Rosa Rubicondior: The Unintelligent Designer - Another Error-Prone Bungle to Compensate for a Bungled Design

Sunday, 23 March 2025

The Unintelligent Designer

Another Error-Prone Bungle To Compensate For A Bungled Design

William Heath Robinson

Peacekeeper cells protect the body from autoimmunity during infection | Biological Sciences Division | The University of Chicago

A significant issue with our immune system is that it is poorly "designed." If it were truly the product of an intelligent designer, as creationists claim, that designer would hardly be competent enough to design a simple household item, let alone a complex biological system.

Because our immune system is so disorganized and inefficient, multiple layers of complexity have evolved to mitigate its worst shortcomings. However, these added layers themselves remain prone to errors, as they reflect the same flawed foundation. The central problem arises because the immune system must balance two contradictory requirements: it needs to be sensitive enough to identify and eliminate genuine threats, yet not so sensitive that it mistakenly attacks the body's own tissues.

While an omnipotent, supremely intelligent designer should have easily resolved such a contradiction, the reality is that our immune system frequently fails on both counts. It often permits pathogens and parasites to invade, and it also frequently turns against the body itself, leading to autoimmune diseases such as lupus, diabetes, multiple sclerosis, arthritis, and kidney or liver failure, among numerous other debilitating conditions that cause immense suffering.

Like the whimsical contraptions created by cartoonist William Heath Robinson — complex machines built from objects originally intended for entirely different purposes - the mammalian immune system is not designed top-down from a clear blueprint. Rather, it's built up gradually from one makeshift adaptation piled onto another, each new solution attempting to compensate for the shortcomings of earlier ones. Eventually, this process results in a ramshackle system so intricate that its complexity itself creates new opportunities for failure. Such complexity is not indicative of intelligent, purposeful design, which would typically favour simplicity and efficiency. Instead, it reflects an ad hoc, utilitarian approach driven by evolutionary constraints and an inability to anticipate future challenges.

And of course, this embarrassment for creationism is made worse by the fact that, according to Michael J. Behe, pathogenic parasites such as E. coli and Plasmodium falciparum are examples of irreducible complexity, so are, in creationist circles, unarguable 'proof' of intelligent design, so the immune system is allegedly designed by the designer of these pathogens to protect us from them.

It seems creationists have no difficulty in believing the same designer would design parasites to make sick, then design a system to protect us from its pathogenic designs, and even though that system doesn't work very well, it is nevertheless evidence of supreme intelligence.

Tell me about the mammalian Immune system and why it often causes autoimmune diseases.

The mammalian immune system is a complex network of biological structures, cells, and molecular processes evolved primarily to defend the body against pathogens (such as bacteria, viruses, parasites, and fungi), toxins, and other harmful substances. It achieves this through two main branches:

Innate Immunity

Definition: The first line of defence; rapid and nonspecific.
Key components:

Physical barriers (skin, mucous membranes)
Chemical defines (enzymes, acidic environments)
Cells such as macrophages, neutrophils, dendritic cells, and natural killer (NK) cells

Response: Quickly identifies and destroys pathogens based on generic molecular patterns.

Adaptive Immunity

Definition: A slower, highly specialized, and memory-based response.
Key components:

T cells: Recognize infected or abnormal cells and coordinate immune responses.

Helper T cells (CD4⁺): Activate and direct other immune cells.
Cytotoxic T cells (CD8+): Directly kill infected or damaged cells.
Regulatory T cells: Suppress immune responses to maintain tolerance to self-tissues.

B cells: Produce antibodies specific to pathogens.

Response: Learns from past infections, allowing rapid response upon future exposures.

Why does the immune system often cause autoimmune diseases?

Autoimmune diseases occur when the immune system mistakenly identifies the body's own tissues as foreign, leading to self-attack and chronic inflammation. Several underlying factors explain why autoimmune diseases arise so frequently in mammals:

Imperfect Tolerance Mechanisms

Central tolerance: During development, the immune system tries to eliminate self-reactive lymphocytes (immune cells), primarily in the thymus (for T cells) and bone marrow (for B cells). However, this process isn't perfect—some self-reactive cells inevitably escape.
Peripheral tolerance: Regulatory mechanisms in peripheral tissues, especially regulatory T cells, try to suppress harmful self-reactivity. Failures or deficiencies in these mechanisms can lead to autoimmunity.

