Central tolerance: immature T and B lymphocytes that recognize self antigens in the central (generative) lymphoid organsare killed by apoptosis; in the B-cell lineage, some of theself-reactive lymphocytes switch to new antigen receptorsthat are not self-reactive.
Peripheral tolerance: mature lymphocytes that recognize selfantigens in peripheral tissues become functionally inactive (anergic),aresuppressedbyregulatoryTlymphocytes,ordiebyapoptosis.
•Thefactorsthatleadtoafailureofself-toleranceandthedevelopmentofautoimmunityinclude(1)inheritanceofsusceptibilitygenesthatdisruptdifferenttolerancepathways,and (2)infectionsandtissueinjurythatexposeselfantigensandactivateAPCsandlymphocytesinthetissues.
Having discussed the general principles of tolerance and autoimmunity, we proceed to a discussion of some of the most common and important autoimmune diseases. Although each disease is discussed separately, considerable overlap is apparent in their clinical and morphologic features and underlying pathogenesis. Here we cover the systemic autoimmune diseases; autoimmune diseases that affect single organ systems are discussed in chapters that deal with the relevant organs.
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. Injury to the skin, joints, kidney, and serosal membranes is prominent, but virtually every organ in the body may be affected. The presentation of SLE is so variable that a complex set of criteria for this disorder have been proposed, to help clinicians and for the design and assessment of clinical trials (
Table 5.10 ). However, the disease is very heterogeneous, and any patient may present with any number of these features. SLE is a fairly common disease, with a prevalence that may be as high as 400 per 100,000 in certain populations. Although SLE often presents when a person is in the twenties or thirties, it may manifest at any age, even in early childhood. Similar to many autoimmune diseases, SLE predominantly affects women, with a female-to-male ratio of 9:1 for 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 2to 3-fold higher in blacks and Hispanics than in whites.
Spectrum of Autoantibodies in SLE
The hallmark of SLE is the production of autoantibodies.
Some antibodies recognize nuclear and cytoplasmic components, while others are directed against cell surface antigens of blood cells. Apart from their value in the diagnosis
Table 5.10 Revised Criteria for
Classification of Systemic Lupus Erythematosus*
AcutecutaneouslupusMalarrash(fixederythema,flatorraised,overthemalareminences),photosensitivity
ChroniccutaneousDiscoidrash:erythematousraisedpatcheswithadherentkeratoticscalingandfollicularplugginglupus
OralornasalulcersOralornasopharyngealulceration,usuallypainless
JointdiseaseNonerosivesynovitisinvolvingtwoormoreperipheraljoints,characterizedbytenderness,swelling,oreffusion
SerositisPleuritis(pleuriticpainorruborevidenceofpleuraleffusion),pericarditis
RenaldisorderPersistentproteinuria>0.5g/24hours,orredcellcasts