IMI 9: Hypersensitivity, Allergy and Autoimmunity

Question 1

Observe the learning outcomes of this session

Answer 1

Question 2

Define parasite

Answer 2

• At its most basic level, ‘parasite’ refers to an organism that lives in or on another organism (host), at the expense of that host.
• Many bacteria and viruses easily fall under that definition.
• In medical terms, however, ‘parasite’ is generally used to describe the collection of motile eukaryotic organisms that have a parasitic lifestyle.
• These may be either unicellular eukaryotes (protozoa), or multicellular organisms such as helminths (worms) or arthropods

Question 3

Describe protozoan parasites

Give some examples of protozoan parasites

Answer 3

• The name protozoa means ‘first animals’ and relates to unicellular eukaryotic microorganisms of astonishing diversity
• Like bacteria, they can be either facultative or obligate intracellular, or extracellular pathogens.
• Protozoan parasites – such as Plasmodium species causing malaria
• Leishmania species causing leishmaniasis; Trypanosoma species causing African sleeping sickness (leishmaniasis); and Toxoplasma gondii causing toxoplasmosis – are major causes of parasitic diseases in both humans and animals.

Question 4

Describe malaria

• species that cause disease
• statistics

Answer 4

• Malaria has probably the biggest disease burden of all the parasitic infections.
• It is a life-threatening disease caused by parasites of the Plasmodium genus, transmitted through bites of infected female Anopheles mosquitoes.
• About 35% of the world’s population is estimated to be infected with malaria.
• It is prevalent across the tropics (wherever Anopheles mosquito species are common), although mosquito control measures have brought down the incidence as countries become more developed, particularly in Asia and South America.
• Nevertheless, an estimated 3.4 billion people in 91 countries and territories are still at risk of being infected with malaria and developing the disease.
• Five species of Plasmodium can cause malaria in humans, of which P. falciparum (prevalent in Africa) and the less severe P. vivax (the common malarial strain in Asia and South America) are the most common.
• All five have a similar 3-stage life cycle

Question 5

Describe the life cycle of malaria in the human host

Answer 5

1. Infection
   - the malaria parasite life cycle involves two hosts
   - during a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the blood of the human host
2. Liver stage:
   - the sporozoites infect liver cells, where they proliferate via a schizont intermediate (a multinucleated mega cell)
   - the proliferated parasites mature into merozoites that are released into the blood
   - plasmodium vivax can become latent in some of the liver cells, resulting in chronic infection
3. Blood stage:
   - the merozoites infect erythrocytes where they can go through several rounds of proliferation, red cell rupture and reinfection
   - it is the damage done by the blood-stage parasites and the immune response to it, that are responsible for the clinical manifestations of malaria
4. Gametocyte production:
   - in some erythrocytes, the merozoites differentiate into the male and female gametocytes
   - these need to be ingested by another Anopheles mosquito during a blood meal
5. Transmission:
   - gametocytes can be taken up during a blood meal by a mosquito
6. Sexual reproduction:
   - the sexual phase of the plasmodium lifecycle proceeds in the mosquito stomach, and results in sporozoites making their way to the mosquito’s salivary gland ready to infect a new host next time the mosquito feeds

Question 6

How do the strategies used by single cell parasites like Plasmodium mirror those used by bacteria

Answer 6

• For instance, many intracellular protozoa can reside within phagolysosomes, and have evolved to ‘defuse’ that toxic and hazardous environment.
• Plasmodium, however, takes this to another level: when the merozoites escape from liver cells, they remain within the cellular vesicles, which lack immunogenic features that might trigger an immune response, enabling them to reach distant parts of the circulation undetected before infecting red blood cells.

Question 7

How does malaria evade detection by the immune system?

Answer 7

• malaria’s strategy of residing in red blood cells also allows them to evade detection.
• Because red blood cells have no nucleus, they lack many of the innate responses used by other cells, that can warn of intracellular infection:
• Since red blood cells lack a nucleus, they cannot activate the transcription (or make pro-inflammatory cytokines) that are the outputs of the innate sensors described in previous sessions.
• Similarly, red blood cells lack the MHC class I antigen presentation system, effectively hiding the Plasmodium from T cells.

Question 8

When do malarial parasites get discovered by the immune system?

