Module 7 - Immunology

Question 1

What is immunity?

Answer 1

the ability to resist infectious disease

Question 2

Immune system is comprised of:

Answer 2

1. Cells – white blood cells (leukocytes), and other cells resident in the tissues e.g. macrophages
2. Organs – e.g. spleen and lymph nodes
3. Secreted factors – e.g. antibodies

Question 3

Immune system functions:

Answer 3

1. control pathogens that enter the body (viruses, bacteria, and parasites) and cancers.
2. maintaining a healthy relationship with the normal microbiome at the body surface.

Question 4

The study of immunology

Answer 4

relates to the functioning of immune cells and systems. This includes roles in homeostasis and non-infectious pathologies.

Question 5

Pros of the immune system

Answer 5

Control of infections
Control of cancer cells
Vaccination
Tolerance of fetus

Question 6

Cons of the immune system

Answer 6

Autoimmunity – immune system attacking
the body
Chronic inflammation – atherosclerosis,
type II diabetes, Alzheimer’s Disease,
asbestosis etc…..
Immunodeficiency – genetic deficiencies
and AIDS
Allergies

Question 7

Different pathogens and their challenges

Answer 7

Viruses: have few molecules, replicate within cells, and have rapid evolution
Bacteria: can live in extracellular space, or within
phagosomes or cytoplasm of cells
Large worm parasites: Live within body fluids or gut
Unicellular eukaryotic: parasites frequently live
inside cells

Question 8

Mechanisms mediating resistance to infection

Answer 8

Physical and chemical barriers:
can be breached by injury, insect bites,
invasive pathogens.

Innate immune system:
* Acts within minutes to days of infection.
* Important for control until acquired response
develops.
* If innate immunity rapidly clears the infection, an
acquired immune response will not develop.
* Responds similarly each time a specific
organism is encountered – no “memory

Adaptive or acquired immune system:
* Effective from about 4-5 days after an initial
infection.
* Has specificity for recognising particular
pathogen molecules, and memory of previous
infections – hence is essential for long-lived
immunity and vaccines.

Question 9

Barriers to entry for pathogens

Answer 9

Physical barriers
* Skin and other epithelial surfaces have tight junctions between cells preventing entry of organisms.
* Mucus in the gut is a thick layer that prevents association between bugs and the epithelium. Mucus
in the lung entraps organisms.
* Physical removal of bacteria – flow of urine, shedding of mucus in gut, ciliated epithelium moving
mucus up and out of the lung.

Chemical barriers
* Acid pH - acid in stomach kills many bacteria (pH 2), surface of the skin is also acidic (pH 5).
* Antimicrobial peptides secreted onto epithelial surfaces – can disrupt bacterial membranes.
* Enzymes e.g. Lysozyme in tears, mucus and saliva degrades some bacterial cell walls.

Biological competition
* Commensals in gut and skin compete with pathogens – if the niche is already occupied, pathogens
cannot easily move in.

Question 10

Innate Immunity

Answer 10

Rapidly acting – first activated within minutes to hours of infection
* Response is similar each time the same pathogen is encountered
* Initiates inflammation = redness, heat, swelling, pain – influx and activation of immune cells
* Complement system – several dozen secreted proteins that can directly attack bacteria by making
pores in the bacterial membrane leading to lysis, or alternatively by “marking” bacteria for
phagocytosis.
Phagocytosis and destruction of pathogens by neutrophils, macrophages, dendritic cells (DC)
* Other innate immune cell types - basophils, eosinophils, natural killer cells in the blood, and mast
cells in the tissues adjacent to blood vessels. Mast cells are involved in allergy

Question 11

Cells of the Innate Immune system

Answer 11

Phagocytes
Neutrophils
Monocytes, Macrophages and DC

Question 12

Phagocytosis

Answer 12

Recognition of organism by phagocyte
receptors
* Extension of membrane around organism,
fusion of membrane to form phagosome
* Fusion of phagosome with a lysosome, an
organelle containing degradative enzymes.
Then, acidification of the phago-lysosome.
* Bacteria are killed and degraded by the
generation of reactive free radicals –
molecules with an upaired electron (e.g.
superoxide O2) and enzymes activated by low
pH.
* Bacteria may evade phagocytosis e.g. through
having a capsule, and evade killing, e.g. by
preventing acidification

Question 13

Phagocytes

Answer 13

play a major role in the early response to pathogens. Phagocytes include macrophages, neutrophils and dendritic cells (DC).

