Faculty Bibliography

BACKGROUND:Infectious agents are important in the pathogenesis of autoimmune disease since they are a major part of the environmental trigger of autoimmunity. A negative relationship between latitude and infectious disease species richness has been suggested. OBJECTIVES/OBJECTIVE:To examine whether their prevalence differs in two latitudinally different populations. METHODS:The prevalence of infections with Toxoplasma gondii, rubella virus, cytomegalovirus, Epstein-Barr virus and Treponema pallidum was compared between subjects from Italy and Colombia. RESULTS:We found high titers of antibodies against four of five microorganisms tested, Toxoplasma gondii (50.8%), rubella virus (German measles) (75%), cytomegalovirus (86.3%), Epstein-Barr virus (83.3%) and Treponema pallidum (6.3%) in completely healthy individuals from a tropical country (Colombia) and a European country (Italy). Differences between two groups of volunteers were noted regarding two infectious agents. The prevalence of immunoglobulin G anti-rubella antibodies was significantly higher among Italian subjects (85% vs. 67.9%, P = 0.002), whereas antibodies against CMV were less prevalent among Italian as compared to Colombian subjects (77% vs. 92.9%, P < 0.001). CONCLUSIONS:These differences might also result in a different tendency towards development of autoimmune diseases associated with these infectious agents in different populations.

Infections can act as environmental triggers inducing or promoting systemic lupus erythematosus (SLE) in genetically predisposed individuals. The aim of the present study was to compare the titres of antibodies (Abs) to infectious agents with neuropsychiatric (NPSLE) clinical manifestations. The sera of 260 individuals (120 patients with SLE and 140 geographic controls) were evaluated for the titres of Epstein bar virus (EBV), cytomegalovirus (CMV), toxoplasma, rubella and syphilis Abs using the BioPlex 2200 Multiplexed Immunoassay method (BioRad) and by the ELISA method for Helicobacter pylori and Hepatitis B core Ag. All BioPlex 2200 kits used were in developmental stages. Data analysis was performed using SPSS 9.0 statistical analysis software (SPSS Inc., Chicago, IL, USA, 1999). Correlation analysis indicated that rubella IgM Ab titres were marginally, positively associated with psychosis (P = 0.09). No other associations were detected between the 17 infectious Abs and five NP manifestations. When the positivity cut-off for anti-rubella IgM Abs was set at three standard deviations above normal, three positive subjects were identified: one patient with psychosis and one with depression, for a total NPSLE prevalence of 33.3%. On the contrary, the prevalence of NPSLE in the remaining subjects was 6.5%. Marginally significant correlations between elevated titres of rubella IgM Ab with psychosis and depression were found. Although this nearly 5-fold increase is not statistically significant, it appears that in a larger sample size, significance would be reached. This is the first study reported that examined the correlation of NPSLE manifestations with anti-infectious Abs.

BACKGROUND:The etiology of autoimmune diseases is not fully clarified and the mechanisms underlying their initiation and progression are still obscure. It is becoming clear that in a genetic susceptible individual an environmental trigger such as infectious agent in general and viruses in particular could initiate the development of an autoimmune disease. Hepatitis B virus (HBV) is notorious in its association with diverse autoimmune diseases. Therefore, we aimed to determine the presence of hepatitis B core antibody (HBcAb), a seromarker for past or present infection with HBV, in a large number of sera collected from patients with different autoimmune diseases. METHODS:A cohort of 675 sera samples of 5 different autoimmune diseases and healthy donors were screened for evidence of a prior infection with HBV. All samples were tested for hepatitis B core antibody (IgG) using the Monolisa anti-HBc PLUS commercial kit (Bio-Rad, Hercules, San Francisco, USA). RESULTS:Lower percentage of HBcAb was found in sera of the autoimmune diseases when compared to normal controls. Fifteen (10.7%) from 140 normal controls were found positive for the presence of HBcAb. Two (2%) out of 98 multiple sclerosis (MS) sera were positive for the presence of HBcAb (OR: 0.17, 95%CI: 0.03-0.77, p=0.01), 3 (2.5%) out of 117 systemic lupus erythematosus (SLE) sera (OR: 0.2, 95%CI: 0.06-0.77, p=0.01), 4 (4.5%) out of 89 type 1 diabetes (T1D), 5 (6.1%) from 82 Sjogren's syndrome (SS) sera and 12 (8%) from 149 rheumatoid arthritis (RA) sera were positive for the presence of HBcAb. CONCLUSIONS:Our data divulge an unexpected low percentage of antibodies to HBcAg in patients with SLE, MS and T1D in comparison to healthy matched donors. This finding may raise a protective role to HBV in some autoimmune diseases i.e. hygiene theory.