Molecular Mimicry

Sometimes, pathogens contain antigens (molecular signatures) very similar to those in host tissues. The immune response aimed at pathogens can mistakenly target host tissues, triggering autoimmune reactions.

Example: Rheumatic fever, in which antibodies against *Streptococcus* bacteria cross-react with heart tissues, damaging heart valves.

Chronic Inflammation and Tissue Damage

Persistent inflammation (caused by chronic infection, environmental triggers, or tissue injury) can expose normally hidden self-antigens. The immune system, encountering these previously hidden molecules, may incorrectly interpret them as threats.

Genetic Predisposition

Certain genetic variants (particularly in immune-related genes such as the Human Leukocyte Antigen (HLA) complex) increase susceptibility to autoimmune diseases. These genetic factors often predispose individuals to weaker self-tolerance or heightened immune reactivity.

Environmental Factors

Diet, exposure to certain chemicals, infections, hormones, stress, and lifestyle can trigger or exacerbate autoimmune responses in genetically susceptible individuals. For example, vitamin D deficiency is associated with increased risk of autoimmune disorders such as multiple sclerosis.

Evolutionary Trade-Offs

The mammalian immune system has evolved primarily to fight pathogens, not necessarily to avoid autoimmune reactions perfectly. Natural selection prioritizes robust pathogen defence at the risk of occasional self-attack, leading to a compromise—autoimmunity is essentially a "side effect" of a highly reactive defence system.

Common Examples of Autoimmune Diseases:

Type 1 diabetes: The immune system attacks pancreatic beta cells, impairing insulin production.
Multiple sclerosis (MS): T cells and antibodies target myelin in the central nervous system.
Rheumatoid arthritis (RA): Immune cells attack joint tissues, causing chronic inflammation and damage.
Systemic lupus erythematosus (SLE): A systemic disorder causing immune attack against DNA, cellular components, and multiple tissues.
Hashimoto’s thyroiditis: Autoimmune destruction of thyroid gland cells.

Conclusion:

Autoimmune diseases arise due to inherent imperfections in the mammalian immune system, driven by evolutionary trade-offs, genetic vulnerabilities, environmental triggers, and molecular mimicry. These vulnerabilities highlight the immune system as a product of natural selection—highly effective at dealing with infections but prone to errors and harmful self-recognition, rather than the work of a flawless "designer."

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Now a team of researchers from the University of Chicago have shown how a special group of cells is needed to control the worst excesses of the immune system during infections, to prevent triggering catastrophic autoimmune responses. Their findings are published in the journal, Science and explained in a University of Chicago news item:

Peacekeeper cells protect the body from autoimmunity during infection
New research from the University of Chicago shows how a specially trained population of immune cells keeps the peace by preventing other immune cells from attacking their own.
During infections, the immune system needs to distinguish foreign antigens that are expressed by invading bacteria and viruses from self-antigens that are expressed by cells of the body. If not, the immune system can mistakenly attack its own cells, causing lasting damage to tissue and potential long-term disease.

New research from the University of Chicago shows how a specially trained population of immune cells keeps the peace by preventing other immune cells from attacking their own. The study, published in Science, provides a better understanding of immune regulation during infection and could provide a foundation for interventions to prevent or reverse autoimmune diseases.

Several groups of white blood cells help coordinate immune responses. Dendritic cells take up proteins from foreign pathogens, chop them up into peptides called antigens, and display them on their surface. CD4+ conventional T (Tconv) cells, or helper T cells, inspect the peptides presented by dendritic cells. If the peptides are foreign antigens, the T cells expand in numbers and transform into an activated state, specialized to eradicate the pathogen. If the dendritic cell is carrying a “self-peptide,” or peptides from the body’s own tissue, the T cells are supposed to lay off.

During an autoimmune response, the helper T cells don’t distinguish between foreign peptide antigens and self-peptides properly and go on the attack no matter what. To prevent this from happening, another group of T cells called CD4⁺ regulatory T (Treg) cells, are supposed to intervene and prevent friendly fire from the Tconv cells.

You can think of them [Treg cells] as peacekeeper cells.

Professor Peter A. Savage, PhD, lead author
Department of Pathology
University of Chicago, Chicago, IL, USA.

Tregs obviously do their job well most of the time, but Savage said that it has never been clear how they know when to intervene and prevent helper T cells from starting an autoimmune response, and when to hold back and let them fight an infection.

