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Specificity of the immune system

Specificity of the immune system


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We know that the adaptive immune system recognizes foreign particles when their proteins are expessed of the the surface of T-cells, complexed with MHCs. But MHCs present only short peptides of length 8-11 amino acids long. How is it that every antigen has one characteristic 8-11 residues long stretch in some protein of its which none of the host's protein has. Conversely, how is it that this 8-11 amino acid long peptide, which the body is recognizing as foreign is not found in any protein of any cell of our body?


For starters, your conception of antigen presentation seems a bit off, but that's not the crux of your question. There's around 10^15 different sequence permutations for a peptide 11-mer. Despite that, it's actually likely that highly conserved regions of some proteins will be present in both the pathogen and the host. T cells will not recognize them, however, as they are negatively selected in the thymus.


The immune system is the most beautiful, complex biological process that operates on a scale that it can be termed as engineering.

MHC polymorphism:

MHC's have two particular properties that give it flexibility in the face of the antigen: Its polygenicitcy (it contains several different MHC class I and MHC class II genes with different ranges of peptide-binding specificities) and secondly, MHCs are polymorphic (having multiple variants of each gene within the population).

Note: MHCs are also called HLA (Human Leukocyte Antigen)

So as you can see, there is a lot of possible variation possible. I'd recommend reading through this:

http://www.ncbi.nlm.nih.gov/books/NBK27156/

From the source above:

The outstanding feature of the MHC molecules is their extensive polymorphism. This polymorphism is of critical importance in antigen recognition by T cells. A T cell recognizes antigen as a peptide bound by a particular allelic variant of an MHC molecule, and will not recognize the same peptide bound to other MHC molecules.

This behavior of T cells is called MHC restriction. Most MHC alleles differ from one another by multiple amino acid substitutions, and these differences are focused on the peptide-binding site and adjacent regions that make direct contact with the T-cell receptor.

At least three properties of MHC molecules are affected by MHC polymorphism: the range of peptides bound; the conformation of the bound peptide; and the direct interaction of the MHC molecule with the T-cell receptor. Thus the highly polymorphic nature of the MHC has functional consequences, and the evolutionary selection for this polymorphism suggests that it is critical to the role of the MHC molecules in the immune response.


Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints

Survival rates for metastatic lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-with its capacity for memory, exquisite specificity and central and universal role in human biology-immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

Keywords: Lung cancer immune checkpoint immunotherapy program death-1 (PD-1) program death-ligand 1 (PD-L1).

Conflict of interest statement

No potential conflicts of interest are disclosed.

Figures

T-cell interaction with APC and…

T-cell interaction with APC and tumor cells: the immune checkpoints CTLA-4 and PD-1/PD-L1.…


Antibodies

Antibodies act as the antigen receptor on the surface of B cells and, in response to antigen, are subsequently secreted by plasma cells. Antibodies recognize specific configurations (epitopes, or antigenic determinants) on the surfaces of antigens (eg, proteins, polysaccharides, nucleic acids). Antibodies and antigens fit tightly together because their shape and other surface properties (eg, charge) are complementary. The same antibody molecule can cross-react with related antigens if their epitopes are similar enough to those of the original antigen.

Antibody structure

Antibodies consist of 4 polypeptide chains (2 identical heavy chains and 2 identical light chains) joined by disulfide bonds to produce a Y configuration (see figure B-cell receptor). The heavy and light chains are divided into a variable (V) region and a constant (C) region.

B-cell receptor

The B-cell receptor consists of an Ig molecule anchored to the cell’s surface. CH = heavy chain constant region CL = light chain constant region Fab = antigen-binding fragment Fc = crystallizable fragment Ig = immunoglobulin L-kappa (κ) or lambda (λ) = 2 types of light chains VH = heavy chain variable region VL = light chain variable region.

V regions are located at the amino-terminal ends of the Y arms they are called variable because the amino acids they contain are different in different antibodies. Within the V regions, hypervariable regions determine the specificity of the immunoglobulin (Ig). They also function as antigens (idiotypic determinants) to which certain natural (anti-idiotype) antibodies can bind this binding may help regulate B-cell responses.

The C region of the heavy chains contains a relatively constant sequence of amino acids (isotype) that is distinctive for each Ig class. A B cell can change the isotype it produces and thus switch the class of Ig it produces. Because the Ig retains the variable part of the heavy chain V region and the entire light chain, it retains its antigenic specificity.