Different types of infection are implicated in the pathogenesis of autoimmune thyroid diseases (AITD) through molecular mimicry or other mechanisms, but their role is disputed. Human studies support direct or indirect evidence of involvement of some viral and bacterial agents, but reports have provided conflicting and inconclusive results. Using a new automated multiplex array platform for the detection of antibodies, we determined seroreactivity against Toxoplasma gondii, Treponema pallidum, rubella virus, cytomegalovirus, and Epstein-Barr virus in a large group of Italian AITD patients and healthy controls. Only IgG concentrations against T. gondii were significantly higher in AITD patients than in controls, suggesting that these protozoa may be involved in the initiation of both Hashimoto's thyroiditis and Graves' disease.

Systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS) are autoimmune diseases causing recurrent pregnancy loss. We hypothesized that anti-phospholipid antibodies (aPL), but not anti-Ro and anti-La antibodies, might have a role through direct placental damage. We cultured human placental explants in sera from women with SLE/PAPS with different antibodies. These sera were found to reduce placental growth and increase trophoblastic apoptosis. No effect was found on estradiol or progesterone secretion, but inhibition in betahCG secretion was detected. BetahCG was reduced in women with a history of recurrent pregnancy loss or thromboembolic events, and was also the most sensitive marker when examining the effects of specific antibodies. High titers of aPL were found to cause the largest reduction in betahCG. Anti-Ro and anti-La did not induce placental damage. A strong correlation was found between the rise in the number of different antibodies in the sera and the incidence of recurrent pregnancy loss, which was also accompanied by a decline in the betahCG levels. In conclusion, aPL, but not anti-Ro or anti-La, may cause placental damage in vitro. Thus betahCG levels might constitute a predictive marker for the risk of placental damage and pregnancy loss in women with SLE/PAPS.

The term "molecular mimicry" was coined by R. Damian in 1964, who was first to suggest that antigenic determinants of micro-organisms may resemble antigenic determinants of their host. Damian suggested that this similarity served as a defense mechanism of a microorganism from the host's immune system and prevented the development of immune response to the micro-organism, thereby protecting it from host defense. Years later, the term "molecular mimicry" was attributed a different meaning-namely, antigenic determinants of microorganisms might elicit an auto-immune response that harms the host. The concept of molecular mimicry is based on a structural similarity between a pathogen or metabolite and self-structures. The similarity could be expressed as shared amino acid sequences (linear or mimotope) or similar conformational structure between a pathogen and self-antigen. "Molecular mimicry" has become a very popular explanation for the frequent association of infection with auto-immune disease.

To date, it is believed that the origin of autoimmune diseases is one of a multifactorial background. A genetic predisposition, an immune system malfunction or even backfire, hormonal regulation, and environmental factors all play important roles in the pathogenesis of autoimmune diseases. Among these environmental factors, the role of infection is known to be a major one. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are considered to be notorious as they are consistently associated with multiple autoimmune diseases. A cohort of 1595 serum samples, of 23 different autoimmune disease groups, was screened for evidence of prior infection with EBV and CMV. All samples were screened for antibodies against EBV nuclear antigen-1 (IgG), EBV viral capsid antigen (IgG and IgM), EBV early antigen (IgG), EBV heterophile antibody, and CMV (IgG and IgM) antibodies using Bio-Rad's BioPlex 2200. A new association is proposed between EBV and polymyositis, as results show a significant increase in titers of various EBV target analytes when compared with healthy controls. Our results also support prior information suggesting the association between EBV and multiple autoimmune diseases, including SLE, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, pemphigus vulgaris, giant cell arthritis, Wegener's granulomatosis, and polyarteritis nodosa (PAN). Elevated CMV IgG titers were observed in sera of SLE patients. Our data support the theory that EBV is notoriously associated with many autoimmune diseases. CMV appears to be associated to autoimmune diseases as well, yet establishing this theory requires further investigation.

Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with the persistence of lupus anticoagulant or anticardiolipin (aCL) antibodies. Accumulating evidence indicates that phospholipid binding protein, beta2-glycoprotein I (beta2GPI) represents the major target antigen for antiphospholipid (aPL) antibodies and plays a role in the pathogenesis of APS. It is widely accepted that aPL antibodies detected by conventional solid phase assays in patients with APS are mainly directed against a complex of aCL and anti-beta2GPI, although antibodies against beta2GPI protein can now also be detected by specific ELISA using purified proteins in solid phase. Despite the fact that these antibodies are not listed in the new diagnostic criteria, a high specificity of anti-beta2GPI assay for the clinical features of APS was established. During the last decade, numerous studies have investigated the clinical link between aCL and/or anti-beta2GPI antibodies and diverse features of APS. This manuscript reviews the current studies published recently in this field and discusses the relationship between the existence of aCL and anti-beta2GPI antibodies and the main and unusual manifestations of APS.