Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer.

Natural killer (NK) cells and cytotoxic T (CD8+) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8+ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8+ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56+CD16dim, CD56dimCD16+, CD57+, and CD57+CD16+ NK cells, the NKT, CD57+CD8+, and KIR+CD8+ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8+ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.

Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach.

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid ß peptide, ß catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.

Cross-sectional analysis reveals autoantibody signatures associated with COVID-19 severity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients.

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID.

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

Reaction of SARS-CoV-2 antibodies with other pathogens, vaccines, and food antigens.

It has been shown that SARS-CoV-2 shares homology and cross-reacts with vaccines, other viruses, common bacteria and many human tissues. We were inspired by these findings, firstly, to investigate the reaction of SARS-CoV-2 monoclonal antibody with different pathogens and vaccines, particularly DTaP. Additionally, since our earlier studies have shown immune reactivity by antibodies made against pathogens and autoantigens towards different food antigens, we also studied cross-reaction between SARS-CoV-2 and common foods. For this, we reacted monoclonal and polyclonal antibodies against SARS-CoV-2 spike protein and nucleoprotein with 15 different bacterial and viral antigens and 2 different vaccines, BCG and DTaP, as well as with 180 different food peptides and proteins. The strongest reaction by SARS-CoV-2 antibodies were with DTaP vaccine antigen, E. faecalis, roasted almond, broccoli, soy, cashew, α+ß casein and milk, pork, rice endochitinase, pineapple bromelain, and lentil lectin. Because the immune system tends to form immune responses towards the original version of an antigen that it has encountered, this cross-reactivity may have its advantages with regards to immunity against SARS-CoV-2, where the SARS-CoV-2 virus may elicit a "remembered" immune response because of its structural similarity to a pathogen or food antigen to which the immune system was previously exposed. Our findings indicate that cross-reactivity elicited by DTaP vaccines in combination with common herpesviruses, bacteria that are part of our normal flora such as E. faecalis, and foods that we consume on a daily basis should be investigated for possible cross-protection against COVID-19. Additional experiments would be needed to clarify whether or not this cross-protection is due to cross-reactive antibodies or long-term memory T and B cells in the blood.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens.

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called "the autoimmune virus." We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.

Cross-Reactivity and Sequence Homology Between Alpha-Synuclein and Food Products: A Step Further for Parkinson's Disease Synucleinopathy.

INTRODUCTION: Parkinson's disease is characterized by non-motor/motor dysfunction midbrain neuronal death and α-synuclein deposits. The accepted hypothesis is that unknown environmental factors induce α-synuclein accumulation in the brain via the enteric nervous system. MATERIAL AND METHODS: Monoclonal antibodies made against recombinant α-synuclein protein or α-synuclein epitope 118-123 were applied to the antigens of 180 frequently consumed food products. The specificity of those antibody-antigen reactions was confirmed by serial dilution and inhibition studies. The Basic Local Alignment Search Tool sequence matching program was used for sequence homologies. RESULTS: While the antibody made against recombinant α-synuclein reacted significantly with 86/180 specific food antigens, the antibody made against α-synuclein epitope 118-123 reacted with only 32/180 tested food antigens. The food proteins with the greatest number of peptides that matched with α-synuclein were yeast, soybean, latex hevein, wheat germ agglutinin, potato, peanut, bean agglutinin, pea lectin, shrimp, bromelain, and lentil lectin. Conclusions: The cross-reactivity and sequence homology between α-synuclein and frequently consumed foods, reinforces the autoimmune aspect of Parkinson's disease. It is hypothesized that luminal food peptides that share cross-reactive epitopes with human α-synuclein and have molecular similarity with brain antigens are involved in the synucleinopathy. The findings deserve further confirmation by extensive research.

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases I: Toxic Chemicals and Food.

Autoimmune diseases affect 5-9% of the world's population. It is now known that genetics play a relatively small part in the pathophysiology of autoimmune disorders in general, and that environmental factors have a greater role. In this review, we examine the role of the exposome, an individual's lifetime exposure to external and internal factors, in the pathophysiology of autoimmune diseases. The most common of these environmental factors are toxic chemicals, food/diet, and infections. Toxic chemicals are in our food, drink, common products, the air, and even the land we walk on. Toxic chemicals can directly damage self-tissue and cause the release of autoantigens, or can bind to human tissue antigens and form neoantigens, which can provoke autoimmune response leading to autoimmunity. Other types of autoimmune responses can also be induced by toxic chemicals through various effects at the cellular and biochemical levels. The food we eat every day commonly has colorants, preservatives, or packaging-related chemical contamination. The food itself may be antigenic for susceptible individuals. The most common mechanism for food-related autoimmunity is molecular mimicry, in which the food's molecular structure bears a similarity with the structure of one or more self-tissues. The solution is to detect the trigger, remove it from the environment or diet, then repair the damage to the individual's body and health.