Question 14

Neutrophils

Answer 14

• 60-70% of all white blood cells in humans
• Multi-lobed nucleus and cytoplasmic “granules”. Granules are membrane-bound vesicles containing
  antimicrobial peptides, lysozyme enzyme that attacks bacterial cell wall, degradative enzymes.
• The first cell type to migrate to sites of infection or tissue damage
• Phagocytose and kill invaders.
• Short-lived, and many die at the site of infection, contributing to the formation of pus. In the process of dying
  they can release DNA and anti-bacterial proteins which together trap and kill organisms.

Question 15

Monocytes, Macrophages and DC

Answer 15

Macrophages are phagocytes resident in tissues – involved in immunity as well as wound healing and
tissue remodelling
* Monocytes are the blood precursors of macrophages, and are approx. 5-10% of leukocytes (white
blood cells)
* In an infection, tissue resident macrophages play a role in phagocytosing pathogens, but there is also
recruitment of monocytes from blood which differentiate into macrophages, and then phagocytose and
kill pathogens
* Release proteins to attract other cells (“chemokines”) and activate other immune cells (“cytokines”)
* Dendritic cells (DC) are phagocytic innate immune cells closely related to macrophages, but are more
specialised for activating T cells and the acquired immune response.

Question 16

Inflammation

Answer 16

The body’s early response to infection or injury – swelling, redness, pain, heat
* Inflammation helps to attract and activate immune cells, and prevent the spread of infection
* Requires release of chemokines and cytokines by innate immune cells. Inflammatory cytokines
increase blood vessel permeability leading to swelling (edema), and cause fever. Fever boosts both
innate and acquired immunity.
* Inflammation should progress to, and promote wound healing as infection clears
* Chronic inflammation that doesn’t get switched off causes tissue damage
* Systemic (body-wide) inflammation can cause septic shock and death

Question 17

Initiation of inflammation

Answer 17

Inflammation can be initiated by:
(i) Cell damage - release of molecules
from damaged cells – “danger signals”
(ii) Recognition of pathogen molecules –
PAMPs

Question 18

How do innate immune cells recognise pathogens?

Answer 18

Innate immune cells recognise characteristic molecules that are conserved amongst classes of
pathogens. These are called “Pathogen Associated Molecular Patterns” or PAMPs
* PAMPs include many bacterial and yeast cell wall products, e.g. lipopolysaccharide, the major
component of Gram-negative bacterial outer membrane. Nucleic acids (DNA and RNA) are major
PAMPs for recognition of viruses.
* These bind to receptors on innate immune cell cell surface or in the cytoplasm. There are a limited
number of different receptors (maybe several dozen) recognising these characteristically foreign
PAMPs

Question 19

Responses to PAMPs include:

Answer 19

1. Secretion of cytokines and chemokines – enhanced inflammation
2. Recognition of organisms for phagocytosis
3. Enhanced killing by phagocytes
4. Maturation of dendritic cells, so they can activate T cells

Question 20

Cytotoxic T Cells

Answer 20

*Kill virally infected cells or tumour cells.
*Release granules which induce apoptosis.

Question 21

Where do immune cells develop?

Answer 21

bone marrow stem cells

Question 22

Why do lymph nodes swell in infections?

Answer 22

– active immune response and cell influx
– infection of node

Question 23

Lymph contains:

Answer 23

*Leukocytes
*Proteins similar to plasma
*Cell debris
*Pathogens
*(Cancer cells)

Question 24

Is the lymph pumped?

Answer 24

Lymph is not pumped, but moved via skeletal muscle contractions

Question 25

Why is fluid from peripheral tissues drained?

Answer 25

Drainage of fluid from the peripheral tissues into lymph nodes allows surveillance for foreign molecules in the lymph node

Question 26

Functions of The Lymphatic System

Answer 26

* Some blood plasma (and a few leukocytes but no red cells) leaves the capillaries and enters tissues. * Fluid drains out of the tissues into the lymphatic capillaries and vessels. * Lymph fluid returns to the blood stream via the thoracic duct. * Lymph nodes are filled with immune cells, and act as filters which capture pathogens, antigens and particulate material.