The amino-terminal (variable) end of the antibody binds to antigen to form an antibody-antigen complex. The antigen-binding (Fab) portion of Ig consists of a light chain and part of a heavy chain and contains the V region of the Ig molecule (ie, the combining sites). The crystallizable fragment (Fc) contains most of the C region of the heavy chains Fc is responsible for complement activation and binds to Fc receptors on cells.

Antibody classes

Antibodies are divided into 5 classes:

The classes are defined by their type of heavy chain: mu (μ) for IgM, gamma ( γ ) for IgG, alpha ( α ) for IgA, epsilon ( ε ) for IgE, and delta ( δ ) for IgD. There are also 2 types of light chains: kappa ( κ ) and lambda ( λ ). Each of the 5 Ig classes can bear either kappa or lambda light chains.

IgM is the first antibody formed after exposure to new antigen. It has 5 Y-shaped molecules (10 heavy chains and 10 light chains), linked by a single joining (J) chain. IgM circulates primarily in the intravascular space it complexes with and agglutinates antigens and can activate complement, thereby facilitating phagocytosis. Isohemagglutinins are predominantly IgM. Monomeric IgM acts as a surface antigen receptor on B cells. Patients with hyper-IgM syndrome have a defect in the genes involved in antibody class switching (eg, genes that encode CD40, CD154 [also known as CD40L], or NEMO [nuclear factor–kappa-B essential modulator]) therefore, IgA, IgG, and IgE levels are low or absent, and levels of circulating IgM are often high.

IgG is the most prevalent Ig isotype in serum and is present in intravascular and extravascular spaces. It coats antigen to activate complement and facilitate phagocytosis by neutrophils and macrophages. IgG is the primary circulating Ig produced after reexposure to antigen (secondary immune response) and is the predominant isotype contained in commercial gamma-globulin products. IgG protects against bacteria, viruses, and toxins it is the only Ig isotype that crosses the placenta. Therefore, this class of antibody is important for protecting neonates, but pathogenic IgG antibodies (eg, anti-Rh0[D] antibodies, stimulatory anti-thyroid-stimulating hormone receptor autoantibodies), if present in the mother, can potentially cause significant disease in the fetus.

There are 4 subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. They are numbered in descending order of serum concentration. IgG subclasses differ functionally mainly in their ability to activate complement IgG1 and IgG3 are most efficient, IgG2 is less efficient, and IgG4 is inefficient. IgG1 and IgG3 are efficient mediators of antibody-dependent cellular cytotoxicity IgG4 and IgG2 are less so.

IgA occurs at mucosal surfaces, in serum, and in secretions (saliva tears respiratory, genitourinary, and gastrointestinal tract secretions colostrum), where it provides an early antibacterial and antiviral defense. J chain links IgA into a dimer to form secretory IgA. Secretory IgA is synthesized by plasma cells in the subepithelial regions of the gastrointestinal and respiratory tracts. Selective IgA deficiency is relatively common but often has little clinical impact because there is cross-functionality with other classes of antibody.

IgD is coexpressed with IgM on the surface of naive B cells. Whether these 2 classes function differently on the surface of the B cell and, if so, how differently is unclear. They may simply be an example of molecular degeneracy. Serum IgD levels are very low, and the function of circulating IgD is unknown.

IgE is present in low levels in serum and in respiratory and gastrointestinal mucous secretions. IgE binds with high affinity to receptors present in high levels on mast cells and basophils and to a lesser extent on several other hematopoietic cells, including dendritic cells. If antigen bridges 2 IgE molecules bound to the mast cell or basophil surface, the cells degranulate, releasing chemical mediators that cause an inflammatory response. IgE levels are elevated in atopic disorders (eg, allergic or extrinsic asthma, hay fever, atopic dermatitis) and parasitic infections.

Antibody-mediated immunity involves the activation of B cells and secretion of antibodies when in contact with a pathogen.

When exposed to the chemicals released by activated helper T cells, a sensitized B cell divides, producing daughter cells that differentiate into memory B cells and plasma cells.

Plasma cells manufacture large quantities of antibody molecules. These antibodies are specific, and will only recognize and attack the antigen that sensitized the original B cell. Antibodies can inactivate or destroy the antigen through a variety of mechanisms. For example, antibodies can bind to their antigenic targets and form antigen-antibody complexes. They can also agglutinate invading cells, forming clusters of antibodies and toxins that are relatively easy for phagocytes to find and engulf. Another potential effect of antibody binding is the activation of nonspecific defenses, such as the complement system or the inflammatory response.