Reaction of Lectin-Specific Antibody with Human Tissue: Possible Contributions to Autoimmunity.

The aim of this study was to examine the direct reaction of specific lectin/agglutinin antibodies to different tissue antigens to confirm the theory that reactivity between them may contribute to autoimmunities. Lectins are carbohydrate-binding proteins found in nearly all fruits and vegetables. Undigested lectins can penetrate the gut barriers, provoking an immune response that results in the production of antibodies against them. Using an enzyme-linked immunosorbent assay, we reacted lectin-specific antibodies with 62 different tissue antigens. Wheat germ agglutinin-specific antibody was the most reactive with the tissue antigens (37 tissues out of 62), followed by red kidney bean phytohemagglutinin-specific antibody (20), soybean agglutinin-specific antibody (20), and peanut agglutinin-specific antibody (15). This reaction between anti-lectin antibodies and many human tissue antigens may be due to possible molecular mimicry and cross-reactivity. After our results confirmed that anti-lectin antibodies bind with human tissues, we wanted to determine the prevalence of these antibodies in the blood of 500 nominally healthy donors. The percentage elevation of antibodies against different lectins ranged from 12 to 16% (Immunoglobulin G), 9.7-14.7% (Immunoglobulin A), 12-18% (Immunoglobulin M), and 7.8-14.6% (Immunoglobulin E). Serial dilutions and inhibition study confirmed that these reactions were specific. Finally, we tested the lectin-specific antibody level in sera both negative and positive for RF and ANA and found that IgM anti-lectin antibody levels were highly correlated with RF but not with ANA level. The reaction of anti-lectin antibodies with human tissue components and their detection in RF-positive samples may describe mechanisms by which the production of antibodies against undigested lectins may contribute to the pathogenesis of some autoimmune diseases.

Correlation between Antibodies to Bacterial Lipopolysaccharides and Barrier Proteins in Sera Positive for ASCA and ANCA.

Individuals with intestinal barrier dysfunction are more prone to autoimmunity. Lipopolysaccharides (LPS) from gut bacteria have been shown to play a role in systemic inflammation, leading to the opening of the gut and blood-brain barrier (BBB). This study aims to measure antibodies against LPS and barrier proteins in samples positive for anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) and compare them with these same antibodies in controls to determine whether a correlation between LPS and barrier proteins could be found. We obtained 94 ASCA- and 94 ANCA-positive blood samples, as well as 188 blood samples from healthy controls. Samples were assessed for antibodies to LPS, zonulin+occludin, S100B, and aquaporin-4 (AQP4). Results show significant elevation in antibodies in about 30% of ASCA- and ANCA-positive sera and demonstrate positive linear relationships between these antibodies. The findings suggest that individuals positive for ASCA and ANCA have increased odds of developing intestinal and BBB permeability compared to healthy subjects. The levels of LPS antibodies in both ASCA- and ANCA-positive and negative specimens showed from low and moderate to high correlation with antibodies to barrier proteins. This study shows that LPS, by damaging the gut and BBBs, contribute to the extra-intestinal manifestation of IBD. We conclude that IBD patients should be screened for LPS antibodies in an effort to detect or prevent possible barrier damage at the earliest stage possible to abrogate disease symptoms in IBS and associated disorders.

Interaction between food antigens and the immune system: Association with autoimmune disorders.

It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.

Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins With Tissue Antigens: Implications for Autoimmune Diseases.

We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.

Reaction of antibodies to Campylobacter jejuni and cytolethal distending toxin B with tissues and food antigens.

BACKGROUND: The bacteria Campylobacter jejuni (C. jejuni) is commonly associated with Guillane-Barré syndrome (GBS) and irritable bowel syndrome (IBS), but studies have also linked it with Miller Fisher syndrome, reactive arthritis and other disorders, some of which are autoimmune. It is possible that C. jejuni and its toxins may be cross-reactive with some human tissues and food antigens, potentially leading to autoimmune responses. AIM: To measure the immune reactivity of C. jejuni and C. jejuni cytolethal distending toxin (Cdt) antibodies with tissue and food antigens to examine their role in autoimmunities. METHODS: Using enzyme-linked immunosorbent assay (ELISA) methodology, specific antibodies made against C. jejuni and C. jejuni Cdt were applied to a variety of microwell plates coated with 45 tissues and 180 food antigens. The resulting immunoreactivities were compared to reactions with control wells coated with human serum albumin (HSA) which were used as negative controls and with wells coated with C. jejuni lysate or C. jejuni Cdt which served as positive controls. RESULTS: At 3 SD above the mean of control wells coated with HSA or 0.41 OD, the mouse monoclonal antibody made against C. jejuni showed moderate to high reactions with zonulin, somatotropin, acetylcholine receptor, ß-amyloid and presenilin. This immune reaction was low with an additional 25 tissue antigens including asialoganglioside, and the same antibody did not react at all with another 15 tissue antigens. Examining the reaction between C. jejuni antibody and 180 food antigens, we found insignificant reactions with 163 foods but low to high immune reactions with 17 food antigens. Similarly, we examined the reaction of C. jejuni Cdt with the same tissues and food antigens. The strongest reactions were observed with zonulin, intrinsic factor and somatotropin. The reaction was moderate with 9 different tissue antigens including thyroid peroxidase, and reaction was low with another 10 different antigens, including neuronal antigens. The reaction of C. jejuni Cdt antibody with an additional 23 tissue antigens was insignificant. Regarding the reaction of C. jejuni Cdt antibody with different food antigens, 160 out of 180 foods showed insignificant reactions, while 20 foods showed reactions ranging from low to high. CONCLUSION: Our findings indicate that C. jejuni and its Cdt may play a role in inflammation and autoimmunities beyond the gut.

