Faculty Bibliography

Infections are believed to often play a role in the immunopathogenesis of autoimmune disorders; such is the case in systemic sclerosis (SSc). In order to evaluate the potential role infections may have on the pathogenesis of SSc, we assessed serological reactivity against various infectious agents in patients with SSc and compared them with healthy controls. Serological samples obtained from 80 patients with SSc were compared with 296 compatible healthy controls. Both groups were of European origin. All samples were tested for the presence of antibodies directed against hepatitis B virus, hepatitis C virus, toxoplasmosis, rubella, CMV, EBV, and Treponema pallidum. We applied Bio-Rad commercial and experimental kits to assess most antigens and ELISA assays to complete the panel. Patients with SSc had elevated IgM and IgG against Toxoplasma gondii and against CMV. Higher titers were also detected against the hepatitis B virus core protein (recombinant HBc antigen) using MONOLISA anti-HBc Plus commercial kit (Bio-Rad). A significantly higher rate of IgM antibodies against the capsid antigen of the EBV was detected in SSc patients compared with healthy controls, as well. These data demonstrate that antibodies against CMV, HBV, and toxoplasmosis were detected more often in patients with SSc. This association implies that infectious agents may have a role in disease pathogenesis and expression.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease with complex interactions between genetic and environmental factors. We compared antibody levels to various infectious agents and of autoimmune-associated autoantibodies between Colombian T1DM patients, their close family members and healthy controls. Significantly lower levels of antibodies against several infectious agents were detected in the T1DM patients. These included Helicobacter pylori (P = 0.01), cytomegalovirus (P = 0.001), Epstein-Barr virus (P = 0.02) and Toxoplasma (P = 0.001). T1DM patients had significantly higher levels of IgG-anti-gliadin antibodies (P = 0.001) and IgG-antitissue transglutaminase antibodies (P = 0.03), and a borderline association with anticentromere antibodies (P = 0.06). The lower level of antibodies against infectious agents in T1DM patients may be related to their younger ages, but may also point to a protective role of those infections in T1DM development in susceptible individuals. Our results confirm the association between T1DM and celiac disease. A possible association with anticentromere antibody needs further studies.

The aim of this study was to reevaluate the role of infection in inflammatory bowel disease (IBD). Sera from 119 patients with IBD [80 with Crohn's disease (CD); 39 with ulcerative colitis] and 98 healthy controls were assessed using the Bio-Rad BioPlex 2200 for the presence of Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus, hepatitis C virus (HCV), and anti-Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. Titers of antibodies toward HCV and T. gondii, and S. cerevisiae were higher in IBD patients than in controls, while the H. pylori autoantibodies were less prevalent among the patient population. Several thrombophilia-associated antibodies were more common in CD patients, and a single patient had a thromboembolic event. Our results show an excess of anti-HCV and anti-T. gondii antibodies among patients with IBD compared to healthy controls. Whereas the former may be the result of immunosuppression from the inflammatory disease itself or from the medications used to treat it, the latter association suggests that T. gondii is involved in the etiopathogenesis of IBD, and especially CD, in humans, as has been shown in the murine model. However, our findings also reiterate the positive association between CD and anti-S. cerevisiae antibodies as well as the negative association with H. pylori infections. These, in turn, lend indirect support to the "hygiene hypothesis" in IBD as well as the newly proposed role of commensal bacteria in the initiation of the disease process.

In this study we assess the presence of antibodies against infectious agents as well as for a variety of autoantibodies in an attempt to establish associations between various vasculitides and infections in order to shed light on the etiopathogenesis of these diseases and perhaps implicate a potential cure. Sera from patients with Wegener's granulomatosis (WG), polyarteritis nodosa, microscopic polyangiitis, Churg Strauss, and giant cell arteritis were compared to healthy control sera. Serum samples were assessed, using the Bio-Rad BioPlex 2200, for the presence of Toxoplama gondii, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus (HBV), hepatitis C virus (HCV), and anti-Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. The prevalence of antibodies toward HCV and H. pylori was significantly higher among patients with WG. IgG antibodies toward T. gondii and IgM antibodies toward CMV were significantly more common among WG patients than among controls. WG patients exhibited more antibodies toward EBV viral capsid antigen IgG and EBV early antigen IgG compared to sera from healthy controls. In WG, positive associations were disclosed between CMV IgG antibodies and the presence of gastrointestinal manifestations and renal involvement, and there was a higher Birmingham vasculitis activity score in association with elevated titers of EBV viral capsid antigen IgG antibodies. Otorhinolaryngeal manifestations were more common in those with positive IgG antibodies for EBV early antigen. Our results unveil novel associations between WG and various infectious agents, including HCV, H. pylori, T. gondii, CMV, and EBV. In addition to putative roles in initiation and exacerbation of the vasculitic process, it seems that these infectious agents also modulate the clinical phenotype of the disease.

