TS1 - Immunology

Question 1

What is somatic recombination?

Answer 1

a type of gene rearrangement by which cells of the adaptive immune system physically cut out small regions of DNA and then paste the remaining pieces of DNA back together in an error-prone way.

Question 2

What is junctional diversity?

Answer 2

The addition or deletion of nucleotides during V(D)J recombination can create new sequences in the complementary determining regions, which can alter the antigen specificity and affinity of the receptor. This process is known as junctional diversity, and contributes to the diversity of antigen receptors in the immune system.

Question 3

What evidence suggests that MHC polymorphism is maintained by natural selection?

Answer 3

1. Within human populations, the number of MHC alleles is far higher than the number expected under neutrality.
2. When alleles don’t differ in their selective effect, they’re generally more evenly distributed within the population than expected under a purely neutral model of evolution.
3. Heterozygote excess are observed more often than predicted by Hardy-Weinberg expectations.
4. Maximum MHC heterozygosity of class I loci delayed AIDS onset among HIV-infected patients.

Question 4

What are opsonin receptors?

Answer 4

Opsonins are molecules that, when attached to the surface of microbes, make them more attractive to phagocytic cells, thus facilitating microbe destruction. Receptors for opsonins are present on phagocytic cells.

Question 5

What is isotype switching?

Answer 5

Isotype switching, also known as class switch recombination, is a process by which B cells change the class of antibody they produce, while maintaining the specificity for the same antigen. During isotype switching, the constant (C) region of the antibody heavy chain gene is rearranged, leading to the production of antibodies with different effector functions but the same antigen-binding specificity.

This occurs during the sequential reactivations and proliferations of memory B cells.

Question 6

Why are MHC molecules polygenic and polymorphic?

Answer 6

Polygenic:
It contains several different MHCI and II genes so that every individual possesses a set of MHC molecules with different ranges of peptide-binding specificities.

Polymorphic:
The MHC genes display the greatest degree of polymorphism in the human genome. There are multiple variants of each gene within the population as a whole. However, one MHC molecule can still bind many different peptides.

Question 7

What are scavenger receptors?

Answer 7

Involved in binding of modified low-density lipoproteins, some polysaccharides and some nucleic acids. They’re involved in the internalization of bacteria and in the phagocytosis of host cells undergoing apoptosis.

Question 8

What two models of balancing selection have been proposed to explain the maintenance of MHC polymorphism?

Answer 8

1. Heterozygote advantage model: heterozygous individuals are fitter than individuals homozygous for an MHC allele because two different alleles will identify a broader range of peptides.
2. Negative frequency-dependent model: more infrequent variants have a selective advantage over more common variants and thus tend to increase in frequency and avoid local extinction.

Question 9

What are the different types of T helper cells?

Answer 9

T helper 1: activates macrophages (intracellular pathogens)
T helper 2: activates B cells (helminths & allergies)
T helper 17: promote inflammation and neutrophil recruitment (extracellular bacteria & fungi)
T reg cells: maintain immune tolerance by suppressing the activation of other T cells

Question 10

What is somatic hypermutation?

Answer 10

Somatic hypermutation is a process by which the DNA sequence of the genes encoding the variable regions of immunoglobulins (Ig) and T cell receptors (TCR) are intentionally mutated in activated B and T cells during an immune response. The process introduces random point mutations into the variable regions of the genes, leading to the production of antibodies and T cell receptors with increased affinity and specificity for the antigen.

Question 11

Which cytokines drive Th17 differentiation, and what is their source?

Answer 11

IL-6, IL-23, and TGF-β from dendritic cells.

Question 12

Why are bats unaffected by Covid-19?

Answer 12

They have developed a special immune system to deal with the stress of flying, making molecules not found in other mammals to help repair cell damage. And their systems don’t overreact to infections, keeping them from falling ill.

Question 13

Which cytokines induce Th1 differentiation, and what is their source?

