to as the secondary

antiphospholipid antibody syndrome. The pathogenesis of thrombosis in these patients is unknown; possible mechanisms are discussed in Chapter 4 . Some patients develop these

autoantibodies and the clinical syndrome without associated SLE. They are said to have the primary antiphospholipid syndrome ( Chapter 4 ).

Given the presence of all these autoantibodies, we still know little about the mechanism of their emergence. Three converging lines of investigation hold center stage today: genetic

predisposition, some nongenetic (environmental) factors, and a fundamental abnormality in the immune system.

Genetic Factors.

SLE is a complex genetic trait with contribution from MHC and multiple non-MHC genes. Many lines of evidence support a genetic predisposition. [51] [61]

• Family members of patients have an increased risk of developing SLE. Up to 20% of clinically unaffected first-degree relatives of SLE patients reveal autoantibodies and other

immunoregulatory abnormalities.

• There is a higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1% to 3%). Monozygotic twins who are discordant for SLE have

similar patterns and titers of autoantibodies.[62] These data suggest that the genetic makeup regulates the formation of autoantibodies, but the expression of the disease (i.e., tissue

injury) is influenced by non-genetic (possibly environmental) factors.

• Studies of HLA associations further support the concept that MHC genes regulate production of specific autoantibodies, rather than conferring a generalized predisposition to

SLE. Specific alleles of the HLA-DQ locus have been linked to the production of anti-double-stranded DNA, anti-Sm, and antiphospholipid antibodies.

• Some lupus patients (approximately 6%) have inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of

circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition. Knockout mice lacking C4 or certain complement receptors are also prone to

develop lupus-like autoimmunity. Various mechanisms have been invoked, including failure to clear immune complexes and loss of B-cell self-tolerance. It has also been proposed

that deficiency of C1q results in failure of phagocytic

clearance of apoptotic cells.[63]Such cells are produced normally, and if they are not cleared their nuclear components may elicit immune responses.

• In animal models of SLE, several non-MHC susceptibility loci have been identified. The best-known animal model is the (NZBxNZW)F1 mouse strain. In different versions of

this strain, up to 20 loci are believed to be associated with the disease. [51]

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