Molecular mimicry in Helicobacter pylori infections

Gram-negative bacteria Helicobacter pylori(H. pylori) colonize gastric mucosa in humans and increase the risk of serious diseases such as gastric and duodenal ulcers, stomach cancers and mucosa associated lymphoid tissue lymphoma. The role of H. pylori infection in the pathogenesis of several extragastric diseases has been suggested including immune thrombocytopenic purpura, iron deficiency anemia, vitamin D deficiency, cardiovascular diseases,diabetes mellitus and dermatological disorders. Also neurological diseases and even lung cancer have attracted researchers concern. The relation between H. pylori infection and a growth retardation in children has also been suggested. Many mechanisms of molecular mimicry between H. pylori and the host have been proposed as a pathogen strategy to manipulate the immune system of the host in order to remain unrecognized and avoid eradication. A lot of effort has been put into the demonstration of homologous sequences between H. pylori and host compounds. However, knowledge about how often autoantibodies or autoreactive T lymphocytes induced during H. pylori infections cause pathological disorders is insufficient. This review provides data on H. pylori antigenic mimicry and possible deleterious effects due to the induction of immune response to the components common to these bacteria and the host.

Molecular mimicry and multiple sclerosis

Multiple sclerosis （MS） is a chronic demyelinating disease of the central nervous system. Although the exact underlying mechanism leading to myelin destruction is unknown, the molecular mimicry theory is the most commonly acknowledged elucidation of MS pathology. Although various antigens have been associated with MS induction, this review presents studies focused on key bacterial and viral antigens that lead to the development of MS. The research specific to a molecular mimicry theory of MS via each implicated agent is weak; however, collectively the reports provide credible support for this theory. Given that homologous sequences are not required to lead to antigenic cross-reactivity, it is reasonable to conclude that certain viral and bacterial antigens with 5-10 similar amino acids in sequence can lead to self destruction of similar myelin sequences. Thus, this literature review has provided insight to further the understanding of the etiology of multiple sclerosis.

Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction

Since the early 1800s vaccines have saved numerous lives by preventing lethal infections.However,during the past two decades,there has been growing awareness of possible adverse events associated with vaccinations,cultivating heated debates and leading to significant fluctuations in vaccination rates.It is therefore pertinent for the scientific community to seriously address public concern of adverse effects of vaccines to regain public trust in these important medical interventions.Such adverse reactions to vaccines may be viewed as a result of the interaction between susceptibility of the vaccinated subject and various vaccine components.Among the implicated mechanisms for these reactions is molecular mimicry.Molecular mimicry refers to a significant similarity between certain pathogenic elements contained in the vaccine and specific human proteins.This similarity may lead to immune crossreactivity,wherein the reaction of the immune system towards the pathogenic antigens may harm the similar human proteins,essentially causing autoimmune disease.In this review,we address the concept of molecular mimicry and its application in explaining post vaccination autoimmune phenomena.We further review the principal examples of the influenza,hepatitis B,and human papilloma virus vaccines,all suspected to induce autoimmunity via molecular mimicry.Finally,we refer to possible implications on the potential future development of better,safer vaccines.

Hepatitis A vaccine associated with autoimmune hepatitis

To describe a case of probable relapsing autoimmune hepatitis associated with vaccination against hepatitis A virus （HAV）. A case report and review of literature were written concerning autoimmune hepatitis in association with hepatitis A and other hepatotropic viruses. Soon a^er the administration of formalin-inactivated hepatitis A vaccine, a man who had recently recovered from an uncharacterized but self-limiting hepatitic illness, experienced a severe deterioration （AST 1687 U/L, INR 1.4）. Anti-nuclear antibodies were detectable, and liver biopsy was compatible with autoimmune hepatitis. The observation supports the role of HAV as a trigger of autoimmune hepatitis. Studies in helper T-cell activity and antibody expression against hepatic proteins in the context of hepatitis A infection are summarized, and the concept of molecular mimicry with regard to other forms of viral hepatitis and autoimmunity is briefly explored.

