The human immune system is irreducible, depending on several macromolecular complexes that work together in a joint venture

The human immune system is irreducible, depending on several macromolecular complexes that work together in a joint venture

https://reasonandscience.catsboard.com/t3016-the-human-immune-system-is-irreducible-depending-on-several-macromolecular-complexes-that-work-in-a-joint-venture

1. Waste management (or waste disposal) includes the activities and actions required to manage waste from its inception to its final disposal. This includes the collection, transport, treatment, and disposal of waste, together with monitoring and regulation of the waste management process, and is always preceded by careful planning and foresight of the entire process by waste management engineers,  and implemented virtually simultaneously. 

2. Biological cells have cleverly engineered mechanisms that grind molecular protein garbage ( Proteasome Garbage Grinders ), coordinate loading and translocation of the waste products ( by superb Multisubunit peptide-loading complexes (PLC) ) to the waste disposal site, where the waste products are processed and sorted out (Histocompatibility complex class I (MHC-I) with 1,6 million atoms that to work with atomic precision ), and the final products are transported to the surface of the cell through the exquisite secretory pathway. There, T-Cells scan the MHC-I with receptors, and recognize when the cell was infected by foreign invaders, and induce their apoptosis ( cell suicide)
At least 9 macromolecular complexes need to work together in a joint venture, which communicate with each other to orchestrate this masterfully information-based process through signaling languages. If one of the complexes in the pathway is missing, no deal, the immune system cannot do its job, and the organism cannot survive and dies. Of course, all this incredible marvel of molecular engineering had to be born fully set up. No stepwise evolutionary process would lead to such a system. 

3. Therefore, the intelligent design theorist is justified to posit an unfathomably clever intelligent designer with foresight, who knew how to implement such a masterfully crafted waste management system on a molecular scale.    



The immune system is the body’s natural defense against infection and disease, including cancer, and protects the body from substances that can cause harm, such as bacteria and viruses (also called germs).
The cells of the immune system continuously flow through the body, looking for germs that may be invading the body. The immune system recognizes invaders by their antigens, which are proteins on the surface of the invading cells . Every cell or substance has its own specific antigens, and a person’s cells carry “self-antigens” that are unique to that individual.

People carry self-antigens on normal cells, such as liver, colon, and thyroid cells. Cells with self-antigens are typically not a threat. Invading germs, however, do not originate in the body and so do not carry self-antigens; instead, they carry what are called “nonself-antigens.”

The immune system is designed to identify cells with nonself-antigens as harmful and respond appropriately. Most immune cells release cytokines (messengers) to help them communicate with other immune cells and control the response to any threats. When, for example,   the immune system’s first barrier, the skin, is broken, harmful substances can easily enter the body.  As soon as the injury occurs, immune cells in the injured tissue begin to respond and also call other immune cells that have been circulating in your body to gather at the site and release cytokines to call other immune cells to help defend the body against invasion. The immune cells can recognize any bacteria or foreign substances as invaders. Immune cells, known as natural killer cells, (Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells) begin to destroy the invaders with a general attack. Now, we will give a closer look at how that happens. 4

Our body constantly encounters pathogens or malignant transformation. Cells that are infected by a virus or carry a carcinogenic mutation produce proteins foreign to the body. The adaptive immune system fights back unwanted invaders through highly sophisticated defense mechanisms.  One of the central hinges of human adaptive immunity is the major histocompatibility complex (MHC) class I antigen presentation pathway. 

Antigenic peptides result from the degradation of unwanted exogenous proteins  ( proteasomal degradation products ) inside the cell. They are generated in the cytosol by proteasomal protein degradation. These antigens are, of the most part, short peptides (8 to 12 amino acids) resulting from the degradation of intracellular proteins.  

Triaging the vast pool of cytosolic degradation products to find the few peptides indicating infection or antigenic invasion requires sophisticated machinery, the highly dynamic multisubunit peptide-loading complex (PLC). The products for degradation are edited by PLC. 

PLC contains as key constituents a transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). 

The antigenic invaders are loaded, and  TAP transports the proteasomal degradation (antigen) products from the cytosol intracellularly to the endoplasmic reticulum ER, where they are loaded and proofread by major histocompatibility complex class I proteins (MHC-I), which play a pivotal role, they are a cornerstone of the human adaptive immune system.5, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface.

The peptide-MHC-I complexes then move via a secretory pathway to the cell surface, presenting their antigenic load to cytotoxic T-cells.

