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Antigen molecular mimicry

Antigen molecular mimicry


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Let us consider a situation in which the body is attacked by a microbe, and the microbe is captured by the immune system for recognition of surface antigens. The surface antigen recognized mimics one of our self antigens. It is stated in textbooks that this situation results in the immune system attacking the microbe along with the tissue containing the self antigen(auto-immunity).
(Reference: Robbins and Cotran pathologic basis of disease)

If a microbial antigen mimicks self antigen, why is the microbial antigen attacked instead of being ignored in the way that all our self antigens are ignored by our immune system?


There are different type of immune cells which falls under either innate or adaptive system.

The cells under the innate are first to respond microbial attack and are able to detect them in extracellular environment by recognizing proteins/peptides called Pathogen-associated Molecular Patterns (PAMPs) on their surfaces; these are only found on microbes.

But when the innate system fails to clear the microbes in time, the adaptive system is kicked-in. This involves T-lymphocytes and B-lymphocytes. T-lymphocytes are trained to ignore cells that are able demonstrated that they self but B-lymphocytes which produces antibodies/immunoglobulins to the detected antigens do not have a mechanism of ignoring self cells.

So the problem lies with when the immune response gets to the point where antibodies are produced, at that point produced antibodies simply attack without discrimination.

I hope this simplified version would help you.


Coronavirus associated molecular mimicry common to SARS-CoV-2 peptide

Relationship of COVID-19 and immunity is complex and can involve autoimmune reactions through molecular mimicry. We investigated autoimmunity related pathological mechanisms involving molecular mimicry that are common to certain coronaviruses, including SARS-CoV-2, by means of a selected peptide sequence (CFLGYFCTCYFGLFC). Accordingly, coronavirus-associated sequences that are homologous to that 15mer sequence in the SARS-CoV-2 proteome are attained first. Then, homologous human and coronavirus sequences are obtained, wherein the coronavirus sequences are homologous to the 15mer SARS-CoV-2 peptide. All the identified query-subject sequences contained at least 7 residue matches in the aligned regions. Finally, parts of those coronavirus and host sequences, which are predicted to have high affinity to the same human leukocyte antigen (HLA) alleles as that of the SARS-CoV-2 sequence, are selected among the query and subject epitope-pairs that were both (predicted to be) strongly binding to the same HLA alleles. The proteins or the protein regions with those predicted epitopes include, but not limited to, immunoglobulin heavy chain junction regions, phospholipid phosphatase-related protein type 2, slit homolog 2 protein, and CRB1 isoform I precursor. These proteins are potentially associated with certain pathologies, but especially the possible CRB1 related coronavirus pathogenicity could be furthered by autoimmunity risk in HLA*A24:02 serotypes. Overall, results imply autoimmunity risk in COVID-19 patients with HLA*A02:01 and HLA*A24:02 serotypes in general, through molecular mimicry. This is also common to other coronaviruses than SARS-CoV-2. These results are indicative at the current stage, they need to be validated. Yet, they can pave the way to autoimmunity treatment options to be used in COVID-19 and its associated diseases.


Molecular mimicry

  • Reproductive abnormalities, including “ovarian dysgenesis, anovulation and male infertility, altered gene expression during oogenesis, premature ovarian failure, diminished ovarian reserve, accelerated primordial follicle loss, oocyte DNA damage, as well as susceptibility to breast/ovarian cancer” and “disorders in spermatogenesis, sperm-egg fusion, or spermatid maturation and male infertility” , including “epilepsy, schizophrenia, bipolar disorder, depression, and brain cancer” manifestations , including “altered control of the vascular dynamics, pain, fevers associated with the menstrual cycle, depression, hypotension, and dysregulation of blood pressure” , including “cardiac autoimmunity and sudden unexplained death”