Question 27

Uses of Antibodies

Answer 27

- as a drug: e.g. in rheumatoid arthritis to inhibit cytokines causing inflammation, and to neutralise toxins after snakebite - in medical diagnosis: e.g. pregnancy testing, infections, blood cell counts - in experimental science used in many applications, including to: * measure the levels of proteins (e.g. in serum) *examine the location of proteins of interest using fluorescently-labelled antibodies and fluorescence microscopy

Question 28

structure of an antibody

Answer 28

a Y-shaped structure which consists of four polypeptides — two heavy chains and two light chains

Question 29

Architecture of the Immune System

Answer 29

Immune cells develop in the primary lymphoid organs - bone marrow and thymus. All immune cells develop from bone marrow stem cells. T cell progenitors move to the thymus in the embryo and early life, where they mature. They undergo “central tolerance” here – i.e. T cells that strongly react to self-molecules die off. All other immune cells develop in the bone marrow. * Mature naïve T and B cells circulate through the blood and lymph and secondary lymphoid tissues in a surveillance pattern, looking for foreign * The B and T cell response to foreign antigens* is initiated in the secondary lymphoid tissues. These are the spleen, lymph nodes and mucosal- associated lymphoid tissues (MALT) – e.g. tonsils, adenoids, Peyer’s patches in the gut.

Question 30

Where do antigens go?

Answer 30

- Antigen from peripheral tissues, drains to lymph nodes - Antigen from blood infections, collects in the spleen - Antigen from mucosal surfaces accumulates in MALT

Question 31

Acquired (or adaptive) immunity

Answer 31

* Acquired immunity involves lymphocytes – T cells and B cells * Secreted antibody proteins are made by B cells. * T cells provide “cell-mediated immunity”. They can directly kill infected cells, or have “helper” functions for B cells and macrophages – see later in this lecture.

Question 32

Acquired immunity has....

Answer 32

- specificity and memory - The key features of acquired immunity are specificity for individual pathogen molecules and memory of prior exposure to infections. * The receptors for foreign antigens are termed B cell receptor (BCR) and T cell receptor (TCR). There are millions of different possible BCR and TCR proteins with different binding specificity. Each B or T cell has receptors with a single binding specificity * Antibodies are a secreted form of the BCR *“Memory” means if an infection occurs a second time, the response is more rapid and effective. This is the basis for vaccination and immunity to subsequent infections * Slower to develop than innate immunity – requires approx. 5 days

Question 33

Clonal Expansion

Answer 33

1. Progenitor cell 2. Lymphocyte pool with different Ag specificity 3. Removal of self-reactive lymphocytes during their development in bone marrow (B cells) and thymus (T cells) leads to self tolerance 4. Recognition of foreign antigen by mature naïve lymphocytes and clonal expansion

Question 34

Acquired immunity can generate long-lasting or slow-lasting protection?

Answer 34

- long-lasting * Some infections (e.g. measles, diptheria) give life-long immunity. * This is due to formation of memory T and B cells which maintain enhanced functions for eliminating a specific pathogen. * This is the basis of vaccination- the secondary response to a foreign protein is faster and more effective

Question 35

what are antibodies?

Answer 35

* Activated B cells become plasma cells that secrete antibodies- also called immunoglobulin (Ig). * Antibodies are soluble proteins which can bind with high affinity to foreign antigens. The origin of the word antigen (Ag) is antibody generating. (N.B. proteins recognised by T cell receptors are also antigens) * Useful against extracellular organisms and toxins. * Individuals can potentially make millions of different antibody molecules which bind different antigens

Question 36

5 “classes” of antibodies

Answer 36

- IgM, IgD, IgG, IgA, IgE - The type of constant region determines different downstream effects. * IgM is the first type of antibody made in an immune response. Specific IgM detected in plasma indicates a recent/ongoing infection. * IgG - the major class found in blood, comes up later than IgM. It crosses the placenta, and protects the newborn for several months. * IgA - Present in tears, saliva, mucus, milk as well as blood. Protects mucous membranes. * IgE – Activation of mast cells and basophils. Involved in allergy and anti-helminth (worm parasite) responses

Question 36

Consequences of Antigen Recognition by T and B cells

Answer 36

1. Proliferation * Particular B cells and T cells recognising antigen will proliferate = clonal selection or clonal expansion. 2. Differentiation * B and T cells develop mature “effector” cell function. * B cells become antibody-secreting cells (“plasma cells”) * T cells become cytotoxic T lymphocytes (CTL) or T helper cells * Some T and B cells become long-lived memory cells