Answer 8

• after malarial parasites have consumed the haemoglobin in the blood cell, the bursting of the red cells releases intracellular components.
• When they are outside the cell, these intracellular molecules can represent damage-associated molecular pattern (DAMP) molecules and, thus, will likely activate immune responses.
• Particularly important for Plasmodium is the waste metabolite of haemoglobin (called haemozoin) which indicates to the immune system that there is a parasitic infection of red blood cells that has degraded its haemoglobin.

Question 9

Why do parasite and bacteria immune response mirror each other?

What are some of the responses?

What differs?

Answer 9

• Conceptually, the immune responses to parasites are broadly the same as to bacteria living in a similar niche.
• Just like response against a bacterium will involve T and NK cell responses to intracellular stages of infection, while complement and antibody opsonisation will work with neutrophils and macrophages to target the extracellular phases of infection, and recruit the adaptive response via dendritic cells.
• The only substantial differences will be the types of PAMPs on (or produced by) the protozoa.
• Because protozoa are eukaryotes, there may be fewer PAMPs that will allow us to distinguish them from our own cells.

Question 10

Describe some of the mechanisms used to sense malaria

Answer 10

• These signals can be broadly separated into generic PAMPs, parasite-specific PAMPs and metabolic signs of infection:
• generic microbial PAMPs (e.g. DNA, RNA);
• eukaryotic-specific PAMPs (e.g. GPI-anchored glycoproteins sensed by TLR2/TLR1 heterodimers);
• DAMPs (e.g. haemozoin and uric acid – digestion products from the degradation of haemoglobin by parasites that invade red blood cells), which are sensed by NLRP3, triggering inflammasome activation.

Question 11

Describe how type I IFN response and pro-inflammatory responses are activated by Plasmodium

Answer 11

• in the liver cells, the Plasmodium can be sensed by intracellular mechanisms similar to an intracellular bacterium, leading to a type I interferon (IFN) response.
• In contrast, sensing the blood stage relies on immune cells such as macrophages and dendritic cells (DCs) (as the red blood cell is largely inert).
• This will lead to a pro-inflammatory response, through activation of pro-inflammatory cytokines, via TLR signalling and the inflammasome.

Question 12

What is a PAMP critical for parasite control?

Answer 12

• A PAMP that appears to be critically important for parasite control is glycophosphatidylinositol (GPI), a glycolipid that anchors proteins into the membrane.
• These are both diverse and numerous on protozoa, and are thought to be recognised by TLR2 heterodimers.

Question 13

Describe parasite immune evasion

Answer 13

• Parasites also use some of the same evasion strategies we have already seen for bacteria.
• For instance, we have seen how Plasmodium species hide away in endosomal compartments, just like many bacteria.
• Similarly extracellular parasites, such as Trypanosoma brucei, which lives in the blood stream, can have a constantly changing surface, with over 1000 genes in its genome each encoding a different variant of its variant-surface glycoprotein (VSG).
• It switches these on, one at a time, so it frequently changes the look of its surface.
• This is the same evasion mechanism as the antigenic variation strategy we saw for bacteria in previous sessions.

Question 14

Which of the following PAMPs is specific to eukaryotic pathogens?

Answer 14

• GPI-anchored proteins

Question 15

Which TLR receptors detect GPI-anchored proteins?

Answer 15

• TLR1/2 heterodimers

Question 16

What name is given to the process of changing the make-up of the cell surface that is used by extracellular parasites to evade detection by antibodies?

Answer 16

• antigenic variation

Question 17

What are helminths?

Answer 17

• multicellular eukaryotic parasites (worms)
• e.g. nematodes (hookworm, pinworm, whipworm), tapeworms (cestodes), flukes (trematodes)

Question 18

What are the three stages in the life cycle of helminths?

Answer 18

• egg
• larva
• adult stage worm

Question 19

Describe how helminths invade host

• proliferation

Answer 19

• They invade their human host through skin penetration, ingestion of contaminated food, or via insect vectors.
• However, they will typically not proliferate in their host, more typically releasing eggs to allow them to infect new hosts.
• They may have complex life cycles where different stages occur in different organisms.

Question 20

Why are the methods of destroying parasites different to immune responses to other smaller entities we have looked at so different?