The role of adjuvants

As Kanduc and Schoenfeld state, the HPV-human protein overlap documented in their study is not unique to HPV many other microbial sequences share significant commonalities with human proteins as well. Because the overlap is so widespread, some researchers are skeptical of cross-reactivity and dismiss it as more “fantasy” than “fact.” To explain why cross-reactivity is plausible in the context of vaccination, the two authors describe, in other publications, another important piece of the puzzle: vaccine adjuvants and comparable environmental “stimuli.” In fact, they argue, the “sole purpose” of a vaccine adjuvant is to gin up an immune response that otherwise would be unlikely to occur—and when the adjuvant is paired with foreign peptides that are similar to human peptides, a “reasonable outcome may be the development of crossreactivity and autoimmunity.”…

I think the authors are missing an important factor here. The timing of adjuvant injection determines what proteins the body considers to be foreign. Whatever proteins are circulating at the time is what’s important, regardless of whether they’re endogenous or a vaccine ingredient. The establishment is consciously using this fact in anti-fertility vaccines:

There are at least two plausible mechanisms by which vaccines are probably linked to the explosion in transgenderism: the induction of autoimmune reactions to endogenous hormones (per the above), and homologous recombination and chimerization of sex-related chromosomes via vaccine contamination with fetal dna. See the articles below. This is nazi science for nazi purposes.


Author information

Affiliations

Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

Yasushi Uemura, Satoru Senju, Shinji Fujii, Leo Kei Iwai, Hiroki Tabata, Takayuki Kanai, Yu-Zhen Chen & Yasuharu Nishimura

Department of Respiratory Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto, Japan

Laboratory of Immunology, Heart Institute (Incor), University of Sao Paulo Medical School, Sao Paulo, Brazil

Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan


Antigen molecular mimicry - Biology

IDIOTOPES are antigenic determinants, unique to an antibody or group of antibodies, defined by the reaction of anti-idiotopic antibodies with the antibodies bearing the idiotopes. The ensemble of idiotopes of an antibody constitutes its idiotype. Idiotypes are useful as markers to follow specific antibodies and clones of cells in immune responses and the inheritance of immunoglobulin genes. As external antigens and anti-idiotypic antibodies can competitively bind the combining site of specific antibodies, some anti-idiotypic antibodies may resemble the external antigen, thus mimicking its structure. It has been proposed 1-5 that an anti-idiotypic antibody, anti-anti-X, may resemble the external antigen X and thus carry its 'internal image', but this idea is not unequivocally supported by the three-dimensional structures of anti-idiotopic antibodies 6-9 , either because the structures of the external antigen8 or of the anti-idiotopic antibody 7 were unknown, or because the anti-idiotopic antibodies showed no resemblance to the external antigens 6,9 (reviewed in ref. 10). Functional mimicry of ligands of biological receptors by anti-idiotypic antibodies has been described in several systems (reviewed in ref. 11). But how closely can antibodies mimic antigens at the molecular level? Here we present the crystal structure of an idiotope-anti-idiotope complex between the Fv fragments of the anti-lysozyme antibody D1.3 and the anti-D1.3 antibody E5.2. D1.3 contacts the antigen, lysozyme and the anti-idiotopic E5.2 through essentially the same combining-site residues. In addition, E5.2 interacts with D1.3, making contacts similar to those between lysozyme and D1.3. Thus, the anti-idiotopic antibody E5.2 mimics lysozyme in its binding interactions with D1.3. Validating these observations, E5.2, used as an immu-nogen, induces an anti-lysozyme response.


Molecular mimicry

Scientists view autoimmunity as the prolonged and pathological response that arises when the immune system gets confused between “self” and “non-self” due to molecular similarities between an environmental agent and the host. The specific hypothesis—called molecular mimicry—is that “either a virus or bacteria…initiate and exacerbate an autoimmune response through sequence or structural similarities with self-antigens.”

