Association of Pepsin with Type II Collagen (CII) Breaks Control of CII Autoimmunity and Triggers Development of Arthritis in Rats

Lewis rats develop arthritis after immunization with heterologous but not homologous rat type II collagen (CII). We have observed that if the rat CII is prepared by pepsin digestion without subsequent extensive purification, it is arthritogenic in Lewis rats. To address whether pepsin in the CII preparations contributed to the development of arthritis and whether this was associated with the induction of an immune response to CII, Lewis rats were immunized with rat CII of various degrees of purity and with various pepsin contents. After immunization with a crude preparation of CII, containing relatively large amounts of pepsin, Lewis rats developed arthritis with an incidence of 80% together with a strong anti-CII autoantibody production. Further purification of the CII on DEAE-Sepharose, which removes pepsin, eliminated the arthritogenic properties and the capacity to activate CH-specific B cells. Likewise, lathyritic CII, prepared without pepsin, induced neither a CII-specific immune response nor arthritis. If, however, pepsin was added to non-arthritogenic batches of rat CII, arthritis appeared at an incidence of 40%. By using an ELISPOT technique to detect antigen-specific interferon-γ-producing T cells and antibody-producing B cells, the immune response to CII and pepsin can be evaluated. Eleven days after immunization with lathyritic CII and pepsin, a B-eell response towards both CII and pepsin was seen. Pepsin-specific T cells were also seen at day 11, but CII-specific T cells did not appear until day 14 after immunization. In addition, a weak CII -specific proliferative response of the T cells could be demonstrated at day 14 but not at day 11 or 12. These data show that pepsin plays an important role in the triggering of a CII-specific immune response. We suggest a carrier-hapten mechanism where pepsin acts as a carrier and CII as a ‘hapten’ which will activate CII-specific B cells. Subsequently these CII-specific B cells will break the T-cell tolerance and evoke a T-cell-mediated immune response towards CII.     

Autoimmunity

The following article has been retracted from publication in Autoimmunity:

1. “Drug-induced lupus erythematosus', Piercarlo Sarzi-Puttini, Fabiola Atzeni, Franco Capsoni, Ennio Lubrano & Andrea Doria., November 2005. Autoimmunity, 38:507–518.

This article has been found to reproduce content, without attribution or acknowledgement, from the following original articles:

• Antonov, D., Kazandjieva, J., Etugov, D., Gospodinov, D., Tsankov, N., (2004). Drug-induced Lupus Erythematosus. Clinics in Dermatology, 22, 157–166.

• Pramatov, K.D., (1998). Drug-induced Lupus Erythematosus. Clinics in Dermatology, 16, 367–377.

The Publishers wish to state that Autoimmunity published the article (1) in good faith, and on the basis of legal warranties made by the authors regarding the originality of their work. We welcome this opportunity to acknowledge and reinstate the rights of the original authors and the copyright of the original publishers.

We note that the authors of the above mentioned article (1) have submitted a written apology.     

Autoimmunity and cancer

In many autoimmune rheumatic diseases, there is an increased risk of cancer compared to the general population. The link between autoimmunity and cancer is dynamic and bidirectional. Recent advances in terms of knowledge of biology, epidemiology, and long-term outcomes for the autoimmune rheumatic diseases have revealed several new connections between these two entities. Data suggest that chronic inflammation from the rheumatic diseases or their therapies may contribute to the onset and promotion of cancer. Conversely, antitumor immune responses may become cross-reactive with self-tissues resulting in the development of autoimmunity. In this review, we discuss about the potential mechanisms that link autoimmune rheumatic diseases and cancer and the association of malignancies with common autoimmune disorders. The increased incidence of malignancy in autoimmune rheumatic diseases has been largely described, although the biology underpinning this relationship should be further investigated. The development of evidence-based cancer screening recommendations in patients with autoimmune rheumatic diseases is complex due to the heterogeneity of clinical rheumatic phenotypes, cancer sites at risk and exposure to anti-neoplastic and anti-rheumatic treatment. In order to lay the foundation of risk stratification and targeted cancer screening, larger longitudinal cohort studies that provide a more detailed framework of the links between cancer and autoimmunity are urgently needed.     

Tuberculosis and Autoimmunity

Tuberculosis remains a common and dangerous chronic bacterial infection worldwide. It is long-established that pathogenesis of many autoimmune diseases is mainly promoted by inadequate immune responses to bacterial agents, among them Mycobacterium tuberculosis. Tuberculosis is a multifaceted process having many different outcomes and complications. Autoimmunity is one of the processes characteristic of tuberculosis; the presence of autoantibodies was documented by a large amount of evidence. The role of autoantibodies in pathogenesis of tuberculosis is not quite clear and widely disputed. They are regarded as: (1) a result of imbalanced immune response being reactive in nature, (2) a critical part of TB pathogenicity, (3) a beginning of autoimmune disease, (4) a protective mechanism helping to eliminate microbes and infected cells, and (5) playing dual role, pathogenic and protective. There is no single autoimmunity-mechanism development in tuberculosis; different pathways may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages and dendritic cells, environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mycobacterium tuberculosis and host.     

Autoimmunity and Pregnancy

ABSTRACT: The general effect of pregnancy on autoimmunity remains controversial. In the majority of cases, pregnancy may have no effect on the disease, while on other occasions, pregnancy induces exacerbations that may be especially pronounced in the immediate postpartum period. The reasons for this preponderance are still unclear. Another important aspect of autoimmune diseases during pregnancy entails the passive transfer of the disease into the fetal compartment. It seems that until the pathogenesis and a better specific therapy for autoimmune diseases are clearly defined, careful clinical and immunologic observation of each mother-infant pair will be invaluable.     

Prolactin and Autoimmunity

The relationship between prolactin and the immune system has been demonstrated in the last two decades, opening new windows in the field of the immunoendocrinology. Prolactin has an important role in the innate and adaptive immune response. Increased prolactin levels have been described in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and systemic sclerosis among others. Hyperprolactinemia is associated with active disease and organ involvement in systemic lupus erythematosus. Therefore, prolactin is an integral member of the immunoneuroendocrinology network and seems to have a role in pathogenesis of autoimmune diseases. Few controlled studies of dopamine agonist treatment in humans with autoimmune disease have been conducted only in systemic lupus erythematosus patients, which support the potential efficacy of such agents even during pregnancy and postpartum. Further studies are necessary to elucidate the mechanisms by which prolactin affects autoimmune disease activity, increase the inflammatory mechanism, and determine the role of anti-prolactinemic drugs to regulate the immune/inflammatory process.