Answer 20

• They are often too big to be phagocytosed, so opsonisation is less likely to be useful.
• Complement-mediated lysis could kill individual cells, and eventually the whole parasite, but in general it does not seem to be adequate to destroy successful parasites (although this could be because the parasites have evolved defences against complement).

Question 21

What are the primary immune defences against helminths?

Answer 21

1. granulocytes releasing toxins to kill the parasite
2. physically disturbing the infected area so that the parasite can be ejected from the body - through coughing, sneezing, itching, vomiting, diarrhoea or mucus production.

Question 22

What mediates the irritation, spasm causing responses to helminths?

Answer 22

• granulocytes:
• neutrophils
• eosinophils
• basophils
• mast cells

Question 23

How do neutrophils respond to helminth infections?

Answer 23

• degranulation
• NETosis

Question 24

What is a crucial molecule that brings granulocytes into play for helminth infections?

Answer 24

• IgE

Question 25

Briefly review mast cell function

Answer 25

• Mast cells (MCs) are important players in parasitic infections.
• They also play key roles in allergy and anaphylaxis.
• Mast cells are tissue-resident cells that upon activation (e.g. via complement activation or the binding of the IgE Fc region) release granular substances, such as histamine and heparin (that prevents blood clotting).
• Activation of MCs is highly dependent on the release of immunoglobulin IgE, which binds to IgE-specific Fc receptors on the MC surface.
• In the absence of disease, the IgE concentration in the serum is the lowest of the five immunoglobulin subtypes.

Question 26

Briefly review basophil function

Answer 26

• Basophils are another IgE-responsive cell type that release granules containing histamine and heparin (that prevents blood clotting).
• They can also in some circumstances act as an antigen presenting cells (APC).

Question 27

Briefly describe eosinophil function

Answer 27

• Eosinophils are motile phagocytic cells that release eosinophil cationic protein and peroxidase.
• They are central players in the host response to helminth infection.

Question 28

Describe how IgE is produced in response to helminth infections

What happens after?

Answer 28

• Production of IgE is reserved for the response to large (multicellular) antigenic stimuli like helminths and bugs (larvae, bites and stings).
• The mechanism that recognises the invader as a helminth and triggers a B cell to class switch to IgE is not well understood.
• However, basophils, eosinophils and mast cells all express an IgE-specific Fc receptor (FcεR) on their cell surface.
• Thus, when IgE molecules (bound to the antibody’s target antigen) binds to the Fcε receptors on one of these cells, it is activated and it will release the contents of its granules.
• The degranulation of mast cells not only releases toxins to (hopefully) kill the parasite, but also triggers tissue level responses that have evolved to purge the parasite from the body.
• This can include muscular tightening, constriction and/or spasm of the airways or gut, vomiting, diarrhoea or elevated mucus secretion.
• In the skin it induces itching, a trigger evolved to make us scratch a parasite out from its hiding place in the skin.

Question 29

What happens when IgE-related responses are over-enthusiastic?

Why does this happen?

Answer 29

• While this is important for the response to helminths, IgE-related responses can also be over-enthusiastic, or directed against harmless antigens (such as pollen grains).
• This misdirected IgE-mediated response is one of four types of hypersensitivity, and it is in this context of immunologically driven disease - seen in allergy and asthma - that the function of IgE has been most widely explored

Question 30

What is a granuloma?

What is fibrosis?

Answer 30

• Additionally, where a prolonged inflammatory reaction fails to clear a large parasite, a granuloma can formed.
• For instance, parasite eggs are often resistant to degradation, and some other inflammatory substances that cannot be phagocytosed and/or degraded, and these can trigger granuloma formation.
• In immunological terms, a granuloma is made up of a cluster of tightly packed macrophages – packed so tightly that the cell membranes fuse to create enormous multinucleated cells.
• These cells can be surrounded by a cage of extracellular matrix proteins: a process called fibrosis.
• While this can trap the parasite (or an area of pathogenic activity) and prevent its spread, if it is not degraded or removed, the macrophages can continue to release inflammatory signals, resulting in ongoing inflammation that can lead to immunopathology.

Question 31

What is atopy?

Answer 31

• the launching of an IgE response against inappropriate targets

Question 32

What are the three major atopic diseases?

