Characteristics and Classification of Systemic Autoimmune Diseases

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Diseases can be characterized as autoimmune by direct, indirect, and circumstantial evidence [1]. Direct evidence is given by the presence of disease-specific autoantibodies (AABs) and/or autoreactive T cells that cause organ dysfunction and/or chronic inflammation. Animal models with spontaneously developed or induced diseases that resemble autoimmune diseases (AIDs) in humans may provide indirect evidence. Circumstantial evidence includes the association with other AIDs, the presence of AABs (regardless of their pathogenic role), the association with major histocompatibility complex (MHC) haplotypes, the infiltration of lymphocytes into target organ(s), germinal centers in the lesions, infiltrating lymphocytes with restricted V-gene usage, and favorable response to im-munosuppression. The etiologies and pathological mechanisms involved in the development of AIDs are incompletely understood. There is no doubt that genetic as well as environmental factors are responsible for the induction, development, and progression of AIDs. According to clinical manifestations and autoimmune responses, AIDs may be considered organ-specific or non-organ-specific (systemic).

Systemic autoimmune diseases represent a very heterogeneous group of AIDs with manifestations on multiple tissues or organs and include rheumatoid arthritis (RA, see Chapter 12), connective tissue diseases (CTDs), anti-phospholipid syndrome, and systemic vasculitides. The CTDs can be classified as systemic lupus erythematosus (SLE; see Chapter 11), systemic sclerosis (SSc, scleroderma), Sjogren's syndrome (SjS), idiopathic inflammatory myopathies (autoimmune myositides, including polymyositis [PM] and dermatomyositis [DM]), as well as various overlap syndromes (mixed connective tissue disease [MCTD] and PM-SSc overlap syndrome) and undifferentiated (unclassifiable) CTDs. Even within a defined disease entity (e.g., SLE according to the criteria of the American College of Rheumatology), there is large heterogeneity, and hence added complexity, regarding clinical manifestations, genetic background, and autoantibody profiles.

Table 10.1 Nature and examples of disease-specific autoantibodies.

Disease group


Examples of autoantibody

directed against


Non-organ-specific (systemic)

Widely distributed autoanti-



• Rheumatoid arthritis

Citrullinated proteins/

Citrullinated filaggrin


• Connective tissue diseases

Non-organ-specific, highly

Double-stranded DNA

conserved nuclear or cyto-

DNA topoisomerase I

plasmic antigens

tRNA synthetases

• Antiphospholipid

Phospholipids (PL) and



PL-associated proteins

jS2-glycoprotein I

• Systemic vasculitides

Enzymes of neutrophil


granulocytes and monocytes

Proteinase 3

Organ-specific AID

Tissue/organ-specific anti-

Acetylcholine receptor


Intrinsic factor


Multiple organ-specific AID

Tissue/organ-specific anti-

gens of different organs

Furthermore, there is strong and accumulating support for familial clustering of specific manifestations of multiple systemic autoimmune diseases caused by genetic but perhaps also shared environmental factors [2].

Circulating disease-specific AABs are hallmarks of AIDs regardless of their pathogenic role. Whereas AABs in organ-specific AIDs are directed against antigens that are expressed in the targeted organ(s), AABs in systemic AIDs respond to widely distributed antigens. In autoimmune polyglandular endocrine syndromes that do not represent systemic but multiple organ-specific diseases, different organ-specific AABs are present (Table 10.1).

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