Answer 13

IL-12 and IFN-γ from dendritic cells, macrophages, and NK cells.

Question 14

What is the immunological synapse?

Answer 14

The immunological synapse is a specialized junction that forms between a T-cell and an antigen-presenting cell (APC) during the process of antigen recognition and activation of the immune response.

Question 15

What are the two B-cell lineages?

Answer 15

B1: little memory or diversity as they don’t require T-cell assistance.
B2: high memory capacity

Question 16

Describe the process of cell-mediated innate immunity when the skin is wounded.

Answer 16

1. Bacteria and other pathogens enter wound.
2. Platelets from blood release blood-clotting proteins at wound site.
3. Mast cells secrete factors that mediate vasodilation and vascular constriction. Delivery of blood, plasma, and cells to injured area increases.
4. Tissue-resident macrophages carry out phagocytosis and recruit neutrophils via cytokine secretion.
5. Complement arrives to aid in opsonization.

Question 17

Which cytokines induce Th2 differentiation?

Answer 17

IL-4 (from mast cells, basophils, or Th2 cells) and IL-10.

Question 18

How does T-cell independent activation of B-cells compare to T-cell dependent activation?

Answer 18

Independent: faster response, but reduced memory (IgM).

Dependent: slower but greater response and has greater memory (IgG).

Question 19

What are Toll-like receptors? What do they do?

Answer 19

TLRs mediate recognition of diverse pathogens. After binding to PAMPs, signal transduction from a TLR to the nucleus leads to enhanced activation of genes encoding cytokines and other molecules involved in antimicrobial activity. The result is synthesis and secretion of the cytokines that promote inflammation and the recruitment of leukocytes to the site of infection.

Question 20

What is opsonization?

Answer 20

Opsonization is a process by which a pathogen or other foreign particle is marked for destruction by phagocytic cells, such as macrophages and neutrophils. The opsonization process involves the binding of opsonins, such as antibodies or complement proteins, to the surface of the pathogen or foreign particle.

Question 21

What comprises the first line of host defence?

Answer 21

1. Skin (keratinization, sloughing, commensal microbes)
2. Mucus

Question 22

What are the implications for infections at the population level with regards to MHC molecules?

Answer 22

The evolution of MHC polymorphism ensures that a population won’t succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to the pathogen. Variations in MHC result from classical germ line inheritance of different MHC molecule combinations and not somatic recombination as seen in TCRs and antibodies.

Question 23

How do we know that variation isn’t evenly distributed across MHC loci?

Answer 23

1. Codons encoding the peptide-binding regions exhibit an excess of both polymorphisms and non-synonymous mutations.
2. The number of distinct MHC alleles present in most populations exceeds expectations under neutral evolutionary models.
3. Individual MHC alleles show divergence at a large number of nucleotide positions.
4. Many polymorphic variants have been retained over evolutionary timescales inconsistent with neutral drift alone.

Together, these observations strongly support the view that balancing selection — which promotes the retention and generation of allelic diversity — has played a major role in shaping the evolutionary trajectory of MHC genes.

Question 24

Describe the B-cell signaling cascade.

Answer 24

Cross-linking of the BCR leads to BCR aggregation, and the close proximity of the cytoplasmic tails of the Iga and IgB allows phosphorylation of their ITAMs by tyrosine kinases. Leads to a signal transduction cascade.

Question 25

Describe alternative activation of complement.

Answer 25

1. C3 breaks into two proteins C3a and C3b. 2. C3b anchors itself tightly to the pathogen. 3. C3b begins recruiting other complement proteins. 4. C5 convertase is formed, starting synthesis of the membrane attack complex. 5. The MAC protein forms a hole in the pathogen. C3a active other immune response proteins, such as macrophages and neutrophils.

Question 26

What can we learn from comparative immunology?

Answer 26

Discovery: - new ways of using the immune system - identify new pathways Controlling diseases in non-human hosts

Question 27

What are the differences between MHC I and II molecules?