Immune reactivity against a variety of mammalian milks and plant-based milk substitutes.

The research reported here seeks to evaluate the allergenicity and antigenicity of different mammalian and plant-based milks/milk substitutes in healthy subjects. We used ELISA to measure IgE and IgG antibodies against cow, goat, sheep, camel, human milks, and soy, almond, and coconut plant-based milk substitutes, as well as IgA antibodies against all these apart from human milk, in 500 individuals in order to find the percentage of antibody elevation. IgG and IgE positivity showed that human milk was the least antigenic and allergenic, followed by camel milk. Cow's milk showed the highest percentage of elevation or reactivity. Among plant-based milk substitutes, the almond-based substitute was the most allergenic with the highest IgE reactivity, while the coconut milk substitute was lowest. For IgG and IgA immuno-reactivity, soy was first, with coconut again the lowest. We found IgE and IgG immune reactivity against coconut, almond and soymilks in some individuals who were non-reactive to mammalian milk, therefore, we should not assume that consumption of these milks is automatically without risk of allergenic response. We selected 24 samples out of the original 500 for the measurement of IgE antibodies against five different types of cow's milk, from non-organic to organic, A1 and A2. Statistical variance analysis detected no significant difference in IgE, IgG and IgA immune reactivities of the five different cow milks. Our results showed that if an individual is immuno-reactive to cow's milk, organic or not, the probability of reacting to goat and sheep milk is very high. Overall, the results presented here showed that for individuals allergic to cow's milk, the least allergenic alternatives in descending order are human, camel, sheep, and goat milks. Before choosing an alternative for cow's milk, one must go through accurate and quantitative blood testing for determination of IgE, IgG and IgA antibodies against different mammalian and plant-based milks/milk substitutes.

Amyloid-Beta 1-42 Cross-Reactive Antibody Prevalent in Human Sera May Contribute to Intraneuronal Deposition of A-Beta-P-42.

Antibodies against many neural antigens are detected in the sera of both patients with Alzheimer's disease (AD) and some healthy individuals. Blood-brain barrier dysfunction could make it possible for brain-reactive autoantibodies to reach the brain, where they can react with amyloid ß peptide (AßP). The origin of these autoreactive antibodies in the blood is unclear. The goals of this study were as follows: (1) to examine the immune reactivity of anti-AßP-42 with 22 neuronal and other associated antigens, some of which are involved in the pathophysiology of AD; (2) to classify antibodies to these 22 different antigens into those that cross-react with AßP-42 and those that do not; (3) to determine whether these antibodies react with BBB proteins, nerve growth factors, and enteric neuronal antigens. Using monoclonal AßP-42 antibody and ELISA methodology, we found that the antibody was highly reactive with Aß protein, tau protein, presenilin, rabaptin-5, ß-NGF, BDNF, mTG, and enteric nerve. The same antibody produced equivocal to moderate reactions with glutamate-R, S100B, AQP4, GFAP, MBP, α-synuclein, tTG-2, and tTG-3, and not with the rest. These antibodies were also measured in blood samples from 47 AD patients and 47 controls. IgG antibodies were found to be elevated against AßP-42 and many other antigens in a significant percentage of controls. Overall, the mean OD values were significantly higher against 9/23 tested antigens (p <0.001) in the samples with AD. We were indeed able to classify the detected neuronal antibodies into those that cross-react with AßP-42 and those that do not. Our main finding is that although these antibodies may be harmless in a subgroup of controls, in individuals with compromised BBBs these antibodies that cross-react with AßP-42 can reach the brain, where their cross-reactivity with AßP-42 may contribute to the onset and progression of AD, and perhaps other neurodegenerative disorders.

Reaction of Amyloid-ß Peptide Antibody with Different Infectious Agents Involved in Alzheimer's Disease.

