Infections and vaccines in the etiology of antiphospholipid syndrome

Purpose of review: To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with ?2-glycoprotein I (?2-GPI) molecule. Recent findings: APS is characterized by the presence of pathogenic autoantibodies against ?2-GPI. The infection etiology of APS was well established. Likewise, a link between vaccination such as tetanus toxoid may trigger antibodies targeting tetanus toxoid and ?2-GPI, due to molecular mimicry between the two molecules. During the years, the pathogenic potential of anti-tetanus toxoid antibodies cross reactive with ?2-GPI were found to be pathogenic in animal models, inducing experimental APS. Summary: Accumulated evidence supports that the presence of anti-?2-GPI antibodies is associated with a history of infections and the main mechanism to explain this correlation is molecular mimicry. The relationship between tetanus toxoid vaccination and APS reveals a novel view on the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). © 2012 Wolters Kluwer Healt

The Homogeneous Multiplexed System-a New Method for Autoantibody Profile in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus

Background: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naive mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intracerebra-ventricularly (ICV) with the 16/6-Id antibody. Methods: C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. Results: 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. Conclusions: Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus

Tumor-Associated Disialylated Glycosphingolipid Antigen-Revealing Antibodies Found in Melanoma Patients' Immunoglobulin Repertoire Suggest a Two-Direction Regulation Mechanism Between Immune B Cells and the Tumor

There is far less information available about the tumor infiltrating B (TIL-B) cells, than about the tumor infiltrating T cells. We focused on discovering the features and potential role of B lymphocytes in solid tumors. Our project aimed to develop innovative strategies to define cancer membrane structures. We chose two solid tumor types, with variable to considerable B cell infiltration. The strategy we set up with invasive breast carcinoma, showing medullary features, has been introduced and standardized in metastatic melanoma. After detecting B lymphocytes by immunohistochemistry, VH-JH, Vκ-Jκ immunoglobulin rearranged V region genes were amplified by RT-PCR, from TIL-B cDNA. Immunoglobulin variable-region genes of interest were cloned, sequenced, and subjected to a comparative DNA analysis. Single-chain variable (scFv) antibody construction was performed in selected cases to generate a scFv library and to test tumor binding capacity. DNA sequence analysis revealed an overrepresented VH3-1 cluster, represented both in the breast cancer and the melanoma TIL-B immunoglobulin repertoire. We observed that our previously defined anti GD3 ganglioside-binder antibody-variable region genes were present in melanoma as well. Our antibody fragments showed binding potential to disialylated glycosphingolipids (GD3 ganglioside) and their O acetylated forms on melanoma cancer cells. We conclude that our results have a considerable tumor immunological impact, as they reveal the power of TIL-B cells to recognize strong tumor-associated glycosphingolipid structures on melanomas and other solid tumors. As tumor-derived gangliosides affect immune cell functions and reduce the B lymphocytes' antibody production, we suspect an important B lymphocyte and cancer cell crosstalk mechanism. We not only described the isolation and specificity testing of the tumor infiltrating B cells, but also showed the TIL-B cells' highly tumor-associated GD3 ganglioside-revealing potential in melanomas. The present data help to identify new cancer-associated biomarkers that may serve for novel cancer diagnostics. The two-direction regulation mechanism between immune B cells and the tumor could eventually be developed into an innovative cancer treatment strategy

Antiphospholipid Syndrome and Vaccines

Antiphospholipid syndrome (APS) is an autoimmune multisystemic disease associated with recurrent fetal loss, thromboembolic phenomena, thrombocytopenia, and neurological, cardiac, and dermatological involvement. APS is characterized by the presence of antiphospholipid antibodies, which bind negatively charged phospholipids, mainly through ?2-glycoprotein I (?2GPI). Tetanus toxoid (TTd) is a potent exotoxin produced by the bacterium Clostridium tetani. DNA hepatitis B virus (HBV) vaccination was given to 85 healthy students and, 1 month post-vaccination, a minority of individuals showed changes in IgG or IgM anticardiolipin and anti-?2GPI antibodies or lupus anticoagulant. Toplak et al. reported the presence of anti-?2GPI antibodies in 15% of 92 healthy medical workers up to 6 months post-influenza vaccination. Molecular mimicry has been proposed as one of the mechanisms by which experimental APS can occur in association with pathogens. © 2015 Wiley-Blackwell