Peptides exposed at the cell surface, therefore, mirror cellular contents: In healthy cells, only peptides from the “self” are exposed; in cells compromised by a virus or cancer-causing mutation, both self and “nonself” peptides, either viral or mutated, are exposed and displayed. A sampling of myriads of different peptide/MHC-I allomorphs ( different protein forms) requires a precisely coordinated quality control network in a single macromolecular assembly, including the transporter associated with antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin.  3 The stability of the human MHC-I PLC requires two editing modules. A single-module PLC cannot assemble the circular belt formed. There is also a crucial role of Tsn in bridging PLC components together.

Patrolling  T lymphocytes ( T cells ) detect and identify tainted cells by scanning the peptide MHC  complexes via T cell receptors and induce their apoptosis ( cell suicide).  This is how our immune system defends us against pathogens. 

Consider what is required for this pathway to be able to operate: 

1. Proteasome Garbage Grinders 6 are analogous to shredders or garbage disposals, indispensable to destroy cellular components, breaking them down to their constituent parts, which can then be recycled
2. Multisubunit peptide-loading complex (PLC)  is essential for establishing a hierarchical immune response. 7
3. A transporter associated with antigen processing (TAP1/2) is essential for peptide presentation to the major histocompatibility complex (MHC) class I molecules on the cell surface and necessary for T-cell recognition 8
4. MHC I-specific chaperone tapasin (Tsn) is essential for the assembly of the PLC and for efficient MHC I antigen presentation. 9
5. Oxidoreductase ERp57 is essential through the participation in the assembly of the major histocompatibility complex class 1. 10
6. ER chaperones tapasin: Tapasin is an essential adapter protein recruiting MHC I molecules to TAP, catalyzes peptide loading of MHC I. 11
7. Histocompatibility complex class I (MHC-I) is extremely important and essential for the adaptive immune system. 12, 15
8. The secretory pathway is ubiquitous to all cells and essential for the export of proteins.13
9. Cytotoxic T-cells are essential in host defense against pathogens that live in the cytosol, the commonest of which are viruses. These cytotoxic T cells can kill any cell harboring such pathogens by recognizing foreign peptides. 14

1. https://phys.org/news/2020-08-giant-nanomachine-aids-immune.html?fbclid=IwAR2JepKjofCYjTYA_x1uBoz8yqGW81rP6Vh6s7iPL1yg5ishSq3S47Ew3bo
2. https://sci-hub.tw/https://www.pnas.org/content/117/34/20597
3. https://cordis.europa.eu/project/id/789121
4. https://www.sitcancer.org/connectedold/p/patient/resources/melanoma-guide/immune-system
5. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00292/full
6. https://reasonandscience.catsboard.com/t1851-proteasome-garbage-grinders
7. https://pubmed.ncbi.nlm.nih.gov/29107940/
8. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transporter-associated-with-antigen-processing
9. https://www.nature.com/articles/srep17341
10. https://link.springer.com/article/10.2478/s11658-011-0022-z
11. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.12-217489
12. https://en.wikipedia.org/wiki/Major_histocompatibility_complex
13. https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1208774
14. https://www.ncbi.nlm.nih.gov/books/NBK27101/#:~:text=Armed%20effector%20cytotoxic%20CD8%20T,to%20MHC%20class%20I%20molecules.
15. https://onlinelibrary.wiley.com/doi/full/10.1002/ece3.5373

T-CELLS AND MHC PROTEINS

Like antibody responses, T‑cell-mediated immune responses are exquisitely antigen-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including most antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that have entered the interior of host cells, where they are invisible to B cells and antibodies. T cell responses differ from B cell responses in at least two crucial ways. First, a T cell is activated by foreign antigen to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of an antigen-presenting cell (APC), usually a dendritic cell in a peripheral lymphoid organ. One reason T cells require APCs for activation is that the form of antigen they recognize is different from that recognized by the Igs produced by B cells. Whereas Igs can recognize antigenic determinants on the surface of pathogens and soluble folded proteins, for example, T cells can only recognize fragments of protein antigens that have been produced by partial proteolysis inside a host cell. Newly formed MHC proteins capture these peptide fragments and carry them to the surface of the host cell, where T cells can recognize them. The second difference is that once activated, effector T cells act mainly at short range, either within a secondary lymphoid organ or after they have migrated to a site of infection. Effector B cells, by contrast, secrete antibodies that can act far away. Effector T cells interact directly with another host cell in the body, which they either kill (if it is an infected host cell, for example) or signal in some way (if it is a B cell or macrophage, for example). We will refer to such host cells as target cells. As is the case with APCs, target cells must display an antigen bound to an MHC protein on their surface for a T cell to recognize them. There are three main classes of T cells—cytotoxic T cells, helper T cells, and regulatory T cells. When activated, they function as effector cells (see Figure below), each with their own distinct activities. 


