Evolution is driven by natural autoencoding: reframing species, interaction codes, cooperation and sexual reproduction.

The continuity of life and its evolution, we proposed, emerge from an interactive group process manifested in networks of interaction. We term this process survival of the fitted. Here, we reason that survival of the fitted results from a natural computational process we term natural autoencoding. Natural autoencoding works by retaining repeating biological interactions while non-repeatable interactions disappear. (i) We define a species by its species interaction code, which consists of a compact description of the repeating interactions of species organisms with their external and internal environments. Species interaction codes are descriptions recorded in the biological infrastructure that enables repeating interactions. Encoding and decoding are interwoven. (ii) Evolution proceeds by natural autoencoding of sustained changes in species interaction codes. DNA is only one element in natural autoencoding. (iii) Natural autoencoding accounts for the paradox of genome randomization in sexual reproduction-recombined genomes are analogous to the diversified inputs required for artificial autoencoding. The increase in entropy generated by genome randomization compensates for the decrease in entropy generated by organized life. (iv) Natural autoencoding and artificial autoencoding algorithms manifest defined similarities and differences. Recognition of the importance of fittedness could well serve the future of a humanly livable biosphere.

Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans.

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires.

Immune Computation and COVID-19 Mortality: A Rationale for IVIg.

COVID-19 infection tends to be more lethal in older persons than in the young; death results from an overactive inflammatory response, leading to cytokine storm and organ failure. Here we describe immune regulation of the inflammatory response phenotype as emerging from a process that is analogous to machine-learning algorithms used in computers. We briefly describe some strategic similarities between immune learning and computer machine learning. We reason that a balanced response to COVID-19 infection might be induced by treating the elderly patient with a wellness repertoire of antibodies obtained from healthy young people. We propose that a beneficial training set of such antibodies might be administered in the form of intravenous immunoglobulin (IVIg).

Human neonatal thymectomy induces altered B-cell responses and autoreactivity.

An association between T-cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T-cell lymphopenia affects B-cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T-cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1-5 years post-Tx, n = 10-27) and older children (>10 years, n = 26), and compared to healthy age-matched controls. T-cell and B-cell subsets were assessed and autoantibody profiling performed. Early post-Tx, a decrease in T-cell numbers (2.75 × 109 /L vs. 0.71 × 109 /L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B-cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx.

The SLE-key test serological signature: new insights into the course of lupus.

Objective: We previously described the multiplex autoantibody SLE-key Rule-Out test, which detects a signature of autoantibody reactivity that distinguishes healthy subjects from SLE patients with 94% sensitivity, 75% specificity and 93% negative predictive value; thus, an individual manifesting a positive Rule-Out test score is unlikely to have SLE (e.g. lupus is excluded). The objective of this current study was to evaluate the stability of the lupus-associated signature over time. Methods: We used banked serum samples from healthy subjects (n = 51) and lupus patients (n = 50 individual samples and n = 181 paired samples, for a total of n = 412 serum samples). The samples were drawn at different times after diagnosis to analyse the impact on the SLE-key Rule-Out test of time elapsed since diagnosis and any changes in disease activity (as reflected by the SLEDAI score). Results: The SLE signature remains stable for the first 10 years after diagnosis; in this time frame, <10% of patients manifested a positive Rule-Out score and the SLE-key Rule-Out score was independent of the underlying disease activity as reflected by the SLEDAI score. After ⩾10 years, ∼30% of lupus subjects scored as SLE Ruled-Out; the proportion of patients manifesting this status was even greater in the subset of individuals with a SLEDAI score of 0. Conclusion: These findings raise the possibility that a significant number of SLE patients manifest a change in their serological signature over time, and that such a signature change may signify an evolution in the immunological features of their disease relevant to patient management.

Real and artificial immune systems: computing the state of the body.

Here I present the idea that the immune system uses a computational strategy to carry out its many functions in protecting and maintaining the body. Along the way, I define the concepts of computation, Turing machines and system states. I attempt to show that reframing our view of the immune system in computational terms is worth our while.