Answer 32

• allergy
• eczema
• asthma

Question 33

Describe allergy

Answer 33

• Allergy describes a typically rapid acute response to diverse environmental antigens (allergens) recognised by IgE .
• It includes hay fever (pollen allergies), food allergies, and insect bite allergies, and is sometimes used to include all atopic diseases.
• The response typically involves itching and swelling of the area that the allergen comes into contact with, as a result of IgE-triggered degranulation of mast cells and basophils.
• Severe systemic (i.e. body-wide) allergic responses can result in anaphylaxis.
• This is a rapid response to the allergen - typically an ingested food protein or insect bite venom - that has become distributed around the body.
• It can result in widespread vasodilation and fluid leakage (swelling) that can compromise the function of internal organs.
• In particular, anaphylactic responses in the heart or lungs can lead rapidly to death.
• Food allergies are often confused with food intolerance.
• Food intolerance is usually a result of enzyme deficiencies that compromise digestion, and usually has gastro-intestinal symptoms.

Question 34

Describe eczema

Answer 34

• Eczema, or atopic dermatitis, is an inflammatory skin condition characterised by itchy, damaged skin.
• It can become worse by frequent washing or scratching, and leaves the skin vulnerable to bacterial/fungal infection.
• Eczema is commonly found alongside other types of food intolerances or allergies.
• Conversely, eczema can often resolve spontaneously (e.g. as a child ages), presumably as the individual develops tolerance for the offending antigen.

Question 35

Describe asthma

Answer 35

• Asthma is a chronic inflammatory response to an antigen within the lungs.
• It is generally characterised by tightening or spasm of airways that results in difficulty exhaling.
• While the patient is generally well, certain exposures can trigger an exacerbation (asthma attack).
• Most asthmatic disease is IgE-induced but around 10-30% of asthma is non-atopic, and does not respond to normal treatments.
• Asthma exacerbations can be triggered by exercise, pollutants, even medication or alcohol.
• They can also be triggered by infections.
• Exacerbations are life threatening, and in the absence of treatment (broncho-dilating drugs or immune-suppressive steroids) can result in compromised airways and potentially death.

Question 36

Why do people develop atopic disease?

Answer 36

• There are many factors driving the development of atopy.
• Twin studies have shown a strong genetic element to the likelihood of developing atopic disease.
• And there are also environmental factors contributing to atopy development: some chemical exposures can promote the development of various intolerances when they occur alongside exposure to a suitable antigen.
• Just like autoimmunity, it is possible that molecular mimicry mechanisms can induce atopic diseases, as they can often first manifest after an otherwise innocuous illness.
• However, one very prominent theory is the hygiene hypothesis.
• There are higher levels of atopic disease where people grow up in more sterile environments.
• In particular this seems to be associated with reduced exposure to helminths or arthropod parasites: allergy is rare in Africa (where there is a large parasite burden), and much more common in developed nations, particularly urban areas, and less common in people with pets.
• The hypothesis is that if our immune system is not exposed to pathogens that stimulate IgE responses, then our immune system will be more highly sensitised to react to something else - such as an innocuous allergen.

Question 37

What is hypersensitivity?

Answer 37

• an exaggerated immune response to a foreign substance, resulting in damage to a host’s own cells
• this can result in various pathologies, from collateral damage of cells in an antiviral response in one individual, to anaphylactic shock in response to peanut allergens in another, such as an allergic individual.

Question 38

What are the four types of immune hypersensitivity?

Answer 38

• Type I hypersensitivity is an over-reaction of the IgE response that is normal during helminth infections and insect bites
• Type II hypersensitivity is antibody-mediated complement activation on cells
• Type III hypersensitivity is mediated by antibody complexes activating cellular inflammatory responses (examples can be found in IMI7)
• Type IV hypersensitvity is driven by inappropriate helper T cell activation of cellular responses.