Helicobacter pylori infection and other bacteria in pancreatic cancer and autoimmune pancreatitis

Helicobacter pylori(H.pylori)is an infectious agent influencing as much as 50%of the world’s population.It is the causative agent for several diseases,most especially gastric and duodenal peptic ulcer,gastric adenocarcinoma and mucosaassociated lymphoid tissue lymphoma of the stomach.A number of other,extragastric manifestations also are associated with H.pylori infection.These include neurological disorders,such as Alzheimer’s disease,demyelinating multiple sclerosis and Parkinson’s disease.There is also evidence for a relationship between H.pylori infection and such dermatological diseases as psoriasis and rosacea as well as a connection with infection and open-angle glaucoma.Generally little is known about the relationship between H.pylori infection and diseases of the pancreas.Most evidence about H.pylori and its potential role in the development of pancreatic diseases concerns pancreatic adenocarcinoma and autoimmune forms of chronic pancreatitis.There is data(albeit not fully consistent)indicating modestly increased pancreatic cancer risk in H.pylori-positive patients.The pathogenetic mechanism of this increase is not yet fully elucidated,but several theories have been proposed.Reduction of antral Dcells in H.pylori-positive patients causes a suppression of somatostatin secretion that,in turn,stimulates increased secretin secretion.That stimulates pancreatic growth and thus increases the risk of carcinogenesis.Alternatively,H.pylori,as a part of microbiome dysbiosis and the so-called oncobiome,is proven to be associated with pancreatic adenocarcinoma development via the promotion of cellular proliferation.The role of H.pylori in the inflammation characteristic of autoimmune pancreatitis seems to be explained by a mechanism of molecular mimicry among several proteins(mostly enzymes)of H.pylori and pancreatic tissue.Patients with autoimmune pancreatitis often show positivity for antibodies against H.pylori proteins.H.pylori,as a part of microbiome dysbiosis,also is viewed as a potential trigger of autoimmune inflammation of the pancreas.It is precisely these relationships(and associated equivocal conclusions)that constitute a center of attention among pancreatologists,immunologists and pathologists.In order to obtain clear and valid results,more studies on sufficiently large cohorts of patients are needed.The topic is itself sufficiently significant to draw the interest of clinicians and inspire further systematic research.Next-generation sequencing could play an important role in investigating the microbiome as a potential diagnostic and prognostic biomarker for pancreatic cancer.

Identification and Characterization of Peptide Mimics of Blood Group A Antigen

In order to investigate peptide mimics of carbohydrate blood group A antigen, a phage display 12-mer peptide library was screened with a monoclonal antibody against blood group A antigen, NaM87-1F6. The antibody-binding properties of the selected phage peptides were evaluated by phage ELISA and phage capture assay. The peptides were co-expressed as glutathione S-transferase （GST） fusion proteins. RBC agglutination inhibition assay was performed to assess the natural blood group A antigen-mimicking ability of the fusion proteins. The results showed that seven phage clones selected bound to NaM87-1F6 specifically, among which, 6 clones bore the same peptide sequence, EYWYCGMNRTGC and another harbored a different one QIWYERTLPFTF. The two peptides were successfully expressed at the N terminal of GST protein. Both of the fusion proteins inhibited the RBC agglutination mediated by anti-A serum in a concentration-dependent manner. These results suggested that the fusion proteins based on the selected peptides could mimic the blood group A antigen and might be used as anti-A antibody-adsorbing materials when immunoabsorption was applied in ABO incompatible transplantation.

Can Campylobacter jejuni play a role in development of celiac disease? A hypothesis