Question 36

Ways in Which Antibodies Act:

Answer 36

1. Neutralisation - antibody binding to virus can block entry into cells. Antibody can also neutralise bacterial toxins (e.g. tetanus toxin) and prevent effects on cells 2. Opsonisation (coating of organisms) to promote phagocytosis via receptors for antibodies on phagocytes. 3. Activation of the complement system –leading to bacterial lysis and inflammation 4. IgE binds to mast cells. When it recognises antigen (frequently allergens) the mast cells release histamine (inflammatory small molecule).

Question 36

Consequences of T Cell Activation

Answer 36

(i) T helper cells that either:- - release cytokines that help promote B cell antibody production - release cytokines that help activate macrophages to kill phagocytosed organisms (ii) Cytotoxic T lymphocytes - “CTL” - Effective against tumour cells and virally infected cells. - They do not directly attack pathogens themselves. - Recognition of antigen causes secretion of granules containing proteins which induce apoptosis (cell death) in target cells

Question 37

Comparison of B and T Cell Antigen Recognition

Answer 37

* The B cell antigen receptor (BCR) is a membrane bound antibody (Ig) molecule. * T cells recognise antigen through the T cell receptor (TCR) which is evolutionarily related to the BCR, but has no secreted form. It has two chains (a and b), with variable and constant regions like BCR. The two chains together form one variable antigen-binding site. * Each B cell makes one specific BCR/antibody and each T cell makes one specific TCR. * Antibodies/BCR and TCR recognise a small region of a whole protein antigen * BCR/antibody can recognise an intact protein antigen, whereas the TCR requires the antigen to be processed by proteases into short peptides (8-13 amino acids) that are bound on the surface of an antigen presenting cell (APC) on MHC molecules.

Question 38

The activation of naïve T cells occurs in:

Answer 38

the spleen and lymph nodes

Question 39

The role of adjuvants in vaccines is:

Answer 39

to provide an innate immune stimulus

Question 40

Which statement regarding the relationship between innate and acquired immunity is FALSE? A. Due to its lack of specificity, the innate immune system cannot clear any infections, but it is important for keeping them under control until the acquired immune response has developed. B. The innate immune response to a particular organism will be the same each time it is encountered, but the acquired immune response is strengthened through generation of memory cells. C. The innate and acquired immune responses both involve cellular receptors recognising foreign molecules. D. The acquired immune response will not develop in the absence of an innate response. E. Some innate immune cells as well as acquired immune cells have capacity to directly kill virally infected cells.

Answer 40

A. Due to its lack of specificity, the innate immune system cannot clear any infections, but it is important for keeping them under control until the acquired immune response has developed.

Question 41

4. Which statement regarding the comparison between B cell receptors (BCR) and T cell receptors (TCR) is FALSE? A. Generation of the variability in BCR and TCR both require recombination, that changes the inherited DNA sequences coding for the receptors. B. The BCR has a secreted form, but the TCR does not. C. The amino acids in a T cell antigen epitope have to form a continuous stretch in the protein sequence, whereas those in a B cell epitope could be brought together from different parts of the polypeptide, through the folded structure of the protein. D. Although each TCR has only one antigen binding site, each BCR has two antigen binding sites, one made by the heavy chains, and one from the light chains. E. Each BCR is made from four separate protein chains, whereas the TCR contains two chains.

Answer 41

D. Although each TCR has only one antigen binding site, each BCR has two antigen binding sites, one made by the heavy chains, and one from the light chains.

Question 42

Allergies are predominantly a result of:

Answer 42

Binding of allergen by IgE antibodies leading to mast cell histamine release.

Question 43

Which statement about neutrophils is FALSE? A. Neutrophils secrete neutralising antibodies. B. Neutrophils are the most abundant white blood cell. C. Neutrophils release DNA to entrap microorganisms. D. Neutrophils are the first cell recruited to sites of inflammation. E. Neutrophils are phagocytes.