As early as the 1980s, molecular virologist Ruth Itzhaki began to investigate if there was a causal connection between infections and neurodegenerative disorder. Although the theory has yet to be universally embraced, in 2016 Itzhaki and 33 other scientists from all over the world published a review article in this very journal presenting evidence for the causal role of pathogens in Alzheimer's disease (AD). Exactly how and in what way pathogens affect the induction of AD has yet to be determined, but one possible answer may involve the cross-reactivity of different pathogens with amyloid-ß (Aß). Aß autoantibodies have been detected in the serum and cerebrospinal fluid of AD patients and in some healthy individuals. In the present study our major goal was to investigate whether antibodies made against Aß would react both with other brain proteins as well as pathogens associated with AD as a result of molecular mimicry or the binding of bacterial toxins to Aß42. Our study used a specific monoclonal antibody made against Aß42, which not only reacted strongly with Aß42, tau protein, and α-synuclein, but also had from weak to strong reactions with 25 different pathogens or their molecules, some of which have been associated with AD. The homology between peptide stretches of microbial origin and proteins involved in AD could be a mechanism by which antibodies to homologous peptides mount attacks against autoantigens in AD. We concluded that bacterial molecules bind to Aß protein, forming small oligomers, then encasing pathogens and their molecules to form amyloid plaques, the tell-tale markers of AD. Conversely, these same Aß peptides induce the production of antibodies to both Aß42 and bacterial molecules, which may inhibit bacterial pathogenesis, but in the process may promote amyloid plaque formation.

Fluctuation of zonulin levels in blood vs stability of antibodies.

AIM: To evaluate the measurement of zonulin level and antibodies of zonulin and other tight junction proteins in the blood of controls and celiac disease patients. METHODS: This study was conducted to assess the variability or stability of zonulin levels vs IgA and IgG antibodies against zonulin in blood samples from 18 controls at 0, 6, 24 and 30 h after blood draw. We also measured zonulin level as well as zonulin, occludin, vinculin, aquaporin 4 and glial fibrillary acidic protein antibodies in the sera of 30 patients with celiac disease and 30 controls using enzyme-linked immunosorbent assay methodology. RESULTS: The serum zonulin level in 6 out of 18 subjects was low or < 2.8 ng/mL and was very close to the detection limit of the assay. The other 12 subjects had zonulin levels of > 2.8 ng/mL and showed significant fluctuation from sample to sample. Comparatively, zonulin antibody measured in all samples was highly stable and reproducible from sample to sample. Celiac disease patients showed zonulin levels with a mean of 8.5 ng/mL compared to 3.7 ng/mL in controls (P < 0.0001). Elevation of zonulin level at 2SD above the mean was demonstrated in 37% of celiac disease patients, while antibodies against zonulin, occludin and other tight junction proteins was detected in up to 86% of patients with celiac disease. CONCLUSION: Due to its fluctuation, a single measurement of zonulin level is not recommended for assessment of intestinal barrier integrity. Measurement of IgG and IgA antibodies against zonulin, occludin, and other tight junction proteins is proposed for the evaluation of the loss of intestinal barrier integrity.

The Gut-Brain Axis: Autoimmune and Neuroimmune Disorders.

No Abstract Available.

Right to left shunting through communications between the left superior intercostal vein tributaries and the left atrium: a potential cause of paradoxical embolism.

OBJECTIVES: To investigate the role of collateral venous pathways between the left brachiocephalic vein (LBV) and the left atrium through an arcade comprising the left superior intercostal vein (LSICV), left vertical vein (LVV), and pulmonary veins as a potential cause of paradoxical embolism. METHODS: A retrospective search was performed to find symptomatic patients with negative work up for paradoxical emboli whose chest CT or MR angiography by left arm contrast injection showed a visible right to left shunt through the LSICV/LVV collateral pathway (symptomatic group). We also evaluated the characteristics of this collateral pathway in 150 chest CT angiographies from general referrals (comparison group). RESULTS: We found 7 symptomatic patients. Initial presentations included neurological symptoms in all patients and episodes of hypoxemia in three patients. Communications between the LBV and left atrium through the LSICV/LVV pathway was seen is all 7 cases and confirmed by transesophageal echocardiography in two. An abnormal LBV was seen in 6 cases (absence in one, stenosis in 5). Moderate superior vena cava stenosis was seen in one and acute right subclavian vein thrombosis in one. Six patients had past history of an upper extremity central line placement. In the comparison group, LSICV was seen in 73 (48%), connecting to the hemiazygos vein in 41, to a LVV in 19 and to the left atrium in 7. CONCLUSION: LSICV/LVV collaterals are common and can be a potential route for paradoxical emboli especially when stenosis of a draining vein such as LBV exists.

Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease.

Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.