So, Savage and his team, led by David Klawon, PhD, a former graduate student in his lab who is now a postdoctoral fellow at the Massachusetts Institute of Technology (MIT), wanted to explore this property of the immune system, known in the field as self-nonself discrimination. T cells are produced in the thymus, a specialized organ of the immune system. During development, Treg cells are trained to recognize specific peptides, including self-peptides from the body. When dendritic cells present a self-peptide, the Treg cells trained to spot them intervene to stop helper T cells from getting triggered.

For the study, Savage and Klawon worked in close collaboration with co-first author Nicole Pagane, a graduate student at MIT, as well as co-corresponding authors Harikesh Wong at the Ragon Institute of the Massachusetts General Hospital, MIT and Harvard University, and Ron Germain at the National Institutes of Health.

T cell specificity is what the team found makes a crucial difference in self-nonself discrimination. The researchers experimentally depleted Treg cells in mice that were specific to a single self-peptide from the prostate. In healthy mice in the absence of infection, this change did not trigger autoimmunity to the prostate. When the researchers infected mice with a bacterium that expressed the prostate self-peptide, however, the absence of matched, prostate-specific Treg cells triggered prostate-reactive T helper cells and introduced autoimmunity to the prostate.

Interestingly though, this alteration did not impair the ability of helper T cells to control the bacterial infection by responding to foreign peptides.

It's like a doppelganger population of T cells. The CD4 helper cells that could induce disease by attacking the self share an equivalent, matched population of these peacekeeper Treg cells. When we removed Treg cells reactive to a single self-peptide, the T helper cells reactive to that self-peptide were no longer controlled, and they induced autoimmunity.

Professor Peter A. Savage, PhD.

Conventional models show that any nearby Treg cells can prevent an autoimmune response, while the new study shows how Treg cells are specifically matched to their Tconv cell "doppelgangers."
(Pete Savage)

The root causes of autoimmune disease are a complex interaction of genetics, the environment, lifestyle, and the immune system. Classic, conventional thinking in the immunology field promoted the idea that the immune system establishes self-nonself discrimination by purging the body of helper T cells that are reactive to self-peptides, thereby preventing autoimmunity. Savage said this study shows that purging is inefficient though, and that specificity matching by Treg cells may be equally as important.

The idea is that specificity matters, and for a fully healthy immune system, you need to have a good collection of these doppelganger Treg cells.

Professor Peter A. Savage, PhD.

As long as the immune system generates enough matched Treg cells, they can prevent autoimmune responses without impacting responses to infections.
It's like flipping the idea of self-nonself discrimination upside down. Instead of having to delete all helper T cells reactive to self-antigens, you simply generate enough of these Treg peacekeeper cells instead.

Professor Peter A. Savage, PhD.

Additional authors include Eric Gai from the Massachusetts Institute of Technology; Matthew T. Walker, Nicole K. Ganci, Christine H. Miller, Donald M. Rodriguez, Ryan K. Duncombe, and Erin J. Adams from the University of Chicago; and Bridgett K. Ryan-Payseur, Mark Maienschein-Cline, and Nancy E. Freitag from the University of Illinois, Chicago.

Structured Abstract

INTRODUCTION
A fundamental feature of the adaptive immune system is its ability to generate immunity to foreign pathogens while restricting collateral damage to self-tissues, a property referred to as self-nonself discrimination. In the T cell compartment, this effect is conferred in part by the purging or inactivation of conventional T (T_conv) cells exhibiting strong reactivity to self-peptides complexed with host major histocompatibility complex (MHC) molecules (self-pMHC). However, despite these mechanisms, self-pMHC–reactive T_conv cells with pathogenic potential persist, requiring continuous control by Foxp3-expressing regulatory T (T_reg) cells to prevent autoimmunity.

RATIONALE
This observation highlights a fundamental unanswered question that sits at the nexus of protective immunity and autoimmunity: During infection, in which both self- and pathogen-derived peptides are presented in an inflammatory environment permissive for T cell activation, how do T_reg cells selectively control T_conv cells reactive to self-peptides while simultaneously enabling robust T cell responses to pathogen-derived peptides? Conventional modes of T_reg cell suppression—such as sequestration of costimulatory ligands, local hoarding of secreted factors, and production of suppressive cytokines—function broadly without regard to the peptide specificity of responding T cells. Therefore, these mechanisms lack the selectivity needed to distinguish between self- and nonself-reactive T_conv cells. To address this gap, we examined the hypothesis that T_reg cells reactive to self-peptides selectively constrain T_conv cells of matched specificity during infection, thereby enforcing self-nonself discrimination.

