Discussion and Conclusions

A common feature of all autoimmune diseases is the presence of autoantibodies. Some autoantibodies are specific for the site of the disease process, as exemplified by thyroid diseases, pemphigus vulgaris, or autoimmune gastritis. However, even in instances in which the autoantibodies are not believed to be the causative agents, they always make an important contribution to the diagnosis of autoimmune diseases. Subdifferentiation of the pattern of autoantibodies allows us to distinguish not only different autoimmune types but also different subsets of autoimmune diseases. For instance, antinuclear antibodies are the most commonly detected autoantibodies in AIH type 1, but they are also frequently (50%) detected in PBC. Subclassification of ANAs shows that in PBC

these autoantibodies are directed against specific nuclear antigens (gp 120, p62, Sp100) that are not detected in AIH type 1. The presence of PBC-associated ANAs in AMA-negative patients may therefore be the only diagnostic serum marker of PBC. Another example is the recognition of different epitopes by LKM-1 autoantibodies, which in the case of localizing between amino acids 257 and 269 appears to be specific for AIH and is discriminatory against LKM-1 au-toantibodies associated with chronic hepatitis C virus infection.

In a number of autoimmune diseases, it is still unknown whether the autoantibodies highlight the responsible pathogenic process, thereby directly contributing to organ-specific autoimmunity and injury, or whether this is indirectly mediated by infiltrating inflammatory cells and proinflammatory cytokine production. Almost all autoimmune diseases depend on the presence of CD4+ T cells that recognize self-antigens. Whether these T cells are stimulated by an autologous antigen or by an exogenous molecular mimic, they are responsible for the production of classes of autoantibodies with pathogenic capabilities or T cells that can attack and damage tissue. Production of proinflammatory cytokines including ligands of death receptors may amplify the autoimmune-mediated tissue injury. As a response to cytokines, exposed T cells become activated and differentiate into Th1 or Th2 cells. Furthermore, proinflammatory cy-tokines may lead to upregulation of death ligands on infiltrating/attacking T lymphocytes as well as of death receptors on parenchymal target cells, thereby contributing to apoptotic tissue injury. Proinflammatory cytokines are therefore believed to play an important role in the initiation and propagation of the autoimmune response. In addition, autoantibodies by themselves have been implicated as playing a role in the activation of T lymphocytes. In this respect, it has been demonstrated that LKM-1 autoantibodies inhibit CYP2D6 activity in vitro and are capable of activating liver-infiltrating T lymphocytes, indicating the combination of B- and T-cell activity in the autoimmune process involved. Liver histology from patients with autoimmune hepatitis shows a periportal infiltrate of lymphocytes and plasma cells as well as piecemeal necrosis, indicating that in this autoimmune disease an inflammatory immune response may predominately contribute to liver injury.

Although the presence of autoantibodies generally does not correlate with disease activity, disease progression, or treatment outcome, in some cases they may be of prognostic value. In the case of AIH type 1, antibodies against actin identify a subgroup of SMA-positive patients with an earlier onset of disease and a more frequent steroid treatment failure. The presence of anti-ASGPR autoantibodies is associated with laboratory and histological disease activity and more frequent relapses after corticosteroid withdrawal in patients with AIH type 1. In the case of AIH type 2, LC-1 autoantibodies seem to correlate with disease activity, whereas LKM autoantibodies do not.

The development of commercial assays for application of autoantibodies with prognostic value is needed and will give further insights into whether these antibodies are useful for monitoring the disease activity and the therapeutic response of the respective autoimmune disease.

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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