Answer 27

MHC I: - captures endogenous antigens - recognized by CD8 killer T cells - present on all cells with a nucleus e.g., viral antigens MHC II: - captures exogenous antigens - recognized by CD4 helper cells - present only on dendritic cells, macrophages, and B-cells e.g., internalized microbes

Question 28

How are peptides loaded onto MHC I molecules?

Answer 28

1. Endogenous antigens are produced within the cell and broken down by proteasomes. 2. The fragments are transported to the ER by TAP proteins. 3. Inside the ER, the fragments bind MHC I molecules. 4. The peptide-MHC complex is transported to the cell surface and presented to CD8 T cells.

Question 29

What are the 3 characteristics of innate immunity?

Answer 29

1. Fast 2. Encoded by the germ line 3. Broad specificity

Question 30

How do dendritic cells activate T cells?

Answer 30

1. DCs take up antigens and process them. 2. DCs undergo a process of maturation, where they upregulate expression of costimulatory molecules and cytokines. 3. Migration from peripheral tissues to lymphoid organs. 4. DCs present antigens to T cells and provide costimulatory signals and cytokines to promote T cell proliferation and differentiation into effector cells.

Question 31

What is antibody-dependent enhancement?

Answer 31

Antibody-dependent enhancement (ADE) is a phenomenon in which certain antibodies can enhance the entry of a virus or pathogen into cells of the immune system. ADE occurs when non-neutralizing antibodies, which are antibodies that do not completely block the virus or pathogen from entering cells, bind to the virus or pathogen and facilitate its uptake by immune cells that express Fc receptors, such as macrophages or monocytes.

Question 32

Describe the expression pattern of MHC molecules and why this is important.

Answer 32

The particular combination of MHC alleles found on a single chromosome is known as an MHC haplotype. Expression of MHC alleles is codominant, with the protein products of both alleles at a locus being expressed in the cell, and both gene products being able to present antigens to T cells i.e., an individual expresses the alleles inherited from each parent. This means that the number of MHC molecules is maximized.

Question 33

What is affinity maturation?

Answer 33

Affinity maturation is a process that occurs in the memory B cells following exposure to an antigen. It involves the selection and proliferation of B cells with higher affinity B cell receptors (BCRs) for the antigen. Over time, the pool of memory B cells in the immune system becomes enriched with B cells expressing high-affinity BCRs, which can provide more rapid and effective protection against subsequent exposures to the same pathogen. This process is essential for the development of long-term immunity to pathogens, and is the basis for the efficacy of vaccines, which can induce memory B cell responses to specific antigens.

Question 34

Describe the process of antigen presentation.

Answer 34

1. Antigen uptake 2. Antigen processing 3. MHC loading 4. T-cell presentation and activation In order for the T cell to engage, you need two signals: the peptide and the recognition of self, through either CD4 or CD8. Only when this happens is the T cell activated.

Question 35

Why was there thought to be a problem of diversity with regards to T-cells? How was this overcome?

Answer 35

The ligand for the TCR - MHC molecules- are extremely polymorphic and may be complexed with a universe of foreign particles. Although the binding of peptide to MHC is degenerate, the TCR must be sufficiently specific to distinguish between the various peptide-MHC complexes that may arise. This is overcome by TCRs being incredibly diverse.

Question 36

What is allelic exclusion?

Answer 36

Allelic exclusion is a process by which a developing B or T cell selects and expresses only one of its two alleles for the gene encoding its antigen receptor, either the maternal or paternal allele, while the other allele is silenced or inactivated. This process ensures that each B or T cell expresses only one unique antigen receptor, and helps to generate a diverse repertoire of receptors capable of recognizing a wide range of antigens.

Question 37

What is the classical complement pathway?

Answer 37

This can be initiated by IgM binding to an antigen on a pathogen surface, triggering recruitment of complement proteins and resulting in MAC formation.

