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Cellular and Molecular pathology > 23. Hypersensitivity Reactions: type 3 and 4 > Flashcards

23. Hypersensitivity Reactions: type 3 and 4 Flashcards

1. Describe how antibody binding to soluble antigens can lead to tissue damage in type 3 reactions, explaining the role of complement and cells of the innate immune system 2. understand that type 4 reactions are primarily mediated by Th1 cells, describing the immunological mechanisms leading to 3 distinct forms of Th1-mediated type 4 reaction

1
Q

What are type 3 hypersensitivity reactions?

A

The non-clearance of small immune complexes that have formed in response to excess soluble antigens.

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2
Q

What is an immune complex?

A
  1. The binding of antibodies to a soluble antigen.
  2. They occur naturally in circulation to things like cell debris.
  3. Cleared by phagocytes
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3
Q

What are large immune complexes?

A
  1. These are rapidly cleared by mononuclear phagocytes.
  2. These don’t generally cause problems.
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4
Q

What are small immune complexes?

A
  1. These are formed when a soluble antigen is in excess.
  2. IF these aren’t cleared they are deposited in tissues causing type 3 reactions.
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5
Q

How are small immune complexes normally cleared?

A
  1. Complement is activated and C3b binds to the immune complex.
  2. Complement receptor 1 expressing cells binds C3b.
  3. This opsonised immune complex is transported to tissue like the liver or spleen.
  4. Tissue resident phagocytic cells expressing FcR strip the immune complexes and degrade them.
  5. CR1 is often stripped off the cells as well and when there are too many immune complexes, CR1 runs out and immune complexes accumulate.
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6
Q

What is the most common cell expressing Complement Receptor 1?

A

erythrocytes

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7
Q

How are type 3 responses different from type 2 responses?

A
  1. In type 2 responses the antibody binds to the cell surface or ECM antigens.
  2. In type 3 responses the antibody binds to a soluble antigen forming an immune complex.
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8
Q

Immune complex formation: persistent infections

A
  1. antibody binding to a soluble microbial antigen.
  2. immune complexes are deposited in infected tissues or kidneys
  3. examples: leprosy, malaria, viral hepatitis
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9
Q

Immune complex formation: autoimmunity

A
  1. Antibody binding to a soluble self antigen.
  2. immune complexes are deposited in kidneys, joints, arteries and skin
  3. examples: systemic lupus erythematosus, Sjögren’s syndrome
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10
Q

Immune complex formation: inhaled antigen

A
  1. Antibody binding to an inhaled antigen like mould, plants or animals.
  2. immune complexes are deposited in the lungs.
  3. examples: farmer’s lung and pigeon fancier’s lung
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11
Q

What is the difference between type 3 response and type 1 response to inhaled antigens?

A

Type 1 response is IgE mediated and type 3 is IgG mediated.

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12
Q

What is the disease process of a type 3 response to an inhaled antigen?

A
  1. Occurs after repeated exposure to antigens.
  2. IgG mediated.
  3. Local immune complexes form in alveoli and causes the accumulation of fluid, proteins and cells in the alveolar walls.
  4. This slows oxygen and carbon dioxide exchange.
  5. This then causes inflammation and fibrosis.
  6. Leads to permanent damage.
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13
Q

What immune mechanisms mediated by immune complexes lead to disease pathology?

A
  1. Drive activation of macrophages to release TNF, IL-1 and ROS.
  2. platelet aggregation that contributes to inflammation.
  3. Binding of complement proteins to activate the complement cascade, form anaphylatoxins and recruitment of neutrophils.
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14
Q

Mechanisms leading to type 3 pathology: triggering inflammation

A
  1. Immune complexes interact with basophils and platelets via FcR which induces vasoactive amine production.
  2. This induces C3a and C5a anaphylatoxins generation causing mast cells and basophils to produce vasoactive amines and chemotactic factors. C5a chemotactic factors for neutrophils and basophils.
  3. Trigger IL-1 and TNF-a production by macrophages.
  4. Increases vascular permeability so leaking from blood vessels and exposure of basement membrane in the blood vessels and immune complexes stick to the basement membrane.
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15
Q

Mechanisms leading to type 3 pathology: Deposition of immune complexes

A
  1. Deposited complexes on the basement membrane continue to trigger C3a and C5a production.
  2. platelets start to aggregate on the exposed collagen from the basement membrane causing micro thrombi (could be seen as a rash).
  3. Platelets express the IgG receptor FcyRIIa and make vasoactive amines.
  4. This platelet action amplifies the cycle of vasodilation and type 3 reaction.
  5. Neutrophils exocytose lysosomal enzymes in frustrated phagocytosis causing local tissue damage like necrosis and vasculitis.
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16
Q

Mechanisms leading to type 3 pathology: Role of the complement

A
  1. Large immune complexes present lots of Fc regions to bind phagocytes and effectively fix complement via C3b and CR1.
  2. Complement components actually improve the solubility of immune complexes as these don’t activate the lytic component of the complement.
  3. A complement deficiency means formation of relatively insoluble complexes which are deposited in tissues
  4. C1q, C2 and C4 deficiencies are associated with lupus.
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17
Q

How is the complement an important mediator of immune complex disease?

