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One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin–angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1–7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches.

T-cell recognition of antigen epitopes is a crucial step for the induction of adaptive immune responses, and the identification of such T-cell epitopes is, therefore, important for understanding diverse immune responses and controlling T-cell immunity. A number of bioinformatic tools exist that predict T-cell epitopes; however, many of these methods highly rely on evaluating conventional peptide presentation by major histocompatibility complex (MHC) molecules, but they ignore epitope sequences recognized by T-cell receptor (TCR). Immunogenic determinant idiotopes are present on the variable regions of immunoglobulin molecules expressed on and secreted by B-cells. In idiotope-driven T-cell/B-cell collaboration, B-cells present the idiotopes on MHC molecules for recognition by idiotope-specific T-cells. According to the idiotype network theory formulated by Niels Jerne, such idiotopes found on anti-idiotypic antibodies exhibit molecular mimicry of antigens. Here, by combining these concepts and defining the patterns of TCR-recognized epitope motifs (TREMs), we developed a T-cell epitope prediction method that identifies T-cell epitopes derived from antigen proteins by analyzing B-cell receptor (BCR) sequences. This method allowed us to identify T-cell epitopes that contain the same TREM patterns between BCR and viral antigen sequences in two different infectious diseases caused by dengue virus and SARS-CoV-2 infection. The identified epitopes were among the T-cell epitopes detected in previous studies, and T-cell stimulatory immunogenicity was confirmed. Thus, our data support this method as a powerful tool for the discovery of T-cell epitopes from BCR sequences.

The network paradigm once dominated immunological research and even garnered its originator a Nobel Prize. It has since been criticized and largely abandoned. This book is a firsthand account of the network paradigm's rise and fall.

Some ideas because of their intuitive appeal never die by neglect and survive because they are not amenable to experimental disproof. They can only be evaluated by weighing them against competing ideas and by invoking a credibility factor when used to explain observation. Most scientists would recommend ignoring such ideas, yet there is much to be learned by engaging their proponents in debate. The immune system viewed as an idiotype network, and its tweaking by the new school of “contextualists” is an example of such an idea. As chance would have it, the supporters of this idea gathered in a meeting, thereby permitting a cumulative analysis of this conceptualization. The goal of this essay is to compare the views of each of the speakers in light of a competing theory with the hope that a better understanding of immune responsiveness will emerge.

Anti-idiotype antibodies (Ab2) were purified from a cancer patient treated with NP-4, a murine monoclonal antibody to carcinoembryonic antigen (CEA). These Ab2 were specific for NP-4 and inhibited the binding between NP-4 and CEA. BALB/c mice immunized with these human Ab2 produced anti-Ab2 antibodies that were also reactive with the CEA epitope recognized by NP-4. These results indicate that human Ab2 to NP-4 can antigenically mimic the CEA epitope recognized by NP-4.

Antibodies have the unique ability to recognize antigens and to be recognized as antigens by other antibodies, creating a balanced network that regulates the humoral part of the immune system. An antibody that uniquely identifies another antibody of a given specificity as its antigen is referred to as an anti-idiotypic antibody. A descriptive literature review was conducted using the PubMed database, including publications up to 2025. This review examines the formation mechanisms of anti-idiotypic antibodies, their functional attributes, and their importance in diverse pathologies. A key focus is their capacity to neutralize pathogenic autoantibodies, offering a novel strategy for treating autoimmune diseases. Conversely, the generation of anti-Id Abs against therapeutic monoclonal antibodies (anti-drug antibodies) represents a significant challenge for biologic therapy, a complication addressed in a dedicated section on detection methods. Furthermore, consideration is given to the application of anti-Id Abs as innovative tools for vaccine design, particularly in oncology. By mimicking tumor-associated antigens, anti-Id Abs can induce a potent, targeted immune response against cancer with minimal side effects, presenting an alternative to conventional chemotherapy and radiation. Anti-Id Abs hold significant therapeutic promise. Their ability to selectively suppress pathogenic autoantibodies allows for precise immune intervention without broad immunosuppression. Additionally, their utility extends to vaccine development for various diseases. Further research into anti-Id Abs will deepen our understanding of immune regulation and open new avenues for targeted therapies.

Published hypervariable region V-beta T cell receptor (TCR) sequences were collected from people with severe COVID-19 characterized by having various autoimmune complications, including blood coagulopathies and cardiac autoimmunity, as well as from patients diagnosed with the Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C). These were compared with comparable published v-beta TCR sequences from people diagnosed with KD and from healthy individuals. Since TCR V-beta sequences are supposed to be complementary to antigens that induce clonal expansion, it was surprising that only a quarter of the TCR sequences derived from severe COVID-19 and MIS-C patients mimicked SARS-CoV-2 proteins. Thirty percent of the KD-derived TCR mimicked coronaviruses other than SARS-CoV-2. In contrast, only three percent of the TCR sequences from healthy individuals and those diagnosed with autoimmune myocarditis displayed similarities to any coronavirus. In each disease, significant increases were found in the amount of TCRs from healthy individuals mimicking specific bacterial co-infections (especially Enterococcus faecium, Staphylococcal and Streptococcal antigens) and host autoantigens targeted by autoimmune diseases (especially myosin, collagen, phospholipid-associated proteins, and blood coagulation proteins). Theoretical explanations for these surprising observations and implications to unravel the causes of autoimmune diseases are explored.

We consider the problem of self-tolerance in the frame of a minimalistic model of the idiotypic network. A node of this network represents a population of B-lymphocytes of the same idiotype, which is encoded by a bit string. The links of the network connect nodes with (nearly) complementary strings. The population of a node survives if the number of occupied neighbors is not too small and not too large. There is an influx of lymphocytes with random idiotype from the bone marrow. Previous investigations have shown that this system evolves toward highly organized architectures, where the nodes can be classified into groups according to their statistical properties. The building principles of these architectures can be analytically described and the statistical results of simulations agree very well with results of a modular mean-field theory. In this paper, we present simulation results for the case that one or several nodes, playing the role of self, are permanently occupied. These self nodes influence their linked neighbors, the autoreactive clones, but are themselves not affected by idiotypic interactions. We observe that the group structure of the architecture is very similar to the case without self antigen, but organized such that the neighbors of the self are only weakly occupied, thus providing self-tolerance. We also treat this situation in mean-field theory, which give results in good agreement with data from simulation. The model supports the view that autoreactive clones, which naturally occur also in healthy organisms are controlled by anti-idiotypic interactions, and could be helpful to understand network aspects of autoimmune disorders.

The V region antigenic determinants (idiotopes (Ids)) of antibodies (Abs) have been suggested to be involved in regulating the immune system. Certain diseases such as diabetes mellitus have recently been associated with a disequilibrium between Id+ and anti‐Id Abs. However, it is unknown how Abs carrying complementary idiotypes (that is, Id+ and anti‐Id Abs) regulate each other at the level of B and T cells. In this study, we show that B lymphoma cells genetically equipped with anti‐Id BCR V regions receive a signal when exposed to Id+Ig. Moreover, they become × 104 more efficient at presenting exogenous Id+ Ab to CD4+ T cells in vitro. Activated Id‐specific T cells in turn regulated the Id‐specific B lymphoma cells. Similar results were obtained in vivo in a surrogate model in which an Id‐peptide was incorporated genetically into the C‐region of a recombinant Ab that targeted IgD on B cells. The findings suggest that conventional T–B collaboration can explain communication between complementary Id+ and anti‐Id Ab at the cellular level. A model is suggested that integrates present and previous data on B‐cell regulation by Id‐specific T cells.