Question 38

What are 3 characteristics of emerging pathogens?

Answer 38

1. RNA viruses 2. Zoonotic (acquired from animal reservoirs) 3. Sapronotic (acquired from the environment e.g., soil, water, corpses)

Question 39

Why are people over the age of 55 more susceptible to infection?

Answer 39

When we're born, our thymus is one of the biggest organs that we have. It makes T cells until we're around 50 years of age. After 50, the thymus shrinks and releases all its contents to circulation. This means those over 55 have a set number of naïve T cells for the rest of their lives (no new production of T cells). These people will start to deplete their pools of T cells as they age, which is why older people are more susceptible to viral infections.

Question 40

Describe the process of T-cell selection.

Answer 40

1. Positive selection - Thymocytes able to interact with MHC molecules are retained. - Make sure T cells interact with MHC molecules 2. Negative selection - Thymocytes that react against self-epitopes on the surface of the thymus are eliminated. Make sure they don't interact with any other self-antigens (self-reactive).

Question 41

What are T-cell receptor proteins?

Answer 41

A protein complex found on the surface of T cells that is responsible for recognizing fragments of antigen as peptides bound to MHC molecules. The binding is low affinity and degenerate, allowing for TCRs to recognize many antigens. They come in two different protein chains: alpha-beta (95%) and gamma-delta (5%).

Question 42

Why does Covid cause lung failure?

Answer 42

The cytokines released in response to the virus can trigger a cytokine storm, leading to lung failure and need for respirators.

Question 43

What are the non-pathogen-mediated mechanisms thought to have driven MHC diversity?

Answer 43

- sexual selection - autoimmunity - reproductive selection

Question 44

What are two key examples of antimicrobial peptides, and how do they work?

Answer 44

1. Lysozyme - breaks down peptidoglycan of gram-positive bacterial cell walls. 2. Defensins - directly attack the cell wall of microorganisms These aim to disrupt the inner membrane to cause either efflux, or will detach part of the membrane and start taking it apart to directly destroy the bacterium.

Question 45

How do B cells develop?

Answer 45

1. Pro-B cell stage - Heavy chain D–J then V–DJ recombination. 2. Pre-B cell stage - Expresses rearranged heavy chain with surrogate light chain (pre-BCR). Successful heavy chain rearrangement → allelic exclusion. Undergoes light chain V–J recombination. 3. Immature B cell - Expresses complete membrane-bound IgM (functional BCR). Undergoes negative selection: 4. Mature naive B cell (transitional stage) - Expresses both IgM and IgD via alternative splicing. Exits bone marrow to peripheral lymphoid tissues.

Question 46

What are T-cell independent antigens? Describe the 2 classes.

Answer 46

Molecules that can stimulate the production of antibodies without the need for T cell help. They come in 2 classes: - type I: induce polyclonal antibody secretion - type II: induce specific antibody secretion, particularly IgM

Question 47

What is dectin-1?

Answer 47

Transmembrane PRR that specifically recognizes fungal cell wall components, such as beta-glucans.

Question 48

Why, in theory, should advanced cancer not exist?

Answer 48

Antigens displayed on cancerous cell surfaces are very different compared to normal cells. Immune cells should destroy these, but this isn't the case. One of the most important adaptations of tumor cells is the suppression of the local immune system.

Question 49

What is meant by complement? How can it be activated?

Answer 49

Complement is a collective term for a system of proteins that function in both innate and adaptive branches of the immune response as soluble means of protection against pathogens. In the innate immune system, complement can be activated by: the alternative pathway, in which antigen is recognized through particular characteristics of its surface, or the mannan-binding lectin (MBL) pathway. The classical pathway is activated after adaptive immune activation.

Question 50

How are peptides loaded onto MHC II molecules?