A
  1. Antigen release
  2. Formation of immune complexes and deposition in tissues
  3. complement activation
  4. damage of host cells and disease perpetuation
  5. Deposition in the kidney causes various autoimmune glomerular diseases
  6. deposition in the skin causes lupus
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18
Q

What is the dual role of complement in systemic lupus erythematous?

A
  1. Patients have autoantibodies against things like DNA, cytoplasmic proteins and small ribonucleoproteins.
  2. These are released during apoptosis
  3. Failure to clear apoptotic bodies properly causes antibody binding to post-apoptotic bodies and form immune complexes.
  4. complement binding to immune complexes can improve solubility, aid clearance and prevent deposition.
  5. If the complement system is overloaded through constant exposure to antigen, immune complexes are deposited in capillary beds of various organs, activating complement in the tissue and furthers tissue damage.
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19
Q

Immune complex deposition in lupus

A
  1. The complement is often rapidly consumed in lupus patients due to widespread immune complex deposition
  2. serum complement levels can indicate activity
  3. deposition of IgG gives a lumpy look in lupus patients as opposed to the even layer in type 2 deposition
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20
Q

How can we measure disease in lupus patients?

A

lower complement levels = more active disease

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21
Q

How does type 2 and type 3 responses differ in the tissue?

A

type 2 response = more specific binding to cellular antigens
type 3 response = random dumping of immune complexes in an organ

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22
Q

What is serum sickness?

A
  1. A systemic type 3 hypersensitivity response.
  2. named for response to horse serum but disease is associated with exposure to any foreign protein and producing antibodies to them.
  3. When both antigen and antibody are present you get immune complex formation and deposition throughout the body.
  4. Duration limited until the foreign antigen is cleared.
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23
Q

What is anti-thymocyte globulin?

A

a poly clonal antibody raised in horses or rabbits against human T cells.

24
Q

What is anti-thymocyte globulin used for?

A
  1. Used to prevent rejection of transplanted organs especially hearts.
  2. but the non-human proteins in to could stimulate antibody production and serum sickness
25
Q

What was one of the first monoclonal antibodies?

A
  1. Orthoclone
  2. Available from 1986
  3. targets CD3 on T cells
  4. works well but ended up with type 3 response or cytokine storms
26
Q

What have improved the function of monoclonal antibodies?

A
  1. reducing the amount of non human parts of the antibody using recombinant technology
  2. this reduces type 3 response as it is more similar to human antibodies
27
Q

Monoclonal antibodies and hypersensitivity reactions

A
  1. type 1 IgE mediated reactions have been reported against mAbs like cetuximab.
  2. type 3 serum sickness has been reported to drugs like infliximab
28
Q

What are type 4 hypersensitivity reactions?

A
  1. Delayed type hypersensitivity
  2. Mediated by T cells (mostly CD4)
29
Q

What is different about type 4 hypersensitivity?

A
  1. not antibody mediated
  2. can be transferred by passive transfer of CD4 T cells
  3. Can’t develop in AIDS patients due to lack of T cells
30
Q

What causes the classic type 4 response?

A

T helper 1 cells

31
Q

What cells can cause non-classical type4 responses?

A

CD8 T cells, Th2 and Th17 all through different mechanisms

32
Q

What causes the tissue damage in type 4 hypersensitivity reactions?

A
  1. Th1 cell activation of macrophages
  2. Th2 cell activation of eosinophils
  3. Direct cytotoxicity via CD8 T cells
33
Q

What are the steps of a Th1 type 4 response?

A
  1. T cell sensitisation through exposure to antigen.
  2. re-exposure causing T cell activation
  3. secretion of inflammatory cytokines
  4. Macrophage activation
  5. If this response is misdirected or excessive then it leads to serious damage to the host.
34
Q

Forms of Th1-mediated type 4 response: Contact

A
  1. takes 48-72 hours to develop
  2. appears as eczema-like rash
  3. histology: lymphocytes, macrophages, edema of the epidermis
  4. Antigen: epidermal like nickel, rubber or poison ivy
35
Q

Forms of Th1-mediated type 4 response: tuberculin

A
  1. takes 48-72 hours to develop
  2. Appears as local thickening of the skin
  3. histology: lymphocytes, monocytes and macrophages
  4. intradermal antigens
36
Q

Forms of Th1-mediated type 4 response: granuloma

A
  1. takes 21-28 days to develop
  2. appears as hardening in the organ
  3. histology: macrophages, epithelioid cells, giant cells, fiborsis
  4. persistent antigen or antibody complexes or non-Ig stimuli
37
Q

What is contact hypersensitivity?