Celiac disease （CD） is an entropathy with malabsortive condition in which an allergic reaction to the cereal grain-protein （gluten） causes small intestine rnucosal injury. CD is a multifactorial disorder in which both genetic and environmental factors contribute to the disease development. Mechanisms have been described to explain the pathology of CD. T cells specific for multiple gluten peptides are found in virtually all patients. Generation of such a broad T cell response may be a prerequisite for disease development. CD is associated with multiple extraintestinal presentations, including neurological deficits. Recent studies have shown a significant correlation between anti-ganglioside antibodies and neurological disorders in patients with underlying CD. Gangliosides are glycosphingolipids which are abundant in nervous system and in other tissues including gastrointestinal tract. It is not known what triggers the release of anti-ganglioside antibodies in people with gluten sensitivity. But, the mechanism is likely to involve the intestinal immune system response to ingested gliadin, a component of wheat gluten. Studies showed that mechanisms different from gluten exposure may be implicated in antibody formation, and other environmental factors may also exist. In addition, considering the fact that genetic predisposition dysregulating mucosal immune responses in the presence of certain environmental triggers like gastrointestinal infections may be strong etiological factors for developing chronic intestinal inflammation including CD, the hypothesis raised in our mind that antiganglioside antibody formation in CD may play a role not only in development of neurological complications in celiac patients, but also in development of CD itself. As presence of Campylobacter jejuni in other diseases with antigangliosides antibody formation has been established, we propose the possible role of Campylobacter jejuni in development of CD in association with other genetic and environmental factors by the mechanism that molecular mimicry of gangliosides-like epitopes common to both lipo-polysacharide coats of certain strains of Campylobacter jejuni and gangliosides in cell structure of gastrointestinal mucosa may cause an autoimmune response and consequently lead to atrophy and degeneration of mucosa possibly by apoptosis.

Guillain-Barrésyndrome following hepatitis E

Guillain-Barrésyndrome(GBS)is often triggered by a preceding bacterial or viral infection.Occasionally,it has been observed in association with acute hepatitis A,B and C,and three cases have been previously described in India in which GBS was associated with acute hepatitis E.A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents,although the nature of the shared epitopes has not been characterized in most instances,including that in the case of hepatotropic viruses.We report a case of GBS following acute hepatitis E in a European individual.The presence of antiganglioside GM2 antibodies in this patient suggested molecular mimicry involving ganglioside GM2 in the pathogenesis of GBS associated with hepatitis E.

Accommodating the bacterial decoding release factor as an alien protein among the RNAs at the active site of the ribosome

The decoding release factor （RF） triggers termination of protein synthesis by functionally mimicking a tRNA to span the decoding centre and the peptidyl transferase centre （PTC） of the ribosome. Structurally, it must fit into a site crafted for a tRNA and surrounded by five other RNAs, namely the adjacent peptidyl tRNA carrying the completed polypeptide, the mRNA and the three rRNAs. This is achieved by extending a structural domain from the body of the protein that results in a critical conformational change allowing it to contact the PTC. A structural model of the bacterial termination complex with the accommodated RF shows that it makes close contact with the first, second and third bases of the stop codon in the mRNA with two separate loops of structure＂ the anticodon loop and the loop at the tip of helix orS. The anticodon loop also makes contact with the base following the stop codon that is known to strongly influence termination efficiency. It confirms the close contact of domain 3 of the protein with the key RNA structures of the PTC. The mRNA signal for termination includes sequences upstream as well as downstream of the stop codon, and this may reflect structural restrictions for specific combinations of tRNA and RF to be bound onto the ribosome together. An unbiased SELEX approach has been investigated as a tool to identify potential rRNA-binding contacts of the bacterial RF in its different binding conformations within the active centre of the ribosome.

Hypothesizing That Pediatric Autoimmune Neuropsychiatric Associated Streptococcal (PANDAS) Causes Rapid Onset of Reward Deficiency Syndrome (RDS) Behaviors and May Require Induction of “Dopamine Homeostasis”

Pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) is a concept that is used to characterize a subset of children with neuropsychiatric symptoms, tic disorders, or obsessive-compulsive disorder (OCD), whose symptoms are exacerbated by group A streptococcal (GAS) infection. PANDAS has been known to cause a sudden onset of reward deficiency syndrome (RDS). RDS includes multiple disorders that are characterized by dopaminergic signaling dysfunction in the brain reward cascade (BRC), which may result in addiction, depression, avoidant behaviors, anxiety, tic disorders, and/or OCD. According to research by Blum et al., the dopamine receptor D2 (DRD2) gene polymorphisms are important prevalent genetic determinants of RDS. The literature demonstrates that infections like Borrelia and Lyme, as well as other infections like group A beta-hemolytic streptococcal (GABHS), can cause an autoimmune reaction and associated antibodies target dopaminergic loci in the mesolimbic region of the brain, which interferes with brain function and potentially causes RDS-like symptoms/behaviors. The treatment of PANDAS remains controversial, especially since there have been limited efficacy studies to date. We propose an innovative potential treatment for PANDAS based on previous clinical trials using a pro-dopamine regulator known as KB220 variants. Our ongoing research suggests that achieving “dopamine homeostasis” by precision-guided DNA testing and pro-dopamine modulation could result in improved therapeutic outcomes.

Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference?

Virus infections have been implicated in both initiation of and protection from autoimmune diseases,such as type 1 diabetes(T1D).In this review we intend to reflect on recent evidence how viruses might on the one hand be involved in the pathogenesis of T1D and on the other hand induce a state of protection from autoimmune-mediated damage.It is important to acknowledge that human individuals encounter more than just one virus infection in their lifetime.Therefore,it is important to integrate more than just one possible environmental triggering factor for autoimmune diseases to occur.

Autoimmune Hepatitis Induced after Treatment of Syphilitic Hepatitis

We present a unique case of biopsy-proven syphilitic hepa-titis which presented as severe acute liver injury with sig-nificant elevation in aminotransferases and bilirubin,and improved with antibiotic therapy.However,the patient re-turned weeks after initial presentation with new-onset acute liver injury and had developed hypergammaglobulinemia,positive autoantibody titers,and repeat liver biopsy dem-onstrating interface hepatitis,supporting a diagnosis of autoimmune hepatitis.He had an otherwise unrevealing etiologic workup,and responded to glucocorticoid therapy.We believe that syphilitic hepatitis and its treatment sub-sequently triggered an immunogenic response,leading to autoimmune hepatitis.Autoimmune hepatitis is a chronic liver disease thought to manifest as a result of predisposing genetic factors in combination with environmental insults,especially hepatotropic pathogens.Syphilis is a sexually transmitted disease caused by Treponema pallidum that has been associated with autoimmunity and the develop-ment of autoantibodies.We propose that in the setting of syphilitic hepatitis,a molecular mimicry event resulting from structural similarities between T.pallidum and liver antigens,as well as impaired regulatory T-cell function,led to the breakdown of immune tolerance and the onset of au-toimmune hepatitis.To support this hypothesis,further mo-lecular analyses and case series are necessary to determine if syphilitic hepatitis and its treatment are risk factors for the onset of autoimmune hepatitis.Autoimmune hepatitis should be considered early as the cause of acute liver injury in susceptible patients with risk factors for the disease,as prompt recognition and appropriate treatment may prevent progression of liver injury and result in improved outcomes.

Impact of pretransplant asplenia vaccination on anti-A/B antibody titers in prospective ABO incompatible kidney transplant recipients

Background:Asplenia vaccination is employed before ABO-incompatible(ABOi)transplantation in case splenectomy is needed.Pneumococcal vaccines have been reported,in different patient groups,to increase anti-A/B titers,through cross-reactivity to shared polysaccharide epitopes.We investigated the impact of pretransplant asplenia vaccinations on anti-A/B antibody titers in prospective ABOi renal transplant recipients.Methods:Published asplenia vaccine microbial structures were reviewed to assess expression of A/B antigens.All patients who underwent ABOi transplantation at Monash Medical Centre with anti-A/B titers taken either side of asplenia vaccination were included in a retrospective cohort study between 2007 and 2021.Patients with paired titers without intervening vaccination were included as controls.Paired titers were compared within groups.Results:A and B antigens were found to be expressed by vaccine specific pneumococcal serotypes.Thirty-nine ABOi renal transplant recipients received vaccination including at least one pneumococcal vaccine.The most common donor to recipient combination was A1 to O.The median pre-and postvaccination anti-A/B titers were 1:32 and there was no significant change in titers following vaccination(median change in titer 0 dilutions,range–2 to 3,P=0.43).The same findings were apparent in the control group(n=20).There was no significant change in titer by donor blood group or vaccine type.No transplants were canceled or delayed by a rise in anti-A/B titers postvaccination.Conclusion:Pneumococcal vaccination had no clinically relevant impact on anti-A/B titers before ABOi transplantation in this cohort.These results provide reassurance regarding the safety of asplenia vaccination before ABOi transplantation.