Anti Saccharomyces cerevisiae Antibodies in Patients With Anti-ß2 Glycoprotein I Antibodies.

BACKGROUND: In this study, cross-reactive epitopes on ß2 glycoprotein I and Saccharomyces cerevisiae have been described. The objective of our study was to determine the frequency of anti S. cerevisiae antibodies (ASCA) in patients with anti-ß2 glycoprotein I antibodies (aß2GPI). METHODS: A retrospective study was conducted in 77 patients with aß2GPI (aß2GPI-IgG or aß2GPI-IgA). Eighty blood donors were used as a control group. ASCA IgG and ASCA IgA were determined by Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Thirteen patients among 77 had ASCA. ASCA (IgA or IgG) was significantly more frequent in patients than in healthy subjects (16.9% vs. 3.7%, P = 0.01). The positivity of both ASCA IgG and ASCA IgA is higher in patients than in control group (6.5% vs. 0%, P = 0.02). The frequency of ASCA IgG was significantly higher in patients than in the control group (15.6% vs. 2.5%, P = 0.009). In females, the frequency of ASCA IgG was significantly higher in patients than in control group (17.5% vs. 3.7%, P = 0.03). The average titer of ASCA IgG was significantly higher in patients than in the control group (9.7 ± 23 U/ml vs. 2.2 ± 2.8 U/ml; P = 0.004). ASCA IgG was significantly more frequent than ASCA IgA in all patients (15.6% vs. 7.8%, P = 0.04). CONCLUSION: The frequency of ASCA was significantly higher in patients with aß2GPI than in the control group.

The role of the gut microbiota in the pathogenesis of antiphospholipid syndrome.

Infectious triggers are associated with the induction of transient antiphospholipid antibodies. One therefore wonders if microbes that permanently colonize us play a role in the pathogenesis of antiphospholipid syndrome (APS). The microbiota represents the collection of all microorganisms colonizing humans and is necessary for normal host physiology. The microbiota, however, is a constant stress on the immune system, which is tasked with recognizing and eliminating pathogenic microbes while tolerating commensal populations. A growing body of literature supports a critical role for the commensal-immune axis in the development of autoimmunity against colonized barriers (e.g., gut or skin) and sterile organs (e.g., pancreas or joints). Whether these interactions affect the development and sustainment of autoreactive CD4(+) T cells and pathogenic autoantibodies in APS is unknown. This review provides an overview of the current understanding of the commensal-immune axis in autoimmunity with a focus on the potential relevance to APS. Additionally, we discuss emerging findings supporting the involvement of the gut microbiota in a spontaneous model of APS, the (NZW × BXSB)F1 hybrid, and formalize hypotheses to explain how interactions between the immune system and the microbiota may influence human APS etiopathogenesis.

Diet, microbiota and autoimmune diseases.

There is growing evidence that the commensal bacteria in the gastrointestinal tract (the gut microbiota) influence the development of autoimmunity in rodent models. Since humans have co-evolved with commensals for millennia, it is likely that people, who are genetically predisposed to autoimmunity, harbor gut microbial communities that similarly influence the onset and/or severity of disease. Beyond the current efforts to identify such disease-promoting or -preventing commensals ("pathobionts" or "symbionts"), it will be important to determine what factors modulate them. Dietary changes are known to affect both the composition and function of the gut microbial communities, which in turn can alter the innate and adaptive immune system. In this review, we focus on the relationships between diet, microbiota, and autoimmune diseases. We hypothesize that the beneficial and life-prolonging effects of caloric restriction on a variety of autoimmune models including lupus might partly be mediated by its effects on the gut microbiome and associated virome, the collection of all viruses in the gut. We give recent examples of the immunomodulatory potential of select gut commensals and their products or diet-derived metabolites in murine models of arthritis, multiple sclerosis, and type 1 diabetes. Lastly, we summarize the published phenotypes of germ-free mouse models of lupus and speculate on any role of the diet-sensitive microbiome and virome in systemic lupus and the related antiphospholipid syndrome.