A
  1. sensitising agents include: metal ions, chemicals, dyes, drugs and plants
  2. These agents are haptens.
38
Q

What are haptens?

A
  1. lipophilic low molecular weight chemicals which can easily get through the skin
  2. haptens bind to self proteins that become new antigenic structures that are seen as foreign
  3. metal ions can binds directly into self peptides in MHC2 binding grooves
39
Q

How does contact hypersensitivity occur following hapten exposure?

A
  1. Sensitising agent penetrates the skin and binds to self proteins.
  2. These then are taken up by Langerhans cells
  3. These then process the agent and present them to Th1 cells which secrete IFN-y and other cytokines.
  4. Activated keratinocytes also secrete cytokines like IL-1 and TNF-a and chemokines
  5. both Th1 cells and keratinocytes activate macrophages to secrete mediators of inflammation.
40
Q

What are Langerhan cells?

A

Tissue resident dendritic cells

41
Q

How does CD8+ T cells contribute to contact hypersensitivity?

A
  1. Some sensitising agents attach to intracellular self proteins.
  2. these are processed and presented on MHC1 to CD8 T cells
  3. CD8 T cells cause direct damage or indirect damage through IFN-y secretion.
42
Q

What is tuberculin-type hypersensitivity reaction?

A
  1. Once an individual is sensitised, a repeat exposure causes recruitment and activation of T memory cells.
  2. these secrete IFN-y and cause macrophage activation.
  3. Adhesion molecules like E-selectin, ICAM1 and VCAM1 are expressed in endothelium for recruitment.
  4. 1-2 hours the neutrophils infiltrate first
  5. after 12 hours monocytes and T cells infiltrate causing inflammation and edema in the dermis
43
Q

What is tuberlin type hypersensitivity useful for?

A
  1. Mantoux test: injecting of mycobacterium tuberculosis to a patient as we expect to see hardening and swelling at the site of injection
  2. This is a good way to test for past or present infection and good response to a vaccine.
44
Q

What is granulomatous hypersensitivity?

A

A slow hypersensitivity reaction that occurs when there is persistence in macrophages.

45
Q

What can persist in macrophages in granulomatous hypersensitivity?

A
  1. intracellular microorganisms
  2. Intracellular particles
  3. Inorganic material not properly processed
46
Q

What does persistence in macrophages cause?

A

chronic stimulation of T cells and cytokine release leading to epithelioid cell granuloma development

47
Q

What different types of granulomatous hypersensitivity are there?

A
  1. chronic infections causing a Th1 response like in TB.
  2. chronic infections causing a Th2 response like in leishmaniasis
  3. absence of infection like in sarcoidosis in Crohn’s disease
48
Q

What is the structure of a granuloma?

A
  1. A ring of macrophages surround and wall off the pathogen in the middle.
  2. These macrophages have tightly interlinked membranes and are called epithelioid macrophages.
  3. Some macrophages become apoptotic.
  4. Some macrophages fuse together to form multinucleated giant cells.
  5. The whole thing is surrounded by T and B cells.
49
Q

What are the essential components of the classic Th1 type 4 response?

A
  1. T cells with the aß TCR
  2. Pro-inflammatory cytokines like IFNy and TNFa.
  3. Chemokines like CCL2, CCL5 and CXCL10 to recruit macrophages
50
Q

What proves IFN-y is essential for granuloma formation?

A
  1. IFN-y knockout mice cannot activate macrophages to control the infection and kill the bacteria.
  2. This means that no granulomas are formed and the infection goes uncontrolled and the mice rapidly die.
51
Q

What proves TNF is essential for granuloma formation?

A
  1. By injecting BCG infected mice with a TNF blocker
  2. Observe no granuloma formation and uncontrolled disease
52
Q

How do cytokines influence macrophages differentiation?

A
  1. Th1 cytokines like IFNy activate macrophages to eradicate intracellular pathogens.
  2. If the infection is not cleared the cytokine release is persistent
  3. cytokines drive differentiation of macrophages into epithelioid cells which secrete a lot of TNFa.
  4. This release of TNF maintains the granuloma
53
Q

Why is TB one of the most successful human pathogens?

A

partially due to the persistence in macrophages

54
Q

How is late phase type 1 hypersensitivity response linked to a Th2 type 4 hypersensitivity response?

A
  1. Late phase reactions in asthmatic patients are characterised by an influx of Th2 cells which recruit eosinophils.
  2. this late phase recruitment can be due to a type 4 response.
  3. This recruits eosinophils and causes significant tissue damage
55
Q

What is the difference between small and large immune complexes?

A
  1. Large immune complexes are formed when the antibody is in excess and there are small amounts of soluble antigen so multiple antibodies bind to each antigen and to each other
  2. Small immune complexes are formed when the antigen is in excess and 1 or 2 antibodies bind per antigen and this cannot bind complement receptors.

Cellular and Molecular pathology (25 decks)

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