Memory B cells, produced by the division of activated B cells, can patrol the body for years. Like other memory cells, memory B cells defend the body against future infections by the same pathogen.


How the immune system deals with the gut's plethora of microbes

A large, multi-colored collection of germinal centers observed in the mesenteric lymph node of a mouse.

The gut is an unusually noisy place, where hundreds of species of bacteria live alongside whatever microbes happen to have hitched a ride in on your lunch. Scientists have long suspected that the gut’s immune system, in the face of so many stimuli, takes an uncharacteristically blunt approach to population control and protection from foreign invaders—churning out non-specific antibodies with broad mandates to mow the gut’s entire microbial lawn without prejudice.

But now, new research published in Nature suggests that the gut’s local immune system can be quite precise, creating antibodies that appear to home in on specific microbiota.

“It was thought that the gut immune system worked sort of like a general-purpose antibiotic, controlling every bug and pathogen,” says Gabriel D. Victora, an immunologist and head of the Laboratory of Lymphocyte Dynamics . “But our new findings tell us that there might be a bit more specificity to this targeting.”

The research suggests that our immune system may play an active part in shaping the composition of our microbiomes, which are tightly linked to health and disease. “A better understanding of this process could one day lead to major implications for conditions where the microbiome is knocked out of balance,” says Daniel Mucida, head of the Laboratory of Mucosal Immunology.

Specificity in the mouse gut

When faced with a pathogen, the immune system’s B cells enter sites called germinal centers where they “learn” to produce specific antibodies until one B cell emerges, finely-tuned to recognize its target with high efficiency. Dubbed a winner clone, this B cell replicates to generate a mob of cells that produce potent antibodies.

Victora, Mucida, and colleagues set out to study how these B cells interact with the melting pot of bacterial species in the gut—an overabundance of potential targets. Looking at the germinal centers that form in mice intestines, they found that about 1 in 10 of these gut-associated germinal centers had clear winner clones. They then homed in on the winning B cells and found that their antibodies were indeed designed to bind with ever increasing potency to specific species of bacteria living in the gut.

The findings show that even in the gut, where millions of microbes wave their thousands of different antigens and vie for the immune system’s attention, germinal centers manage to select specific, consistent winners.

“We can now investigate the winners and look at evolution in germinal centers as an ecological issue involving many different species, as we try to figure out the rules underlying selection in these complex environments,” Victora says. “This opens up a whole new area of inquiry.”


Biology of the Immune System in Animals

Animals are under constant threat of microbial invasion. These potential invaders gain access to the body through the intestine and respiratory tract and the skin. The large and diverse microbiota of the intestine serves to protect the intestine from infectious invaders by occupying a niche that precludes other organisms from establishment there. Other potential invaders are infectious agents spread from other individuals.

To prevent microbial invasion, the body has as part of the innate immune system a series of defenses that collectively constitute a highly effective defense against invasion. These mechanisms include physical barriers such as the skin, which has its own microbiota and utilizes dessication as a mechanism to discourage colonization with other organisms. Inhaled microorganisms and other material are rapidly removed by the mucociliary apparatus, which consists of ciliated epithelial cells and mucus-secreting cells that move inhaled material from the lower to the upper respiratory tract from which they are removed by the cough reflex.

The second line of defense is a “hard-wired” system of innate immunity that depends on a rapid stereotypical response to stop and kill both bacteria and viruses. This is typified by the process of acute inflammation and by the classic illness responses such as a fever.

The third line of defense is the highly complex, specific, and long-lasting adaptive immunity. Because an animal accumulates memory cells after exposure to pathogens, adaptive immunity provides an opportunity for the host to respond to exposure by creating a highly specific and effective response to each individual infectious agent. In the absence of a functional adaptive immune system survival is unlikely.


Immune System Biology

Salk Professor Susan Kaech examined the immune cells in the lungs, a significant site of damage during the COVID-19 infection. When we are first exposed to bacteria or viruses, immune cells called killer T cells destroy the infected cells to prevent the spread of the disease. Killer T cells effectively provide long-term protective immunity against the invader, a fundamental concept behind vaccination. Kaech’s team, including first author and then-graduate student Jun Siong Low, found that the cells responsible for long-term immunity in the lungs can be activated more easily than previously thought. The insight could aid in the development of universal vaccines for influenza and the novel coronavirus.