Presence of Mycoplasma fermentans in the bloodstream of Mexican patients with rheumatoid arthritis and IgM and IgG antibodies against whole microorganism.

BACKGROUND: Increasing evidence incriminates bacteria, especially Mycoplasma fermentans, as possible arthritogenic agents in humans. The purpose of this study was to investigate M. fermentans in the bloodstream of patients with rheumatoid arthritis. METHODS: Two hundred and nineteen blood samples from patients with rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, and healthy individuals were screened by bacterial culture and direct PCR in order to detect mycoplasmas; IgM and IgG against M. fermentans PG18 were also detected by ELISA and Immunoblotting assays in patients with rheumatoid arthritis and healthy individuals. RESULTS: Blood samples from patients with antiphospholipid syndrome and healthy individuals were negative for mycoplasma by culture or direct PCR. In blood samples from patients with systemic lupus erythematosus were detected by direct PCR M. fermentans in 2/50 (2%), M. hominis in 2/50 (2%) and U. urealyticum in 1/50 (0.5%). In patients with RA M. fermentans was detected by culture in 13/87 blood samples and in 13/87 by direct PCR, however, there was only concordance between culture and direct PCR in six samples, so M. fermentans was detected in 20/87(23%) of the blood samples from patients with RA by either culture or PCR. Antibody-specific ELISA assay to M. fermentans PG18 was done, IgM was detected in sera from 40/87 patients with RA and in sera of 7/67 control individuals, IgG was detected in sera from 48/87 RA patients and in sera from 7/67 healthy individuals. Antibody-specific immunoblotting to M. fermentans PG18 showed IgM in sera from 35/87 patients with RA and in sera from 4/67 healthy individuals, IgG was detected in sera from 34/87 patients and in sera from 5/67 healthy individuals. CONCLUSION: Our findings show that only M. fermentans produce bacteremia in a high percentage of patients with RA. This finding is similar to those reported in the literature. IgM and IgG against M. fermentans PG18 were more frequent in patients with RA than healthy individuals.

Antiphospholipid Syndrome Complicating Pneumococcal Meningitis.

BACKGROUND: Antiphospholipid syndrome is a multisystem auto-immune disorder characterized by arterial or venous thrombosis in children. CASE CHARACTERISTICS: 11-year-old child with pneumococcal meningitis also had cerebral sinus vein thrombosis and pulmonary artery segmental thrombosis. OBSERVATION: Pro-thrombotic evaluation showed positive lupus anticoagulant at baseline and after 12 weeks. Investigations for lupus were negative at admission and after one year of follow-up. MESSAGE: Antiphospholipid syndrome is a possibility even in thrombosis occurring in the setting of meningitis.

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

From molecular mimicry to cross-reactivity or pathogen expansion? A hypothesis.

Very recently, several studies have convincingly demonstrated the role of infection in the development of the antiphospholipid syndrome. Cross antibody-mediated reactivity due to molecular mimicry between endothelial glycoproteins and microbial products was considered as an important pathogenic mechanism. However, another consequence of the molecular mimicry may be proposed. Similar tissues have less likelihood of being rejected and have a greater chance of being accepted by the host. According to this principle, pathogens with common-to-host antigens may attach readily and not be eliminated. A direct expansion of such pathogens may involve new territories. The targets of the approach 1, "from molecular mimicry to cross-reactivity," are T-B cells system inhibition-modulation. The targets of approach 2, "from molecular mimicry to pathogen expansion," are pathogens, enforcement of barriers, elimination techniques, and preventive strategy.

The catastrophic antiphospholipid (Asherson's) syndrome in 2004--a review.