Although the molecular mimicry concept has been floating around for at least three decades, relatively few researchers have been willing to make the conceptual leap to inquire whether the viral or bacterial antigens in vaccines provoke the same pathological response. In their Pathobiology study, however, the two authors—Drs. Darja Kanduc (Italy) and Yehuda Shoenfeld (Israel)—do just that, looking at HPV through the lens of both HPV infection and “active immunization.” Using cutting-edge molecular biology techniques to look at matching peptide sequences in HPV “epitopes” and human proteins, Kanduc and Shoenfeld examine epitopes from 15 different HPV types, including eight of the nine types included in Gardasil 9. (An epitope is the portion of an antigen capable of stimulating an immune response.)

Confirming that there is an “impressively high extent” of peptide sharing between HPV epitopes and human proteins, the two authors then outline numerous pathological implications of their results, giving examples of “human proteins that—when hit by cross-reactions generated by HPV infection/active immunization—may associate with diseases and autoimmune manifestations.” The latter include:

    , including “ovarian dysgenesis, anovulation and male infertility, altered gene expression during oogenesis, premature ovarian failure, diminished ovarian reserve, accelerated primordial follicle loss, oocyte DNA damage, as well as susceptibility to breast/ovarian cancer” and “disorders in spermatogenesis, sperm-egg fusion, or spermatid maturation and male infertility” , including “epilepsy, schizophrenia, bipolar disorder, depression, and brain cancer” manifestations , including “altered control of the vascular dynamics, pain, fevers associated with the menstrual cycle, depression, hypotension, and dysregulation of blood pressure” , including “cardiac autoimmunity and sudden unexplained death”

Discussion

Low-affinity self-reactive T cells are found in the body where these autoreactive T cells are normally controlled. These pre-existing, self-reactive T cells can be activated in response to similar antigens from environmental microbes and/or food and become pathogenic under certain circumstances.

Molecular mimicry of environmental antigens in conjunction with the ability of T cells to escape immune tolerance has been suggested as a potential mechanism for the pathogenesis not only of autoimmune uveitis but also of other autoimmune diseases, including: multiple sclerosis, diabetes mellitus and spondylarthropathies (10).

Retinal autoantigens are sequestered behind the BRB (1, 2) and therefore normally invisible for naïve T cells. Since only activated T-lymphocytes can pass the BRB and enter the eye their primary activation must be extraocular.

The activation of pattern recognition receptors (PRR) by pathogens is a prerequisite for the initiation of an immune response, however, this is lacking for usually tolerizing food proteins. In that situation we proposed a concomitant infection with the presentation of the food antigen (33), leading to an erroneous bystander activation of effector T cells instead of (oral) tolerance induction. For example to orally induce EAU with milk casein we used Cholera toxin for the activation of PRR in the gut-associated lymphoid tissue (GALT) (34).

Interestingly, in addition to peripheral activation, which enables the T cells to pass the BRB, the barrier itself and the passage of the T cells through the barrier seemed to be essential for the pathogenicity of the T cells, since intravitreal injection of autoreactive T cells does not cause inflammation (35).

Autoimmune uveitis is mediated by CD4 + Th cells which recognized peptide presented on MHC class II molecules. For an antigen recognition the minimum prerequisite is the binding of the antigen peptide to the presenting MHC molecule and the subsequent recognition of this complex by a TCR. Crossreactivity of antigen peptides could be observed either with partially overlapping consecutive amino acid sequences, identities between ocular antigens and viral or bacterial proteins (4, 5, 11�, 36) or by discontinuous sequence homologies with amino acids at respective positions to anchor the peptide to the MHC and also to bind to the TCR (6) (Figure 1). The interactions between antigen peptides, presenting MHC and TCR are based on charges of amino acid side chains, hydrogen bonds and complementary structures. Even a peptide with structural homology but not sharing identical/similar amino acids can be sufficient for antigenic mimicry (10, 37), thus complicating the search and definition of mimotopes.

While Wucherpfennig and Strominger could demonstrate antigenic mimicry with similar peptides at the clonal level of T cells (38), a certain T cell might also express a second T cell receptor, one recognizing a foreign peptide and the other a self peptide (39, 40). We have shown a cross-reactivity on the T cell population level (41), but we could not prove the use of a certain single T cell receptor to crossreact with peptides PDSAg, Rota and Cas (unpublished). In that case, we might not have a single T cell receptor recognizing all three peptides, but perhaps several T cells crossreacting with two of the mimotopes, finally resulting in crossreactivity to all three peptides on the population level of T cell lines.