Activation of the Akt-CREB signalling axis by a proline-rich heptapeptide confers resistance to stress-induced cell death and inflammation.

Cell stress of various kinds can lead to the induction of cell death and a damaging inflammatory response. Hence, a goal of therapeutic cell-stress management is to develop agents that might effectively regulate undesirable cell death and inflammation. To that end, we developed a synthetic peptide of seven amino acids based on structural mimicry to a functional domain of p53, a key factor in the responses of cells to stressful stimuli. This heptapeptide, which we term Stressin-1, was found to inhibit both cell death and the secretion of inflammatory mediators by various cell types in response to different stressful agents in vitro. The combined anti-inflammatory and anti-apoptotic activities of Stressin-1 were associated with a cellular signalling cascade that induced activation of Akt kinase and activation of the cAMP response element-binding protein (CREB) transcription factor. These immediate signalling events led to the inhibition of the signal transducer and activator of transcription and nuclear factor-κB pathways 24 hr later. Unexpectedly, we found no evidence for a direct involvement of p53 in the effects produced by Stressin-1. Intraperitoneal administration of 100 µg of Stressin-1 to lethally irradiated mice significantly protected them from death. These findings show that activating the Akt-CREB axis with Stressin-1 can counteract some of the undesirable effects of various cell stresses. Stressin-1 may have clinical usefulness.

T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity.

The T-cell receptor (TCR) repertoire is formed by random recombinations of genomic precursor elements; the resulting combinatorial diversity renders unlikely extensive TCR sharing between individuals. Here, we studied CDR3ß amino acid sequence sharing in a repertoire-wide manner, using high-throughput TCR-seq in 28 healthy mice. We uncovered hundreds of public sequences shared by most mice. Public CDR3 sequences, relative to private sequences, are two orders of magnitude more abundant on average, express restricted V/J segments, and feature high convergent nucleic acid recombination. Functionally, public sequences are enriched for MHC-diverse CDR3 sequences that were previously associated with autoimmune, allograft, and tumor-related reactions, but not with anti-pathogen-related reactions. Public CDR3 sequences are shared between mice of different MHC haplotypes, but are associated with different, MHC-dependent, V genes. Thus, despite their random generation process, TCR repertoires express a degree of uniformity in their post-genomic organization. These results, together with numerical simulations of TCR genomic rearrangements, suggest that biases and convergence in TCR recombination combine with ongoing selection to generate a restricted subset of self-associated, public CDR3 TCR sequences, and invite reexamination of the basic mechanisms of T-cell repertoire formation.

Tumor-associated and disease-associated autoantibody repertoires in healthy colostrum and maternal and newborn cord sera.

In this work, we studied autoantibody repertoires and Ig isotypes in 71 mothers and their 104 healthy newborns (including twins and triplets delivered term or premature). Newborns receive maternal IgG Abs via the placenta before birth, but developing infants must produce their own IgM and IgA Abs. We used an Ag microarray analysis to detect binding to a selection of 295 self-Ags, compared with 27 standard foreign Ags. The magnitude of binding to specific self-Ags was found to be not less than that to the foreign Ags. As expected, each newborn shared with its mother a similar IgG repertoire-manifest as early as the 24th week of gestation. IgM and IgA autoantibody repertoires in cord sera were highly correlated among the newborns and differed from their mothers' repertoires; the latter differed in sera and milk. The autoantibodies bound to self-Ags known to be associated with tumors and to autoimmune diseases. Thus, autoantibody repertoires in healthy humans--the immunological homunculus--arise congenitally, differ in maternal milk and sera, and mark the potential of the immune system to attack tumors, beneficially, or healthy tissues, harmfully; regulation of the tissue site, the dynamics, and the response phenotype of homuncular autoimmunity very likely affects health.

Autoantibody repertoires, natural biomarkers, and system controllers.