An unusual variant of the antiphospholipid syndrome (APS) termed the Catastrophic Antiphospholipid Syndrome (CAPS) in 1992 by Asherson is described. The condition may arise "de-novo" in a patient previously not suspected of having an APS or during the course of a "Primary" APS or Secondary APS (most commonly SLE). The patient may already be on therapy. "Trigger" factors (infections most commonly) have been identified in 45% of patients but in the majority, they remain unidentified. Clinically, the patients present with small vessel occlusions involving organs (e.g. bowel, brain, heart, kidney) but large vessels occlusions do occur. Unusual organs are involved and the clinical features depend on which organs are affected. Because of tissue necrosis, the Systemic Inflammatory Response ensues ("SIRS") and many patients develop ARDS. Despite seemingly adequate therapy (parenteral heparin, steroids, antibiotics), the mortality remains high (approximately 50%).

Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics.

Antiphospholipid antibodies (aPL) were originally detected in human serum almost 100 years ago when the Venereal Disease Research Laboratory (VDRL) test was described. A phospholipid called cardiolipin was the major tissue extract utilized in performing these tests. In 1983, cardiolipin was used for the first time as the antigen in solid-phase aPL specific assays for the now termed antiphospholipid syndrome (APS). Since then, many infections have been found to be associated with aPL positivity, although a pathogenic role for these antibodies was not usually obvious except in a few isolated cases.

The infectious etiology of the antiphospholipid syndrome: links between infection and autoimmunity.

Like many other autoimmune diseases, the antiphospholipid syndrome (APS) is considered as of a multifactorial etiology, mainly genetic susceptibility coinciding with environmental triggers, of which infectious agents are considered most prominent. Different clinical and experimental studies of the beta2 glycoprotein I (beta 2 GPI) molecule, one of the target autoantigens in APS, have linked infection to the development of APS. Using a peptide phage library, it has been shown that target epitopes of beta 2 GPI share similarities with common infectious pathogens. Also, circulating anti-beta 2 GPI antibodies have been identified in the sera of patients with different infectious conditions, and have been associated with various clinical APS manifestations. Molecular mimicry as a key mechanism linking infection and APS has been demonstrated in experimental models. In these studies, APS was induced by immunization of mice to various microbial pathogens. Anti-beta 2 GPI titers were found to be especially high following immunization with Haemophilus influenzae, Neisseria gonorrheae or tetanus toxoid. These findings contribute greatly to the understanding of APS pathogenesis, as well as create new directions for therapy modalities, namely specific peptide toleragens and antimicrobial treatment.

[Morphologic features of the gastric mucosa in systemic lupus erythematosus and antiphospholipid syndrome]. / Morfologicheskie osobennosti slizistoi obolochki zheludka pri sistemnoi krasnoi volchanke i antifosfolipidnom sindrome.

Morphology of gastric mucosa is characterized in the presence of Helicobacter pylori (HP) and Herpes viruses (HSV-1 and CMV). A total of 85 patients were examined (20 patients with primary APS and 65 with SLE). Chronic active gastritis was revealed in 85% patients with APS and 96% with SLE. 60% patients with APS and 45% with SLE had mucosal erosions. HP was detected in 70-87% of cases. Mixed infection of the gastric mucosa was observed in all the groups which was significantly associated with increased fibroblast and plasma cell number in the tunica propria. Tissue eosinophilia of the antral part of the stomach was observed in 39% of SLE patients. Glucocorticoid therapy was not associated with erosions and was combined with vascular thrombosis of gastric mucosa.

Beta-2-glycoprotein-I, infections, antiphospholipid syndrome and therapeutic considerations.

Evidence supports the association between infectious agents, antiphospholipid syndrome (APS), and the presence of antiphospholipid antibodies and anti-beta2-glycoprotein-I (beta2GPI) antibodies. Several mechanisms have been proposed to explain the role of bacteria/viruses in induction of an autoimmune condition, such as molecular mimicry between structures of a pathogen and self antigen and bystander activation or bacterial/viral superantigens. Protein databases reveal high homologies between the beta2GPI-related synthetic peptides and infectious agents. Studies employing experimental APS models proved molecular mimicry between beta2GPI-related synthetic peptides, which serve as target epitopes for anti-beta2GPI Abs, and structures within bacteria, viruses (e.g., CMV), and tetanus toxoid. Any explanation of how microbial infections might induce APS must take into account the genetic predisposition. In this paper, we discuss the association of antiphospholipid antibodies, infectious states, and molecular mimicry as a proposed mechanism for development of APS.

Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients.

OBJECTIVE: To describe and analyse the clinical characteristics of 100 patients with antiphospholipid syndrome (APS) associated with infections. METHODS: Patients were identified by a computer assisted search (Medline) of published reports to locate all cases of APS published in English, Spanish, and French from 1983 to 2003. The bilateral Fisher exact test was used for statistics. RESULTS: 59 female and 41 male patients were identified (mean (SD) age, 32 (18) years (range 1 to 78)): 68 had primary APS, 27 had systemic lupus erythematosus, two had "lupus-like" syndrome, two had inflammatory bowel disease, and one had rheumatoid arthritis. APS presented as a catastrophic syndrome in 40% of cases. The main clinical manifestations of APS included: pulmonary involvement (39%), skin involvement (36%), and renal involvement (35%; nine with renal thrombotic microangiopathy, RTMA). The main associated infections and agents included skin infection (18%), HIV (17%), pneumonia (14%), hepatitis C (13%), and urinary tract infection (10%). Anticoagulation was used in 74%, steroids in 53%, intravenous immunoglobulins in 20%, cyclophosphamide in 12%, plasma exchange in 12%, and dialysis in 9.6%. Twenty three patients died following infections and thrombotic episodes (16 with catastrophic APS). Patients given steroids had a better prognosis (p = 0.024). The presence of RTMA and requirement for dialysis carried a worse prognosis (p = 0.001 and p = 0.035, respectively). CONCLUSIONS: Various different infections can be associated with thrombotic events in patients with APS, including the potentially lethal subset termed catastrophic APS. Aggressive treatment with anticoagulation, steroids, and appropriate antibiotic cover is necessary to improve the prognosis.

Antiphospholipid syndrome infectious origin.

Antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta 2-glycoprotein-I (beta 2GPI). The factors causing production of anti-beta 2GPI remain unidentified, but an association with infectious agents has been reported. Studies on experimental APS models proved that molecular mimicry between beta 2GPI-related synthetic peptides and structures within bacteria, viruses, tetanus toxoid, and CMV are a cause for experimental APS. Any explanation of how microbial infections might set off APS must take into account the observation that all individuals appear to harbor potentially autoreactive lymphocytes, as well as natural antiphospholipid antibodies, but that these cells or antibodies remain innocuous unless somehow activated. Herein, we discuss the association of antiphospholipid antibodies in the infectious state, molecular mimicry as a proposed cause for development of APS, and the contribution of the database to this topic.

Membranous glomerulonephritis, antiphospholipid syndrome, and persistent low C3 levels associated with meningococcal disease.

A young male patient with a recent history of meningococcemia was referred to our hospital in his recovery period. He had signs suggesting deep venous thrombosis in the legs but no other abnormalities on physical examination at admission. Laboratory results showed proteinuria (3.1 g/day), prolonged activated partial thromboplastin time (56.3 s), low level of C3c (0.19 g/l), high titers of both IgM (27.04 MPLU/ml) and IgG (74.88 GPLU/ml) anticardiolipin antibodies and recanalized thrombotic changes in the deep veins of the lower extremities on venography. Histopathological diagnosis of the kidney disease was membranous glomerulonephritis. He was started on an angiotensin-converting enzyme inhibitor to reduce proteinuria and an oral anticoagulant to prevent thromboembolic events. Since no reduction in proteinuria was observed at the 10th month of therapy, the angiotensin-converting enzyme inhibitor was discontinued. On his last follow-up, approximately 1.5 years after meningococcemia, he had no complaints and no abnormal findings on physical examination. While both IgM and IgG anticardiolipin antibody titers returned to the normal range, he still had persistent proteinuria and hypocomplementemia.