Question 39

Observe the diagram and describe type I hypersensitivity reactions

Answer 39

• Type I: Allergy, anaphylaxis and atopy
• IgE-dependent degranulation of mast cells
• triggered by antigen which leads to crosslinking of IgE bound to Fc receptors on a mast cell or basophil
• this leads to the release of histamine from granules and causes symptoms of allergic reactions such as hay fever and asthma

Question 40

Observe the diagram and describe type II hypersensitivity reactions

Answer 40

Type II: antibody-dependent cytotoxicity:

• antibody-dependent complement lysis of cells (ADCC)
• IgM or IgG binds to an antigen on a host cell
• either due to a pathogen-derived protein stuck to a host cell surface
• or by directly recognising a host protein antigen (often an autoimmune process)
• the antibody then fixes complement to the cell, leading to MAC formation and cell lysis by ADCC
• e.g. the destruction of red blood cells in ABO-mismatched blood transfusions
• rheumatic fever after a streptococcal throat infection induces self-reactive antibodies

Question 41

Observe the diagram and describe type III hypersensitivity reactions

Answer 41

Type III: Immune complex disease:

• type III immunosensitivity arises from accumulation (often on cell surfaces) of immune complexes that are not properly cleared by phagocytes
• these can trigger pro-inflammatory processes such as:
• by generating complement-derived inflammatory cytokines, such as C3a and C5a
• ban opsonins (Fc or complement) binding to their receptors on immune cells leading to their activation
• e.g. macrophages, neutrophils and other granulocytes
• this chronic inflammation can then cause tissue damage
• examples of this include rheumatoid arthritis and kidney disease in SLE

Question 42

Observe the diagram and describe type IV hypersensitivity reactions

Answer 42

Type IV Delayed:

• type IV hypersensitivity is referred to as delayed hypersensitivity that occurs when the antigen activates pro-inflammatory Th1 cells
• which in turn activate macrophages and cytotoxic Cd8+ T cells causing direct cellular damage
• the delay of this response is due to the length of time (a few days) required to activate the cellular component of the reaction
• this reaction is dependent on the reactivation of a Th1 memory cell response, rather than the damage being caused directly by antibody-based mechanisms
• examples include: food intolerances or skin reactions

Question 43

Study the figure, then complete the activity below. Assign the type of T helper (TH) cell to the cytokine they produce.

Answer 43

Question 44

Which form(s) of hypersensitivity can be provoked by helminth infection?

Answer 44

• type I allergic anaphylaxis and atopy

Question 45

Which form(s) of hypersensitivity can be driven by complement cleavage?

Answer 45

• type II Antibody-dependent cytotoxicity
• Type III Immune complex disease

Type II is usually driven by the fixation of the MAC by C3b lysing host cells, whereas type III hypersensitivity is driven by anaphylotoxins C3a and C5a recruiting innate immune cells.

Question 46

How does an autoimmune disease occur?

Answer 46

• when the adaptive immune system produces and uses antigen receptors that are specific for molecules that are normally present in our bodies
• for this to happen, our tolerance mechanisms must be broken which likely leads to tissues in the body being attacked by their own immune system

Question 47

Give some examples of autoimmune diseases

Answer 47

• type 1 diabetes (T1D),
• Hashimoto’s thyroiditis (HT),
• systemic lupus erythematosus (SLE) and
• Crohn’s disease (CD).

Question 48

Why is diagnosis a challenge for autoimmune diseases?

Answer 48

• The experiences of these individuals really highlight the diversity and symptomatic complexity of autoimmune diseases.
• This makes diagnosis a huge challenge.
• And it is proving even more challenging to discover the immunology that initiates these diseases, and treatments that can damp down autoimmunity without leaving patients vulnerable to infectious disease or cancer.
• It really is a tricky balance.

Question 49

What are the two aspects to consider when thinking about autoimmune diseases?

Answer 49

• How can the immune system develop an immune response to a self-protein, despite all the mechanisms that exist to prevent this from happening?
• How do such inappropriate adaptive immune responses cause damage to the body?

Question 50

What are some environmental factors that may be involved in autoimmune diseases?

Answer 50

• Such environmental modulation can include a typical Western diet, rich in saturated fat and salt, which can have a profound impact on local and systemic immune responses.

Question 51

What are self-reactive cells?

What are the outcomes for self-reactive B, CD8 and CD4 cells?