Salk scientists discover genetic “dial” to turn immune function up and down to target cancer, autoimmune disease

Associate Professor Ye Zheng, Assistant Professor Diana Hargreaves, co-first authors Jovylyn Gatchalian and Eric Chin-San Loo, and colleagues discovered a way to control regulatory T cells, immune cells that act as a cease-fire signal, telling the immune system when to stand down. Being able to increase or decrease regulatory T cell activity could one day help treat numerous diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus and even some cancers.


Multispecificty vs. Monospecificity

How can Ab multireactivity be reconciled with the apparent monospecificity of the many mAbs that are used reliably in analytical assays, and even as therapeutic agents? Some possible answers stem from the changes undergone over time as naive B cells respond to an Ag (Fig. 2). The binding of an Ag to membrane-bound Ab on a naive B cell stimulates the cell to divide. A cytidine deaminase activated in proliferating B cells causes mutations throughout V domains of both H and L chains (44). (It also causes “class switching” of the V domain from the Ab's H chain (μ in naive B cells) to the C domain of one of the lower molecular weight H chains (γ, α, or ε) expressed in more mature B cells. The mutated Abs vary in affinity for the Ag, and their average monovalent (intrinsic) affinity increases over time, with the rate of increase depending on the amount of Ag exposure: Small amounts lead to rapid increases in affinity, and large amounts greatly reduce the rate of increase (45). It thus appears that decreasing levels of Ag act selectively to stimulate B cells that produce higher affinity Ab. After Ag disappears, some B cells survive and endure indefinitely as “memory cells.” When restimulated by Ag even years later, they promptly produce the high-affinity Abs they were making before becoming quiescent (46). H-chain class switching and hypermutation take place within germinal centers of lymph nodes (47, 48). Hence, B cells that have undergone this process and then dispersed throughout the body are called “postgerminal center” memory B cells, and the Abs they produce are “affinity-matured.”

Maturation of Ag-stimulated B cells. Ag (X)-stimulated naive B cells (I) proliferate and acquire mutations in Ab V domains (II), yielding progeny cells that express cell-surface Abs that differ in their affinity for the Ag (lower affinity, open symbols higher affinity, closed symbols) and in their ability to bind just a few ligands (V domain, rectangles) or a variety of different ligands (V domains, irregular circles). Decreasing Ag levels selectively stimulate the higher affinity Ab-producing B cells (III), some of which become memory cells that can be restimulated later (IV) by an Ag that is the same as the original (X), a variant of it (X′), or structurally entirely different (Y) to produce higher affinity relatively specific (Upper) or multispecific (Lower) Abs.

Against this background (Fig. 2), it has been proposed that the Abs made in the initial (primary) response to an Ag are flexible and multireactive, whereas those made later have combining sites that are less cross-reactive, more rigid, and better adapted conformationally to the Ag, thereby binding it with higher affinity (31, 49–51). Some evidence supports this possibility for instance: (i) crystal structure differences between some affinity-matured Abs and their presumed precursor early response Abs (49), (ii) molecular dynamics simulations that show decreasing conformational flexibility of an Ab that has been subjected to successive rounds of mutation and selection for higher affinity variants by directed evolution in vitro (52), (iii) more unfavorable entropy changes associated with ligand binding by the IgM Abs made initially to an Ag than with the affinity-matured IgG Abs produced later (30, 50), and (iv) considerable conformational flexibility and multireactivity of a germline-encoded Ab (39).

In apparent conflict with the foregoing, most of the mAbs demonstrated to be multireactive are affinity-matured (i.e., they have V domain mutations and switched H chains). The contradictory findings are inconclusive, however, because the increase in average affinity of the Abs produced over time is accompanied by increasing heterogeneity of affinity values (45), a likely consequence of the stochastic nature of the cytidine deaminase-driven hypermutation in V domains (44). Hence, mAbs derived from a few B cells plucked at random from heterogeneous pools of B cells with diversified Ab combining sites might be highly specific or highly multireactive.

An entirely different explanation for degenerate Ag recognition by some affinity-matured IgG Abs has emerged from studies by Nussenzweig and colleagues (34, 53, 54) of hundreds of mAbs derived from single human B cells. About 5% of mAbs from mature naive B cells bind multiple ligands (e.g., dsDNA, ssDNA, insulin, LPS) (54). The frequency of multireactivity with these ligands is increased to about 20% of mAbs from IgG memory B cells (34). In some HIV-infected individuals, it is increased even more, to about 75% of the B cells that make mAbs that bind gp140, a prominent antigenic glycoprotein spike on the HIV-1 virus (53). Many of these mAbs, like the multireactive 2F5 and 4E10 mAbs from other HIV-infected individuals, also bind cardiolipin, a phospholipid in many cell membranes (32, 33). The remarkably high frequency of these multireactive Abs, which have switched H chains and mutated V domains, suggests that they are selected by the HIV-1 virus, particularly during affinity maturation.