Most peptide mimics were defined for retinal S-Ag in animal models and in humans (5, 6, 11�, 24, 36). We have demonstrated the proliferative response and cytokine secretion to several ocular autoantigens (IRBP, S-Ag, cRALBP) of PBL from a patient experiencing uveitis as an adverse event after BCG-treatment. Whether this rarely observed recognition of multiple retinal autoantigens is due to mimicry of multiple mycobacterial antigens and several autoantigens or just a broad autoimmune response developing over time by epitope spreading cannot be ascertained (7). Both, intramolecular as well as intermolecular epitope spreading has been described in experimental models of uveitis (42�).

Autoreactive lymphocytes are not only found in the peripheral blood of patients with autoimmune diseases but also in healthy people (45, 46), indicating that further conditions are required for pathogenicity. We assume that in addition to the presence of autoreactive T cells the target organ itself contributes to the initiation and maintenance of uveitis. In the eye the autoantigen must be expressed and properly processed and presented by local antigen-presenting cells to reactivate immigrating T cells with a corresponding receptor followed by the recuitment of inflammatory cells that finally cause destruction of ocular tissues (18, 47).


Artificial Biology: Molecular Design and Cell Mimicry

Artificial biology is a sub-discipline of biomolecular engineering that aims to mimic and/or reconstruct the structure and the function of native biomolecules and small life forms – often using non-biological building blocks. Questions that comprise the field of artificial biology are diverse. Can we design artificial enzymes and/or make inorganic or non-organic materials that perform catalysis like enzymes do, possibly in complex intracellular environments or in living organisms? Can we make molecules self-replicate? Is artificial recognition, i.e., mimicking antibody–antigen affinity or the molecular fingerprints of human cells, possible? Can we engineer compartmentalized processes that imitate the performance of our organelles inside of cells? How do we facilitate controlled transport and mobility of cargo-loaded carriers at the micro- and nanoscale? To what extent can artificial cells exchange information among each other or with their natural role models? Can we integrate artificial and biological entities into 3D tissue structure?

The answer to some of these questions is ‘yes' but remains ‘probably' for others. The tools that are used on the quest to identify answers to these complex questions are originating from chemistry, physics, biology, material science and engineering. Artificial biology is a highly interdisciplinary field and products of these studies are impactful, with interest to a broad scientific readership. All of the above makes it relevant to the readership of Small.

The different contributions to this Special Issue represent selected aspects of artificial biology, and all submissions underwent the regular, stringent peer-revision. The result is an exciting collection of original contributions and review articles on artificial biology, reflecting the field's inherent interdisciplinary nature. In terms of length scale, contributions cover examples of artificial biology from low nanometer to hundreds of microns in size.

This Special Issue contains Reviews on protein engineering (https://doi.org/10.1002/smll.201903093), artificial glycocalyx (https://doi.org/10.1002/smll.201906890), molecularly imprinted synthetic antibodies (https://doi.org/10.1002/smll.201906644), artificial metalloenzymes (https://doi.org/10.1002/smll.202000392), and nanozymes that use endogenous substrates (https://doi.org/10.1002/smll.201907635). Further, original contributions discuss nanozymes for scavenging reactive oxygen species (https://doi.org/10.1002/smll.201902123) and to produce the natural signaling molecule nitric oxide (https://doi.org/10.1002/smll.201906744).

Increasing in size and complexity, this Special Issue includes original articles that consider the development of artificial organelles in the form of theranostic nano-compartments (https://doi.org/10.1002/smll.201906492), or as functional giant unilamellar vesicles (https://doi.org/10.1002/smll.201906424). Intracellular fate of polymer–lipid hybrid vesicles was discussed with the aim to focus on structural integrity of artificial organelles (https://doi.org/10.1002/smll.201906493).

