Elsevier

Autoimmunity Reviews

Volume 10, Issue 12, October 2011, Pages 779-789
Autoimmunity Reviews

Review
Antibodies against acute phase proteins and their functions in the pathogenesis of disease: A collective profile of 25 different antibodies

https://doi.org/10.1016/j.autrev.2011.06.001Get rights and content

Abstract

The acute phase response is a defense system in which the innate immune response is activated following injury or infection. Positive and negative acute phase proteins (APPs) are crucial for protecting the host organism, as well as returning it to homeostatic levels, the first with elevated concentrations and the latter with decreased concentrations during the acute phase. Reports about the presence of antibodies against APPs are known, however their individual, as well as potentially collective, pathological or physiological roles are still emerging. Some of these autoantibodies are specifically connected with diseases (such as pancreatic secretory trypsin inhibitor and C3, C4 nephritic factors), while others have been reported as natural antibodies. The persistent presence (even if only minor) of autoantibodies in healthy blood donors indicates an overlapping category of autoantibodies, which could become pathogenic, depending on the autoantibody characteristics such as avidity, epitope specificity, changes in the microenvironment leading to different oxidative status and others. This review uses the novel approach of studying the overall autoantibody population against APPs, their functions and connections to diseases. The primary function of autoantibodies against APPs (anti-APPs) is thought to promote their clearance, however autoantibodies against negative APPs have also been found and applying the same role to those is doubtful. There is also the theory of consumption in the stage of inflammation, which could be relevant to anti-APPs. Reports about protective roles of autoantibodies are also emerging, showing lowered levels of antibodies in diseases, which could be interesting for therapeutic intervention.

Section snippets

Acute phase proteins (APPs)

The acute phase response is an ancient, evolutionarily conserved defense system reacting to injury or infection, achieving modified levels of APPs in the circulation and ultimately leading to the resolution of inflammation. The terminology of APPs encompasses the majority of plasma proteins the levels of which are modulated at least 25% during the acute phase, synthesized mainly by the liver and stimulated by injury and/or infections. APPs are divided into major APPs, which can be elevated more

Anti-APPs and their role/s in autoimmunity

Twenty five anti-APPs have been described in the current review. Until now, the most comprehensive review article described three APPs and two other plasma proteins important for autoimmunity, their roles and autoantibodies [2].

During the acute phase response, the innate immune system mobilizes the adaptive immune response in order to combat antigen-specific invaders. In such a state, the level of costimulatory mediators and antigen presentation is enhanced and many non-native self molecules

Other potentially protective roles of anti-APPs

Natural antibodies are found in normal individuals in the absence of apparent antigen stimulation [10]. Reports of naturally-occurring anti-APPs playing protective roles in homeostasis have been emerging, such as anti-albumin antibodies [11], anti-SAA antibodies [12], anti-factor VIII antibodies [13]. Natural antibodies in healthy individuals predominantly participate in the clearance of modified and non-functional plasma proteins [14], a role that could fit into the anti-APP antibody

Methodology

For the purpose of review we divided APP autoantibodies according to the roles of their antigens into major APPs, moderate and minor APPs, with different functions (such as metal binding, protein inhibitors, complement ad others) and negative APPs. We did not focus on certain plasma proteins which are known for their autoimmune response, but do not belong to the defined category of APPs in humans, such as C1q, SAP and prothrombin [2], [7], [20]. A collective profile of autoantibodies against 25

C-reactive protein (CRP)

CRP is widely used for laboratory assessment of inflammation and cardiovascular risk. The main functions of pleiotropic CRP include opsonization, activation of complement and binding to Fc receptors [23]. According to Sjowall et al. [24] antibody activity against CRP targets monomeric CRP, with some differences in its activity as compared to pentameric CRP [25].

The first report of antibodies against CRP was published by Bell et al. in 1995 [26]. They discovered antibodies against CRP in 74% of

Haptoglobin

Haptoglobin is a hemoglobin-binding plasma glycoprotein. The physiological function of the protein is not completely understood, it may limit iron loss during normal erythrocyte turnover and during hemolysis. It also inhibits prostaglandin synthesis [38] and suppresses Th type 2 response [39].

Case reports with hypohaptoglobinemia or haptoglobinemia (Hp0 genotype) of a genetic origin are known with the production of antibodies against haptoglobin following repeated blood transfusions and severe

Ceruloplasmin

Ceruloplasmin exhibits a copper-dependent oxidase activity, which is associated with possible oxidation of Fe2+ into Fe3+, therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state.

In the only study found, 45% of patients with systemic sclerosis had predominantly IgG antibodies to ceruloplasmin detected as compared to 14% in SLE [3].

Ceruloplasmin binds and inhibits also myeloperoxidase and impaired inactivation of

Albumin

Albumin is a well known negative APP. Its functions are generally well characterized (reviewed in [89]).

As seen from early studies, anti-albumin autoantibodies were present in all normal controls tested, but all acute phase hepatitis B patients had significantly lowered titers. These findings support the concept that anti-albumin autoantibodies have a normal physiological function (probably for removal of changed albumin molecules) and that, in hepatitis B viral infection, there is a decrement

Conclusions

The following review article points out the current status of anti-APPs. Their expected roles could influence future diagnostics and prognostics in different diseases, not limited to the area of autoimmunity. Currently, there are no definite conclusions in this respect, presumably also due to the problem of the lack of detection standardization and statistical methodology of anti-APPs in population studies, as well as of information regarding their various Ig classes and avidity.

Therapeutical

Take-home messages

  • A collective profile of autoantibodies against 25 different acute phase proteins and their presence in different diseases is described, which is (as far as we know) the largest compilation to date.

  • In systemic lupus erythematosus, antibodies against 8 specific acute phase proteins are described, 7 in antiphospholipid syndrome, 5 in rheumatoid arthritis, and 4 and below, in connection with other diseases such as cancer, atherosclerosis and inflammation.

  • The profile of anti-APPs' quality and

Acknowledgements

This work was supported by the Ministry of High Education, Science and Technology of Slovenia, (#P3 0314 to B.R.) and the European Commission (MC-IRG #028414 to SSS.).

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