RESULTS
Through the study of CD4⁺ T cell responses to a natural prostate-specific self-peptide, we identified two tiers of T_reg cell–mediated regulation. T_reg cells of matched specificity were not required for the control of self-peptide–reactive T_conv cells at steady state or after innate immune activation. However, such T_reg cells became crucial in a setting of pathogen-associated epitope mimicry, in which levels of both innate activation and self-peptide presentation rise concurrently. When self-peptide–specific T_reg cells were present, mice were protected from autoimmunity after infection with a bacterium expressing the self-peptide. In the absence of such T_reg cells, infection induced extensive autoimmunity of the prostate. T_reg cells reactive to the self-peptide did not prevent the priming of T_conv cells of shared specificity but instead stifled their subsequent proliferation and differentiation. The expansion of self-peptide–reactive T_reg cells occurred earlier than that of T_conv cell counterparts, suggesting that antigen-activated T_reg cells were intrinsically poised to accumulate more rapidly, thereby providing a numerical advantage in the early stages of the response. Quantitative imaging revealed heterogeneous patterns of T_reg cell–mediated control; some self-pMHC–specific T_conv cells were restrained by locally enriched polyclonal T_reg cells, whereas others required the local enrichment of T_reg cells of shared specificity to attenuate T cell receptor (TCR) and interleukin-2 (IL-2) signaling, thereby stifling proliferation and effector differentiation. Notably, T_reg cell–mediated control of self-peptide–reactive T_conv cells had no impact on the T_conv cell response to pathogen-derived nonself peptides, demonstrating self-peptide specificity of the observed suppression.

CONCLUSION
The selective control of self-peptide–reactive T_conv cells by T_reg cells of matched specificity may be especially relevant for immunological insults that are proposed drivers of autoimmunity, including pathogen-associated epitope mimicry or the release of self-antigens and inflammatory signals triggered by infection-induced cell death. These findings support a T_reg cell–centric model of self-nonself discrimination in which the immune system generates T_reg cells reactive to highly antigenic self-peptide ligands, selectively focusing immunosuppression on T_conv cells of matched specificity during strong immunological challenges. This model complements and advances classical paradigms of self-nonself discrimination, illustrating how the adaptive immune system operates on a knife’s edge between effective pathogen control and the risk of autoimmunity during infection.

T_reg cells enforce self-nonself discrimination during infection by selectively constraining T_conv cells of shared self-specificity.
Upon infection with a pathogen expressing a self-peptide—a model of pathogen-associated epitope mimicry or elevated self-antigen elicited by tissue damage—self-peptide–specific T_reg cells selectively control CD4⁺ T_conv cells reactive to the same peptide by attenuating TCR stimulation, IL-2 signaling, and proliferation. This selective suppression simultaneously prevents autoimmunity and enables robust T_conv responses against foreign pathogen–derived peptides to protect the host.

Abstract
During infections, CD4⁺ Foxp3⁺ regulatory T (T_reg) cells must control autoreactive CD4⁺ conventional T (T_conv) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We defined the basis of this selectivity using mice in which T_reg cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide–specific T_reg cells were dispensable for the control of T_conv cells of matched specificity at homeostasis. However, they were required to control such T_conv cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the T_reg cell response to self-peptide did not affect protective T_conv cell responses to a pathogen-derived peptide. Thus, self-peptide–specific T_reg cells promoted self-nonself discrimination during infection by selectively controlling T_conv cells of shared self-specificity.

David E. J. Klawon et al.
Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection. Science 387, eadk3248 (2025). DOI:10.1126/science.adk3248

Copyright: © 2025 The authors.
Published by American Association for the Advancement of Science. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

So, we have yet another layer of complexity - which creationists equate to evidence of intelligent design - added to the immune system to try to control its tendency to over-react.

And yet still we become infected with viruses, bacteria, fungi, parasitic worms and other organisms, all allegedly designed by a single supreme designer, and our immune system still plagues us with autoimmune diseases - a bodily system that has few equals in its refutation of the notion that our bodies were intelligently designed, and confirmation of the scientific theory of Evolution.

If our body had truly been intelligently designed, we would have no need for medicines and medical science; if an omnibenevolent designer had designed it, there would be no pathogens requiring the protection from an immune system in the first place.

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