A model for the cellular basis of immunological memory.
When stimulated by their specific antigen and co-stimulatory signals, naïve lymphocytes proliferate and differentiate. Most become effector cells, which function and then usually die, while others become memory cells. During a subsequent exposure to the same antigen, the memory cells respond more readily, rapidly, and efficiently than did the naïve cells: they proliferate and give rise to effector cells and to more memory cells. Some memory T cells also develop from a minority of effector T cells (not shown). It is not known how the decision to become an effector cell versus a memory cell is made.

Effector cytotoxic T cells directly kill cells that are infected with a virus or some other intracellular pathogen. Effector helper T cells help stimulate the responses of other immune cells—mainly macrophages, dendritic cells, B cells, and cytotoxic T cells;  there are a variety of functionally distinct subtypes of helper T cells. Effector regulatory T cells suppress the activity of other immune cells. They recognize foreign antigens on the surface of APCs or target cells and the crucial part played by MHC proteins in the recognition process. We begin by considering the cell-surface receptors that T cells use to recognize antigen.

T Cell Receptors (TCRs) Are Ig‑like Heterodimers
T cell receptors (TCRs), unlike Igs made by B cells, exist only in membrane-bound form. They are composed of two transmembrane, disulfide-linked polypeptide chains, each of which contains two Ig‑like domains—one variable and one constant. On most T cells, the TCRs have one α chain and one β chain. 


A T cell receptor (TCR) heterodimer. 
(A) Schematic drawing showing that the receptor is composed of an α and a β polypeptide chain. Each chain has a large extracellular part that is folded into two Ig‑like domains—one variable (V) and one constant (C). A Vα and a Vβ domain (shaded in blue) form the antigen-binding site. Unlike Igs, which have two binding sites for antigen, TCRs have only one. The αβ-heterodimer is noncovalently associated with a large set of invariant membrane-bound proteins (not shown), which help activate the T cell when the TCRs bind their specific antigen. A typical T cell has about 30,000 TCRs on its surface. (B) The three-dimensional structure of the extracellular part of a TCR. The antigen-binding site is formed by the hypervariable loops of both the Vα and Vβ domains (black), and it is similar in its overall dimensions and geometry to the antigen-binding site of an Ig molecule.  The genetic loci that encode the α and β chains are located on different chromosomes. Like an Ig heavy-chain locus 


The human heavy-chain locus. 
There are 40 V segments, about 23 D segments, 6 J segments, and an ordered cluster of C‑region coding sequences, each cluster encoding a different class of heavy chain. The D segment (and part of the J segment) encodes amino acids in the third hypervariable region, which is the most variable part of the heavy chain V region. The genetic mechanisms involved in producing a heavy chain for light chains, except that two DNA rearrangement steps are required instead of one: first a D segment joins to a J segment, and then a V segment joins to the rearranged DJ segment. The rearrangements lead to the production of a VDJC mRNA that encodes a complete Ig heavy chain. The figure is not drawn to scale: the total length of the heavy-chain locus is over two megabases. Moreover, a number of details are omitted: for example, the exons encoding each C-region Ig domain and the hinge region and the different subclasses of Cγ‑coding segments are not shown.

the TCR loci contain separate V, D, and J gene segments (or just V and J gene segments in the case of the α-chain locus), which are brought together by site-specific recombination during T cell development in the thymus. With one exception, T cells use the same mechanisms to generate antigen-binding site diversity of their TCRs as B cells use to generate antigen-binding site diversity of their Igs, and they use the same V(D)J recombinase; thus, humans or mice deficient in this recombinase cannot make functional B or T cells. The mechanism that does not operate in TCR diversification is antigen-driven somatic hypermutation. Thus, the affinities of TCRs tend to be low (Ka ≈ 105–107 liters/mole). Various co-receptors and cell–cell adhesion proteins, however, greatly strengthen the binding of a T cell to an APC or target cell.