The immune system is composed of networks of interacting cells and molecules; therefore, to understand and control immune behavior we need to adopt the thinking and tools of systems immunology. This review describes the use of an antigen microarray device and informatics to profile the repertoires of autoantibodies in health and disease. Autoantibody profiling provides an insight into the biomarkers used by the immune system in its dialog with the body. Heat shock protein 60 (HSP60) and HSP70 are cited as examples of key hubs in physiological regulatory networks; HSP molecules and peptides can be viewed as natural regulators because the immune system itself deploys them to modulate inflammatory reactions. The discovery of such natural biomarkers paves the way towards natural control.

Do all creatures possess an acquired immune system of some sort?

Recent findings have provided evidence for the existence of non-vertebrate acquired immunity. We survey these findings and propose that all living organisms must express both innate and acquired immunity. This is opposed to the paradigm that only vertebrates manifest the two forms of immune mechanism; other species are thought to use innate immunity alone. We suggest new definitions of innate and acquired immunity, based on whether immune recognition molecules are encoded in the inherited genome or are generated through somatic processes. We reason that both forms of immunity are similarly ancient, and have co-evolved in response to lifestyle, cost-benefit tradeoffs and symbiosis versus parasitism. However, different species have evolved different immune solutions that are not necessarily genetically related, but serve a similar general function - allowing individuals to learn from their own immune experience; survival of species is contingent on the acquired immune experience of its individuals.

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin.

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell-mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

Guanine polynucleotides are self-antigens for human natural autoantibodies and are significantly reduced in the human genome.

In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome.

Gut feelings of safety: tolerance to the microbiota mediated by innate immune receptors.

To enable microbial colonization of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Recognition of safety, paradoxically, is mediated by the same environmental sensors that are involved in signaling danger. Indeed, in addition to their well-established role in inducing inflammation in response to stress signals, pattern recognition receptors and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated molecular patterns", markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical roles of immune receptors and other environmental sensors define the microbiota signature of an individual.

Pemphigus vulgaris is characterized by low IgG reactivities to specific self-antigens along with high IgG reactivity to desmoglein 3.

Pemphigus vulgaris (PV) is an autoimmune skin disease, which has been characterized by IgG autoantibodies to desmoglein 3. Here we studied the antibody signatures of PV patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus and scleroderma), using an antigen microarray and informatics analysis. We now report a previously unobserved phenomenon--patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.

Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

Activation of benign autoimmunity as both tumor and autoimmune disease immunotherapy: a comprehensive review.

Here, I consider how benign autoimmunity, the immunological homunculus, can be used to reinstate the healthy regulation of inflammation in both autoimmune diseases and in tumor immunotherapy. Different autoimmune diseases manifest clinically distinct phenotypes, but, in general, they all result from the transition of benign, healthy recognition of key body molecules into a damaging effector reaction. Tumors, in contrast to autoimmune diseases, grow by subverting the immune system into supporting and protecting the growing tumor from immune surveillance. Therefore our therapeutic aim in autoimmune disease is to induce the immune system to down-regulate the specific autoimmune effector reaction that causes the disease; in tumor immunotherapy, on the contrary, we aim to deprive the growing tumor of its illicit activation of immune suppression and to unleash an autoimmune disease targeted to the tumor. The recent success of anti-PD1 and anti-CTLR4 treatments exemplify the reinstatement of tumor autoimmunity subsequent to inhibition of immune suppression. With regard to the therapy of autoimmune diseases, I cite examples of immune system down-regulation of autoimmune diseases by T cell vaccination or HSP60 peptide treatment. Inducing the immune system to regulate itself is safer than global immune suppression and may be more effective in the long run.

The HSP60 immune system network.

Heat shock proteins (HSPs) were initially discovered as participants in the cellular response to stress. It is now clear, however, that self and microbial HSPs also play an important role in the control of the immune response. Here, we focus on HSP60 and its interactions with both the innate and adaptive immune system in mammals. We also consider that circulating HSP60 and the quantities and specificities of serum antibodies to HSP60 provide a biomarker to monitor the immune status of the individual. Thus, the dual role of HSP60 as an immune modulator and a biomarker, provides an opportunity to modulate immunity for therapeutic purposes, and to monitor the immune response in health and disease.