Locomotion is of paramount importance in living systems. It is therefore not surprising that the assembly of artificial motile entities (often referred to as micro/nanomotors or swimmers) is fascinating science. The prime objective of these studies is to mimic the triggered, controlled and efficient transport phenomena observed in nature. This Special Issue contains Reviews that outline the recent advances in biomedical cargo transportation using micromotors (https://doi.org/10.1002/smll.201902464), that focus on biocompatibility of micromotors (https://doi.org/10.1002/smll.201906184), and on engineering micromotors that are activated by light for a variety of applications (https://doi.org/10.1002/smll.201903179). The original contributions discuss an effort on distinguishing micromotors by fluorescence (https://doi.org/10.1002/smll.201902365), light-triggered micromotors (https://doi.org/10.1002/smll.201902944), and bubble-propelled micromotors in confined space (https://doi.org/10.1002/smll.202000413).

When considering the larger length scale, the assembly of artificial cells aims to address different challenges including elucidating the origin of life, understanding the complexity of the cellular machinery or engineering synthetic entities that can support their natural role models. This Special Issue contains Reviews on bottom-up assemblies that can mimic cellular behavior,(https://doi.org/10.1002/smll.201907680) and on protein encapsulation in coacervates,(https://doi.org/10.1002/smll.201907671) and a discussion on the emerging concept of ‘printing biology' that explores the combination of printing with bottom-up assembly of biomimetic structures(https://doi.org/10.1002/smll.201907691). The original articles outline the use of 3D-printed protein cages to change the shape of giant unilamellar vesicles (https://doi.org/10.1002/smll.201906259), and the arrangement of amphiphilic polymers in GUVs (https://doi.org/10.1002/smll.201905230). Further, vesicles made from cyclophospholipid and fatty alcohol are presented to be resilient to metal ions, which is an anticipated prerequisite for protocells in early Earth environment (https://doi.org/10.1002/smll.201903381). In addition, the rudimentary communication between enzyme-loaded giant unilamellar vesicles and red blood cells is discussed (https://doi.org/10.1002/smll.201906394).

This Special Issue was put together with the prospect of hosting an international conference on ‘Artificial biology: Molecular Design and Cell Mimicry' in Aarhus, Denmark. The lock-down events of 2020 put to practice worldwide to prevent the spread of the SARS-CoV-2 has led us to postpone the conference to a later date (not set at the time of publication of this editorial). We are committed to hold the conference as soon as the epidemiological situation permits, and we hope that this Special Issue will spur the interest of the broad scientific community in the field of artificial biology.

As organizers of this conference and guest editors of this Special Issue, we thank all those who supported the conference as keynote and invited speakers as well as all the authors of the articles that comprise this issue.


Author information

These authors jointly supervised this work: Hugh H. Reid, Jamie Rossjohn.

Affiliations

Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia

Jan Petersen, Laura Ciacchi, Mai T. Tran, Khai Lee Loh, Nathan P. Croft, Anthony W. Purcell, Hugh H. Reid & Jamie Rossjohn

Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia

Jan Petersen, Laura Ciacchi, Hugh H. Reid & Jamie Rossjohn

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands

Yvonne Kooy-Winkelaar & Frits Koning

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Melinda Y. Hardy & Jason A. Tye-Din

Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

Melinda Y. Hardy & Jason A. Tye-Din

Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

Zhenjun Chen & James McCluskey

ImmusanT, Cambridge, MA, USA

Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia

Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK

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Contributions

J.P., H.H.R., L.C., M.T.T., K.-L.L., Y.K.-W., N.P.C. and M.Y.H. contributed to data generation and analysis. Z.C. and J.M. provided key reagents. R.P.A., A.W.P., J.A.T-D. and F.K. contributed to data analysis and manuscript writing. H.H.R. and J.R. are joint senior and corresponding authors and, with J.P., conceived the study, analyzed data and co-wrote the manuscript.

Corresponding authors


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