Answer 43

A. Neutrophils secrete neutralising antibodies Only B cells secrete antibodies. Neutrophils are phagocytes.

Question 44

7. Which statement about autoimmunity is FALSE? A. Autoimmunity is more common in women than men. B. Type I diabetes is an autoimmune condition. C. Development of autoimmunity is partly genetically determined, but is also thought to have environmental triggers such as infections. D. Autoimmunity can be generated by chronic activation of the innate immune system, without T and B cell involvement. E. Amongst people of similar ethnic background, multiple sclerosis is less prevalent in those who live closer to the equator than those who live at high latitudes.

Answer 44

D. Autoimmunity can be generated by chronic activation of the innate immune system, without T and B cell involvement.

Question 45

Short answer question A new virus that replicates in the liver was found in intravenous drug users. (i) Describe one acquired immune response that should act directly against virally-infected cells, and discuss the mechanism involved. (2 marks)

Answer 45

Cytotoxic T lymphocytes (CTL) will directly kill the virally-infected liver cells. The viral antigens are cleaved into peptides and displayed on MHC molecules on the surface of the infected cell. The T cell receptor of the CTL recognises the peptide displayed on the infected cell surface and releases granules that induce cell death in the target cell.

Question 46

(ii) Describe one acquired immune response that attacks the extracellular virus, and a mechanism through which this might reduce viral load. (2 marks)

Answer 46

Antibody is produced by B cells and will bind to molecules on the surface of the viral particles. This may have a neutralising effect, whereby it blocks binding to cell surface receptors or blocks the function of a viral surface protein, stopping entry into the cell. This then stops infection of new cells and production of more virus.

Question 47

What is the major class of pathogen associated molecular patterns (PAMPs) in viruses that lead to activation of the innate immune system? (1 mark)

Answer 47

Viral nucleic acids (RNA and DNA) are the principal PAMPs activating the innate immune response.

Question 48

Outline of an Immune Response to Infection

Answer 48

1.Detection of pathogen molecules or cellular damage by cells at site 2. Release of chemokines and cytokines 3. Inflammation – redness, swelling, pain, heat 4. Influx of neutrophils – phagocytosis 5. Influx of macrophages - phagocytosis 6. Phagocytosis of organism by dendritic cell (DC) and activation of DC by foreign molecules 7. Migration of DC bearing foreign antigen in the draining lymph to the lymph node if infection is in tissues (or MALT if in mucosa or spleen if in blood) 8. Presentation of foreign antigen on major histocompatibility molecules (MHC) of DC to T cells in lymph node/MALT/spleen 9. Activation of naïve T cells which specifically recognise foreign antigen 10. Proliferation of specific T cell into a large clone of cells 11. T cells become cytotoxic T cells (CTL) or T helper cells 12. In lymph node/MALT/spleen, T helper cells promote differentiation and proliferation of B cells which secrete antibodies binding to pathogen 13. Activated T cells leave lymph node and travel to site of infection 14. T helper cells help macrophages kill ingested organisms 15. CTL directly kill virally infected cells 16. After infection is cleared, B and T cell clones decline, but memory cells remain

Question 49

Dendritic Cells (DC)

Answer 49

* The major antigen-presenting cell (APC) involved in activation of naïve* T cells (*“naïve” T or B cells are those that have never responded to their cognate antigen) * Immature DC reside in tissues and blood as sentinels, looking out for infection * DCs take up soluble antigens and whole pathogens *Upon pathogen encounter, they are activated to mature and migrate to lymph node (or if they are in the blood they exit into the spleen). There they activate T cells which recognise peptide on MHC.

Question 50

MHC Molecules

Answer 50

* Proteins involved in display of Ag to T cells are MHC (major histocompatibility complex) * In humans, the MHC proteins are called HLA *The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells.

Question 51

COVID-19 vaccines

Answer 51

* SARS-Cov2 is the cause of COVID19. spike protein facilitates entry of lung epithelial cells by binding to the angiotensin- converting enzyme 2, or ACE2 receptor. * Spike protein is the main target for vaccine development, as antibodies will block viral entry into cells * But spike evolves to evade immunity, so including other more conserved proteins in the vaccine may help.

Question 52

Critical Immunisation Threshold

Answer 52

- The fraction of the population who need to be vaccinated for a given disease - qc =1–1/R0 - “R-nought” - the Basic Reproduction Number - The average number of people who will be infected by one infectious person in a completely susceptible population

Question 53

What kind of immunity do vaccines work through?