Answer 51

• At the core of autoimmunity are T-cells and/or B cells, whose antigen receptors (TCR or BCR) are specific for self-antigens.
• Cells with this specificity are described as self-reactive. These self-reactive cells can have the following outcomes:
  1. Self-reactive B cells will have an antigen receptor that binds to the native state of a self protein.
• As a result, they will be able to release auto-antibodies – antibodies that can bind to a self protein – and initiate antibody responses triggering hypersensitivity reactions to own proteins.
  2. Self-reactive CD8 (cytotoxic) T cells will have a TCR that recognises a self-peptide (a peptide from one of our own proteins) presented on MHC class I.
• This will enable them to kill cells making that antigen.
  3. Self-reactive CD4 (helper) T cells have a T cell receptor that can bind to self-peptides presented on MHC class II. This has two major consequences:
  a) they have the potential to wrongly induce an inflammatory state in response to normal tissue homeostasis process (e.g. macrophages cleaning up debris and presenting self peptides could activate these cells);
  b) they could support the survival (and thus generation) of self-reactive B cells in the germinal centre.

Question 52

List some mechanisms that can give rise to breaches in tolerance that can lead to autoimmunity

Answer 52

• molecular mimicry
• epitope spreading
• immune desregulation
• epitope modification (cryptic epitope exposure)
• idiotype cross-reactivity
• T cell bypass

Question 53

Describe how this mechanism breaches tolerance leading to autoimmunity: molecular mimicry

Answer 53

• Our immune system makes diverse antibodies against pathogens.
• Sometimes, however, there may be structural similarities between the exogenous antigen and host antigens.
• Therefore, antibody can be produced through legitimate means that is specific for a pathogen (with T cell help via pathogen-specific epitopes, and PAMPs inducing cytokines), but the antibody can also bind to (cross reacts with) a self protein.
• Thus the pathogen antigen mimics self-antigen to initiate a self reactive immune response.
• Pathogens may have such epitopes for many reasons: this might be a method of immune evasion (because the immune response will not react to antigens that look like itself) but more likely, because the pathogen has ‘stolen’ a host gene for their own genome, which is then slightly altered to help the pathogen manipulate their host.

Question 54

Describe how this mechanism breaches tolerance leading to autoimmunity: epitope spreading

Answer 54

• Epitope spreading is a process where an initial antigenic recognition leads to the development of specificity for other epitopes from the same molecular complex, which turn out to be self epitopes.
• One example might be a case where a molecular mimicry event allows the immune system to react to a similar epitope in a self protein.
• By thus initiating recognition of this protein as ‘foreign’, the immune system can then promote recognition of other epitopes in the self protein (even those that do not mimic the pathogen).
• This is particularly relevant to spreading of auto-reactive T cell epitopes.
• Epitope spreading can also lead to auto reactive antibodies, without requiring an initial mimicry event:
• Many pathogen proteins (especially viral proteins) form multimolecular complexes with host proteins.
• If a high affinity antibody was raised against one of these host proteins in the germinal centre, it would be able to internalise the complex (including the viral protein), and therefore present valid pathogen T cell epitopes, avoiding the normal tolerance mechanism

Question 55

Describe how this mechanism breaches tolerance leading to autoimmunity: immune deregulation

Answer 55

• It is easy to see that anything that alters the expression or recognition of cytokines, and other immune functions could interfere with the regulation of tolerance mechanisms, and facilitate generation of autoimmunity
• For instance a number of autoimmune patients exhibit dysregulated cytokines, although whether this is a cause or effect of autoimmunity is not clear.
• Also, many pathogens have evolved mechanisms that mess with the adaptive immune response in order to evade immune recognition , but these can have a side effect of promoting autoimmunity.
• For instance, bacterial super antigens can cross link TCR-MHC interactions independently of the peptide (IMI6), which could activate otherwise anergic self-reactive T cells

Question 56

Describe how this mechanism breaches tolerance leading to autoimmunity: epitope modification (cryptic epitope exposure)

Answer 56

• Most Eukaryotic sugars have particular complex carbohydrates on their outside.
• However, some circumstances could result in more simple sugars at the base of complex branched carbohydrates to be exposed (the ‘cryptic epitope’) and recognised by a PRR that induces an inflammatory response in that absence of pathogens.
• This can result in a break-down in the normally tolerogenic state of sterile tissues, allowing the activation of auto-reactive B and/or T cells.
• This mechanism (caused by deletion of a gene responsible for assembling glycan structures) has been demonstrated in a mouse model, but its importance in humans is unknown.