Infections may act as environmental triggers for the induction of systemic lupus erythematosus (SLE). In this study, we determine the relationship between disease manifestations of SLE patients and the titers of five Epstein-Barr virus (EBV) Abs. We evaluated the titers of early antigen IgG (EAG), nuclear antigen IgG, viral capsid antigen (VCA) IgG and IgM, and heterophile IgM, using the BioPlex 2200 multiplexed immunoassay method in 260 sera (120 SLE patients and 140 controls). EAG titers were significantly elevated (P < 0.024) in patients with cutaneous symptoms and increased anti-Ro antibody titers (P < 0.005). VCA IgG titers were significantly elevated (P < 0.003) in patients with joint involvement. None of the titers differed by central nervous system or renal involvement or antiphospholipid syndrome. We conclude that exposure to EBV infection may predict a disease phenotype of mild SLE disease with cutaneous and joint manifestations and elevated titers of anti-Ro Abs.

Infectious agents have been implicated in the pathogenesis of many autoimmune diseases via various pathogenic mechanisms, such as molecular mimicry, resulting in modulation of the host's immune tolerance. In the following article we examine the association between serological evidence of past infection with Toxoplasma gondii, rubella virus, cytomegalovirus, Treponema pallidum, and Epstein-Barr virus, and the co-existence of celiac disease. Our results imply that certain infections may generate an immunological environment that disfavors future appearance of certain autoimmune conditions such as celiac disease.

The objective of our study was to determine the prevalence of anti-infectious agent antibodies and autoantibodies in a unique non-Westernized population from Kitava, Papua New Guinea (PNG), compared to Western populations. We matched 120 serum samples from Kitavans with 437 samples from four healthy control groups. Sera were tested for the presence of anti-infectious agent antibodies (treponema, toxoplsmosis, Epstein-Barr virus, cytomegalovirus, rubella) and autoantiobodies [anti-double-stranded (ds)DNA, anti-chromatin, anti-ribonucleoprotein (RNP), anti-SSB, anti-SSA, anti-Scl-70, anti-Smith, anti-centromer, anti-SmRNP, anti-Jo-1, and anti-ribosomal-P] using the Bio-Rad BioPlex 2200. Antitreponemal antibodies were detected in 87% of PNG sera versus 0-6% of controls (P < 0.0001). Anti-dsDNA antibodies were detected in 31% of PNG samples, which was significantly higher than in three of the control groups (<10%). The outstanding high rate of antitreponemal antibodies detected in Kitavans possibly represents prior yaws disease. A low prevalence of cardiovascular disease was previously documented in Kitavans and has been attributed, in addition to their diet, to the high prevalence of natural cardioprotective autoantibodies (the IgM-antiphosphorylcholine antibodies) in this population. Treponemal infection has been shown to induce the appearance of antiphosphorylcholine antibodies. These protective autoantibodies may cross-react with the pathogenic anti-dsDNA antibodies. Thus, it is suggested that infection with treponema is associated with the presence of protective as well as pathogenic autoantibodies.

Infections can act as environmental triggers that induce or promote systemic lupus erythematosus (SLE) in genetically predisposed individuals. New technologies, developed recently, enable simultaneous assessment of multiple antibodies. Antibodies to specific infectious agents may shed light into the mechanisms of induction of SLE. The aim of this study was to investigate the prevalence of seropositivity and the titers of antibodies to bacterial, viral, and parasitic agents in SLE patients compared with non-autoimmune controls. Sera from 260 individuals (120 SLE patients and 140 controls) were tested by the BioPlex 2200 Multiplexed Immunoassay method (BioRad) for the prevalence and titers of antibodies to eight infectious agents (Epstein-Barr virus: early antigen IgG, nuclear antigen IgG, viral capsid antigen IgG and IgM, heterophile IgM; cytomegalovirus IgG and IgM; Toxoplasma gondii IgG and IgM; rubella IgG and IgM; Treponema pallidum TPr15G, TPr17G, TPr47G; herpes simplex virus type 1 and 2 IgG; hepatitis C virus and hepatitis B core antibodies. Cytomegalovirus IgM and Epstein-Barr virus early antigen IgG (but not other Epstein-Barr virus antigens) were significantly more prevalent in SLE patients than in controls. Conversely, positive titers of hepatitis B core and rubella IgG antibodies were less prevalent in the SLE patients than in controls. Other differences in titer positivity prevalence were not detected between patients and controls. The titers of the cytomegalovirus IgM, Toxoplasma IgG, Epstein-Barr virus early antigen, and viral capsid antigen IgG antibodies were significantly higher in SLE compared with controls. Our data suggest the importance of previous exposure to infectious agents in the induction and the prevention of SLE.

Antiphospholipid syndrome is characterized by thrombosis and pregnancy loss. Infections are generally associated with autoimmune diseases, but in the setting of antiphospholipid syndrome this link has been suggested as having a pathogenic role. In this study, 98 patients with antiphospholipid syndrome were screened for antibodies directed to several infectious agents. The main finding in this study is the significantly higher prevalence of IgM antibodies to toxoplasma and rubella. This novel finding suggests that these infections might be associated with antiphospholipid syndrome. As autoimmune diseases and, in particular, antiphospholipid syndrome are associated with infections, mainly the catastrophic type of the syndrome, this finding implies that a current infection with these agents, i.e. toxoplasma and rubella, might either be related to the pathogenesis of antiphospholipid syndrome or alternatively to its manifestations.