Answer 53

- Vaccines work through herd immunity * If a high enough proportion of the community are vaccinated, the infection cannot maintain transmission * Some immunocompromised people can’t be vaccinated, but they can be protected by community vaccination

Question 54

Smallpox

Answer 54

- The smallpox vaccine is live vaccinia virus. - highly effective vaccine generating antibodies to multiple target antigens – and the memory response lasts 60 years!

Question 55

Different approaches to vaccination

Answer 55

1. Live attenuated organisms: The pathogen has become non-virulent through mutations. Examples of attenuated viral vaccines - yellow fever; measles/mumps/rubella; chicken pox. 2. Live vectored vaccines: e.g. Adenovirus engineered to express SARS-CoV2 spike protein - Astra- Zeneca vaccine 3. Inactivated (killed) pathogens: Pathogen killed by chemical treatment, detergent or heat. Examples for viruses - influenza, inactivated polio vaccine; bacteria- Vibrio cholerae (cholera), Yersinia pestis (plague). Effect can often be improved with adjuvants. 4. Subunit vaccines: Purified single antigen or group of antigens used as vaccine. Good safety profile. Examples – hepatitis B, Bordetella pertussis – whooping cough, human papilloma virus. Needs adjuvant. 5. Toxoid vaccines: Vaccinate with a toxin secreted by the pathogen. Example – tetanus, diptheria 6. mRNA vaccines: Administer mRNA that needs to get into host cells to be translated into the pathogen protein. Pfizer and Moderna SARS-CoV2 vaccines. RNA itself can act as an adjuvant.

Question 56

Activation of naïve T cells needs....

Answer 56

- activated DCs - The DC must recognize that there is “danger” (e.g. PAMP recognition) to be competent for T cell activation. - Since T helper cells are needed for B cell responses, the process of DC activation controls the whole acquired immune response. Thus, PAMPs or other means to activate innate immune cells are critical. - A vaccine must supply both the foreign antigen, and a means of activating DC

Question 57

Most vaccines work primarily through....

Answer 57

- antibody production. - This requires T helper and B cell activation.

Question 58

Vaccines need ...

Answer 58

both an antigen and an innate immune stimulus

Question 59

What modern lifestyle factors might alter the microbiome?

Answer 59

* caesarian birth, and bottle-feeding * antibiotic use * household cleanliness, and parents preventing kids eating dirt * antibacterial products – cleaning products, pillows, cutting boards, dish cloths, toothpaste (triclosan – a surgical “scrub” antiseptic until recently in Colgate Total.) * urban and indoor lifestyle – lack of contact with nature and soil * exposure to animals, particularly on traditional farms, is protective against allergy * diet and obesity modify gut flora extensively

Question 60

Dietary Fibre

Answer 60

* Dietary fibre is complex carbohydrates that are resistant to digestion in the small intestine. Highly processed food is lacking in fibre. We need whole grains, fruits and veges. * High fibre diet changes the gut flora * These are anti-inflammatory. They act on receptors on immune cells and prevent excessive immune activation. * reduce cholesterol, control blood glucose, reduce colon cancer

Question 61

Epidemiological studies point to ________ promoting allergy and autoimmunity

Answer 61

Epidemiological studies point to lifestyle factors promoting allergy and autoimmunity

Question 62

COVID-19 is the illness caused by

Answer 62

SARS-CoV2 coronavirus

Question 63

SARS-CoV2

Answer 63

evolved originally from bat viruses, but whether it took a path through other animals is not known. SARS, MERS, Ebola, Hendra and Nipah viruses all provide recent examples of epidemics that have started from wildlife.

Question 64

COVID-19 can cause.....

Answer 64

COVID-19 is highly variable, but can cause severe lung inflammation, vascular and cardiac inflammation, disseminated intravascular coagulation, and organ failure. Excessive innate immune activation and cytokine production is likely a major culprit in the pathology.