Question 57

Describe how this mechanism breaches tolerance leading to autoimmunity: idiotype cross-reactivity

Answer 57

• The idiotype of an antibody is the sequences in the V region other than the CDR.
• It is known that antibodies can develop against this region of the antibody, while the V region can also provide unique T cell epitopes that could support a prolonged immune response.
• However because the idiotype is a reflection of one or more V segments, it is likely to be found on many different antibodies, so can result in the formation of immune complexes composed entirely of antibodies, that can initiate a type III hypersensitvity reaction, and consequently, chronic inflammation.

Question 58

Describe how this mechanism breaches tolerance leading to autoimmunity: T cell bypass

Answer 58

• T cell bypass describes any situation where a B cell survives the germinal centre reaction without T cell help.
• This might include T-independent antigens, or immune dysregulation processes such as superantigens cross-linking the TCR to the B cell’s MHC and providing T cell help regardless of the TCR epitopes the B cell is presenting.

Question 59

Describe the pathogenic mechanisms of autoimmunity

Answer 59

• self-reactive adaptive immune molecules will trigger an immune reaction causing damage through either complement-mediated cell killing, or chronic inflammation triggered by immune complexes, or T cell activation.
• Since every autoimmune disease is the product of its antigen(s) and the nature of the aberrant immune response(s), there is no simple way to describe the pathogenesis of immune diseases.

Question 60

What are the 3 types of treatment for autoimmune diseases?

Answer 60

1. Steroids
2. Immunosuppressants
3. Biologics

Question 61

Describes the autoimmune disease treatment: steroids

Answer 61

• Steroids such as prednisolone have been vital in the improvement of SLE.
• They have a profound effect by reducing inflammation through suppression of multiple inflammatory gene pathways.
• They have such a broad mode of action, and are taken for such long periods, that their side-effects can often be problematic.
• There include weight gain, muscle weakness, and osteoporosis that weakens bones and can lead to fractures.

Question 62

Describes the autoimmune disease treatment: immunosuppressants

Answer 62

• Immunosuppressants are widely used in more severe stages of autoimmune disease.
• The most commonly used are azathioprine, methotrexate and cyclophosphamide.
• They all have multiple modes of action, but are generally thought to inhibit both CD4+ and CD8+ T cell activation, and reduce expression of adhesion molecules involved with recruitment of leukocytes during inflammatory responses.
• The major problem with immunosuppressants is that they cannot be given during pregnancy, which is problematic given the prevalence of autoimmune diseases in young females.
• Moreover, immunosuppressants will obviously increase the risk of harm from infections.

Question 63

Describes the autoimmune disease treatment: biologics

Answer 63

• Biologics are a relatively new and promising class of treatment for autoimmune disease.
• These are biological molecules (most often monoclonal antibodies) that are specific for a particular receptor, or molecule of the immune system.
• They do not have as broad effects as the other two categories, thereby reducing potential off-target side effects.
• A good example is Rituximab, which has been shown to be effective, even curative, in several autoimmune diseases.
• Rituximab is an antibody directed against CD20, a transmembrane protein present on B cells, from the pre-B cells to naive to memory cells, but not plasma cells.
• Thus Rituximab will attract complement and phagocytes to kill B cells, wiping out the source of the autoantibodies, and the induction of autoimmunity.
• Of course this also wipes out the patients naïve and memory B cells, making them highly vulnerable to new infections until their naïve B cell pool is restored, and their immunisation status restored.
• Other biologics target either inflammatory mediators, or their critical signalling pathways: For example:
• TNF-α soluble receptor or blocking antibodies;
• IL‐6R blocking antibody;
• Janus kinases (JAKs) inhibitors - small molecule inhibitors that block intracellular signalling downstream of IL-6, and inhibit inflammation.
• In principle, biologicals offer the possibility of more precisely targeted interventions but, while promising, they need to be further studied so that we can understand in greater detail how inhibiting one cytokine such as TNF-α may affect other signalling pathways triggered by other cytokines, or the inflammatory response itself, in what is a highly integrated immune system.

Question 64

How are self-reactive antigens removed?

Answer 64

• apoptosis in a process known as clonal deletion
• induction of anergy, when they can no longer respond to that antigen

Question 65

Review this diagram of tolerance

Answer 65