Answer 50

1. Exogenous antigens are taken up by endocytosis/phagocytosis and transported into endosomes. 2. The antigens are broken down by lysosomal proteases. 3. MHC II molecules are synthesized in the ER and transported to endosomes, where they bind the fragments. 4. The complex is transported to the cell surface and presented to CD4 T cells. [loading is related to pH]

Question 51

What are NODs/NOD-like receptors?

Answer 51

NODs and NLRs are intracellular PRRs that sense bacterial peptidoglycans. Upon recognition of their respective ligands, NODs and NLRs activate downstream signaling pathways which lead to production of pro-inflammatory cytokines and antimicrobial peptides, as well as the initiation of apoptosis or autophagy.

Question 52

How do CD4+ cells differentiate?

Answer 52

When a naive CD4+ T cell encounters an antigen presented by an APC, the TCR and CD4 molecule on the T cell bind to the antigen-MHC-II complex on the APC. This interaction leads to the activation of the CD4+ T cell and the production of cytokines such as IL-2. IL-2 promotes CD4+ T cell proliferation and the expression of transcription factors T-bet or GATA-3, master regulators of CD4+ T cell differentiation. The differentiation of CD4+ T cells into specific effector subsets depends on the cytokine environment and the type of pathogen encountered.

Question 53

What are tissue-resident macrophages?

Answer 53

Tissue-resident macrophages are a specialized population of macrophages that reside in various tissues throughout the body, including the liver, lung, spleen, brain, and skin. They have specialized functions that are tailored to the specific needs of each tissue.

Question 54

What is the process of CD8+ T cell activation?

Answer 54

1. Antigen presentation 2. Co-stimulation 3. Clonal expansion 4. Differentiation into effector CTLs 5. Migration to site of infection 6. Effector CTLs kill target cells by releasing perforin and granzymes, as well as releasing other cytokines.

Question 55

How are immune complexes removed from circulation?

Answer 55

- Phagocytosis via Fc regions - Complement proteins that are bound to immune complexes can be targeted by erythrocytes for transport to the liver and spleen for phagocytosis.

Question 56

How are memory T cells generated?

Answer 56

1. Activation and expansion of T-cells 2. Contraction phase, leaving a smaller population of T cells 3. Remaining T cells differentiate into memory T cells 4. Migration to specific niches for long-term maintenance.

Question 57

What happens within T-cells when TCRs bind MHC molecules?

Answer 57

1. Receptor dimerization and autophosphorylation of tyrosine residues (ITAM motif). 2. Signaling cascade activated that gives NFAT and AP-1. 3. CD45 ligand on the T-cell dephosphorylates and results in a MAPK cascade.

Question 58

How was pattern recognition discovered?

Answer 58

It was seen that when a vaccine was prepared and followed a very strict preparation of antigen, the response in people was lower than if they weren't as strict in purification which allowed impurities in the form of fragments of the microbe i.e., less purification gave a better vaccine. This suggested the presence of receptors that recognize the impurities first, and then the immune system recognizes the antigen. Hence the innate system acts before the adaptive system.

Question 59

Describe the MBL pathway of complement activation.

Answer 59

1. Binding of glycoproteins commonly found on microbial surfaces by lectins. 2. Formation of C3 convertase, producing C3b. 3. Formation of C5 convertase, producing MAC.

Question 60

How can cytotoxic T cells induce cell death?

Answer 60

1. Granzymes 2. Perforins 3. Fas and FasL (binding of these two receptors induces activation of the caspase cascade and ultimately programmed cell death)

Question 61

What are the key models used to describe how the immune system recognizes and responds to self vs nonself?

Answer 61

1. Self-nonself model - splits all antigens into self and nonself. 2. Infectious-nonself model - splits antigens into non-infectious self and infectious non-self, suggesting the existence of PAMPs on pathogens that are recognized by PRRs on antigen-presenting cells. 3. The Danger model - This model suggests that the immune system is more concerned with damage than with foreignness, and is called into action by alarm signals from injured tissues, rather than by the recognition of non-self.