Antiphospholipid Syndrome Patients Display Reduced Titers of Soluble CD21 in Their Sera Irrespective of Circulating Anti-β2-Glycoprotein-I Autoantibodies

A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The sCD21 is able to bind all known ligands such as CD23, sCD23, Epstein-Barr virus and C3d in immune complexes. Here, we show the serum levels of sCD21 in sera the of antiphospholipid syndrome (APS) patients. Antiphospholipid syndrome is an autoimmune disorder in which autoantibodies cause heart attack, stroke and miscarriage. Antiphospholipid syndrome may appear as primary or in association with systemic lupus erythromatosus (SLE) and other autoimmune diseases. Here, we ask whether APS patients have different sCD21 titers compared to healthy persons and whether sCD21 levels correlate with the presence of anti-β2-GPI autoantibodies. We show that autoimmune APS patients have significantly reduced amounts of sCD21 in their sera, irrespective of the presence of anti-β2-GPI autoantibodies. In our APS patients cohort additional SLE, vasculities, DVT (deep vein thrombosis), fetal loss or thrombosis did not correlate to the reduced level of sCD21

Infections and vaccines in the etiology of antiphospholipid syndrome

Purpose of review: To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with ?2-glycoprotein I (?2-GPI) molecule. Recent findings: APS is characterized by the presence of pathogenic autoantibodies against ?2-GPI. The infection etiology of APS was well established. Likewise, a link between vaccination such as tetanus toxoid may trigger antibodies targeting tetanus toxoid and ?2-GPI, due to molecular mimicry between the two molecules. During the years, the pathogenic potential of anti-tetanus toxoid antibodies cross reactive with ?2-GPI were found to be pathogenic in animal models, inducing experimental APS. Summary: Accumulated evidence supports that the presence of anti-?2-GPI antibodies is associated with a history of infections and the main mechanism to explain this correlation is molecular mimicry. The relationship between tetanus toxoid vaccination and APS reveals a novel view on the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). © 2012 Wolters Kluwer Healt

Shared pathogenicity features and sequences between EBV, SARS-CoV-2, and HLA class I molecule-binding motifs with a potential role in autoimmunity

Epstein-Barr virus (EBV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are extraordinary in their ability to activate autoimmunity as well as to induce diverse autoimmune diseases. Here we reviewed the current knowledge on their relation. Further, we suggested that molecular mimicry could be a possible common mechanism of autoimmunity induction in the susceptible individuals infected with SARS-CoV-2. Molecular mimicry between SARS-CoV-2 and human proteins, and EBV and human proteins, are present. Besides, relation of the pathogenicity associated with both coronavirus diseases and EBV supports the notion. As a proof-of-the-concept, we investigated 8mer sequences with shared 5mers of SARS-CoV-2, EBV, and human proteins, which were predicted as epitopes binding to the same human leukocyte antigen (HLA) supertype representatives. We identified significant number of human peptide sequences with predicted-affinities to the HLA-A*02:01 allele. Rest of the peptide sequences had predicted-affinities to the HLA-A*02:01, HLA-B*40:01, HLA-B*27:05, HLA-A*01:01, and HLA-B*39:01 alleles. Carriers of these serotypes can be under a higher risk of autoimmune response induction upon getting infected, through molecular mimicry-based mechanisms common to SARS-CoV-2 and EBV infections. We additionally reviewed established associations of the identified proteins with the EBV-related pathogenicity and with the autoimmune diseases