Question 65

Immunodeficiency Diseases

Answer 65

* Immunodeficiency can be genetic, or due to exposure to chemical or biological agents e.g. human immunodeficiency virus (HIV). Stress can also lower immune function. * Immunodeficient people are subject to recurring infections and cancer

Question 66

Genetic Deficiencies in the Acquired Immune System

Answer 66

* Defects in B cell production/function cause susceptibility to extracellular bacterial infections and gut viruses, but many other infections are cleared, as T cell responses are intact. * T cell deficiency is more severe than B cell deficiency, as T helper cells are required for most B cell activation and antibody production. Consequently T cell deficiency causes “Severe Combined Immunodeficiency” (SCID) * SCID Patients would typically die before 1 year of age if untreated. Approx. 1 in 100,000 births have SCID

Question 67

Acquired Immunodeficiency Syndrome (AIDS)

Answer 67

* Human Immunodeficiency Virus-1 (HIV-1) is a retrovirus – a virus with an RNA genome which is reverse transcribed into double stranded DNA. This DNA integrates into the genome of infected cells. * HIV-1 infects cells with the surface molecule CD4 including T helper cells * HIV-1 leads to the death of T helper cells, resulting in immunodeficiency and development of AIDS. * AIDS patients are subject to many infections (e.g. tuberculosis, fungal pneumonia, Candida yeast infections) and cancers. * HIV is now well controlled with drug treatment.

Question 68

Autoimmunity – Type I Diabetes

Answer 68

* An organ-specific autoimmune condition * Pancreatic islet b-cells that are responsible for insulin production are specifically destroyed by CTL * Loss of insulin production = loss of control of blood glucose levels * Islet-specific T helper cells and CTL recognise a range of b-cell specific antigens, including insulin itself

Question 69

Autoimmunity - Multiple sclerosis

Answer 69

* Affects nerves of central nervous system - problems with sensation, movement, vision * Myelin sheath surrounding nerve axons is attacked, which disrupts transmission of nerve signals * More common in Caucasian women living in Northern Europe than in the tropics – consequently a role for sunlight is proposed. Sunlight is known to regulate immune responses. * All patients have Epstein Barr virus (EBV) infection – this virus lives long-term in B cells although the specific role of EBV is not understood * Both T and B cells are important in this disease

Question 70

Allergy

Answer 70

* Allergy is an inappropriate immune response to environmental or food molecules. * The antigens eliciting allergic responses are called allergens (pollen grains, house dust mite allergen, peanut allergen, bee venom) * Allergies involve: (i) Prior sensitization to allergen by activation of acquired immune responses, resulting in production of IgE antibody specific for the allergen. The IgE binds to receptors on mast cells (ii) Allergen binding to the IgE on Mast Cells leading to “degranulation”- release of histamine which increases blood vessel permeability and smooth muscle contraction and causes symptoms of allergy (iii) Severe responses can lead to anaphylactic shock - large scale mast cell degranulation causing dangerous drop in blood pressure * Allergic responses involve similar processes to defence against worm parasites. IgE and mast cell responses trigger effects that are useful in expelling parasites, such as increased mucus production.

Question 71

Autoimmunity: The Immune System Sometimes Attacks The Body

Answer 71

* Tolerance involves the deletion (killing) or control of T and B cells which attack “self” molecules. Failure of tolerance leads to autoimmunity. * Generation of autoimmunity involves: (1) genetic factors (2) environmental factors - e.g. infections. Infections can provide “molecular mimicry” where a foreign antigen has similarity to a self protein. Alternatively they could also provide excessive inflammation promoting responses to self antigens * Autoimmunity has a sex bias with many (but not all) conditions being more prevalent in women. On the flip-side women deal better with many infectious diseases than men * Autoimmunity can be organ-specific or systemic (body-wide) depending on the specific autoantigens (self proteins that become antigens for the acquired immune system)

Question 72

SARS-CoV-2 Immunology and Evolution

Answer 72

* SARS-CoV2 infects and replicates in airway epithelial cells * Also non-productively infects monocytes, and resulting excessive inflammatory response seems to be the key to severe disease * Immune responses to SARS-CoV2 seem fairly typical for viral infection – there is reasonable activation of T helper, CTL and B cell immunity * 20-50% of people not exposed to SARS-CoV2 have pre-existing CTL or T helper responses that cross- react with SARS-CoV2. This may represent memory cells from common cold coronaviruses. Whether this is responsible for some people having mild disease has not yet been established. * The virus naturally evolved to become more infectious (e.g. delta and omicron strains) because faster replicating and transmitting viruses will be selected for. But as the pandemic progresses, the virus has to accumulate mutations to evade antibody neutralization. Current strains have numerous mutations that change the amino acid sequence of the spike protein relative to the original Wuhan strain.