Why might B cells that make multireactive IgG Abs be selected? The two ligand-binding sites per IgG Ab molecule are structurally and functionally identical. They can characteristically bind simultaneously to closely spaced copies of the same epitope, as on common microbial Ags, like the hemagglutinin spikes on influenza virions or capsular polysaccharides of pneumococci. The affinity enhancement conferred by this form of bivalent binding may not be possible, however, for the multireactive anti-gp140 Abs, because the very few gp140 spikes per HIV-1 virion are likely too far apart (>15 nm) (53, 55). If, however, the binding sites of these Abs are conformationally flexible, one site could bind with high affinity to gp140 and the second site of the same Ab molecule could bind with low affinity to a different epitope on the same virion. The cooperativity inherent in this bivalent interaction could enhance an Ab molecule's binding to the virion (53) even if one of the ligands is bound very weakly. This asymmetrical binding or “heteroligation” requires multireactive combining sites. It differs distinctly from other forms of heteroligation, such as that displayed by genetically engineered bispecific Abs [formed by joining two half molecules (H-L heterodimers) from different mAbs].

Like some mAbs from HIV-1–infected individuals, serum Abs that bind cardiolipin and other self-Ags have long been known to occur in some persistent infections in humans (e.g., Epstein–Barr virus, hepatitis B virus, syphilis treponeme) and in mice (e.g., vaccinia virus) (56). Indeed, myeloma proteins, where evidence for Ab multireactivity surfaced about 40 y ago, have recently been found to have multiple V region mutations, and the myeloma tumor cells that produce them have been found to arise from postgerminal center memory B cells (57, 58). It is thus possible that highly multireactive mAbs, such as SPE-7, CB4-1, and others (see above), are products of memory B cells that remain from previous responses to certain pathogens and are later cross-stimulated by different Ags (59, 60) (Fig. 2, represented by Y).

Overall, it appears that affinity-matured Abs may be relatively rigid and highly specific or conformationally flexible and multireactive, depending on the nature of the selecting Ag, especially during affinity maturation (Fig. 2).


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Insect Infection and Immunity: Evolution, Ecology, and Mechanisms. Oxford University Press, 2009.

Research output : Chapter in Book/Report/Conference proceeding › Chapter

T1 - Specificity of the innate immune system

T2 - A closer look at the mosquito pattern-recognition receptor repertoire

N2 - The insect innate immune system is encoded by three major functional categories of genes that are involved in (1) recognition of invading microbes (2) immune-signal amplification and transduction and (3) effector mechanisms that mediate the killing and clearance of infectious microorganisms. Despite its lack of adaptive immune mechanisms and antibodymediated defences similar to those found in vertebrates, the innate immune system in insects is quite specific in its antimicrobial action. Once invading microbes are recognized through specific interaction between patternrecognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs), a variety of defence reactions can be activated. This chapter discusses the specificity of the innate immune responses at the level of PRRs, with a major focus on the mosquito Anopheles gambiae as a model system. It first provides a general overview of the insects' PRR repertoire and highlights some of its most interesting features with regard to antimicrobial defence. It then provides detailed molecular and functional descriptions of some of the best characterized PRR families.

AB - The insect innate immune system is encoded by three major functional categories of genes that are involved in (1) recognition of invading microbes (2) immune-signal amplification and transduction and (3) effector mechanisms that mediate the killing and clearance of infectious microorganisms. Despite its lack of adaptive immune mechanisms and antibodymediated defences similar to those found in vertebrates, the innate immune system in insects is quite specific in its antimicrobial action. Once invading microbes are recognized through specific interaction between patternrecognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs), a variety of defence reactions can be activated. This chapter discusses the specificity of the innate immune responses at the level of PRRs, with a major focus on the mosquito Anopheles gambiae as a model system. It first provides a general overview of the insects' PRR repertoire and highlights some of its most interesting features with regard to antimicrobial defence. It then provides detailed molecular and functional descriptions of some of the best characterized PRR families.


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Figure 1

Figure 1. Biologically relevant muramyl dipeptide fragment MDP-( ld ), the 6-amino-derivatives of the naturally occurring MDP-( ld ), and its unnatural diastereomer MDP-( ll ). The amine functionality installed at the 6-position provides a chemical handle for surface tethering in SPR.


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