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BMS 3052 > Inflammatory Disease > Flashcards

Inflammatory Disease Flashcards

1
Q

How does triggering of pattern recognition receptors activate the innate immune system?

A
  1. Innate immune cells recognise PAMPs on foreign antigens using different PRRs
  2. The activation of PRRs leads to an inflammatory response due to the release of pro-inflammatory cytokines such as IL-1B, IL-6, TNF-a, IL-12 and chemokines such as CXCL8 (IL-8)
  3. These cytokines bind receptors on target cells can cause lymphocyte migration, an increase in vascular permeability, activation of NK cells, the differentiation of T cells and the chemokine CXCL8 recruits neutrophils, basophils and T cells to the site of infection
  4. Neutrophils are the first responders to the site of injury/infection, and monocytes take 2-3 days
  5. Activation of PRRs (such as RIGs) also leads to type 1 interferon production which has potent antiviral activity and activates NK and dendritic cells
    - Some PRRs (nod-like receptors) are components of the inflammasome which cleaves and activates IL-1B
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2
Q

What is the first form of antibody produced?

A
  • IgM is the first antibody produced, it has high avididity (pentamer) which can compensate for low affinity
  • As affinity maturation occurs B-cells undergo heavy chain class switch recombination due to the action of AID which causes the production of IgG, IgA or IgE
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3
Q

How does the nature of the antigen influence the immunoglobulin antibody switching?

A
  • The nature of the antigen e.g. helminth, is sensed by the dendritic cell
  • The dendritic cell when presenting the antigen to the T-cell releases factors that instruct the T-cell as to how it should differentiate e.g. into a Th2 cell
  • The T-cell then produces specialised cytokines e.g. IL-4 and IL-5 and when it comes into contact with a B-cell that is sentized to the same antigen, those cytokines target the AID enzyme to specific S-regions in the heavy chain
  • This causes the CSR of the B-cell to form a different isotype e.g. IgE producing cell
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4
Q

How is central tolerance of T-cells established in the thymus?

A
  • First the immature double positive T-cell undergoes positive selection, if it does not recognise MHC it dies by neglect
  • If the cell recognises MHC it recieves survival signals
  • The cell then undergoes negative selection, if the cell binds to MHC will low affinity it will survive, but if it binds MHC with too high affinity it will die by apoptosis (means of preventing autoimmunity)
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5
Q

What drives the differentiation of Th1 cells? What do they produce?

A
  • IL-12 and IFN-y drive the differentiation of Th1 cells

- Th1 cells produce IFN-y and upregulate macrophages to become superb killers intracellular bacteria

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6
Q

What drives the differentiation of Th2 cells? What do they produce?

A
  • Th2 differentiation is driven by IL-4
  • Th2 cells produce IL-4, IL-5 and IL-13
  • IL-4 and IL-13 trigger the weep and sweep response
  • IL-5 triggers eosinophils
  • IL-4 drives B-cells CSR to produce IgE antibodies (which crosslink of mast cells)
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7
Q

How do Th2 cells drive allergy? What are the two kinds of allergic responses?

A
  • IL-4 drives the CSR of allergin specific B cells to produce IgE
  • The allergin specific IgE bind their Fc regions to mast cells and then bind their variable regions to the allergin and crosslink and activate
  • Cross-linking of the IgE on the mast cells causes the mast cell to degranulate and release lipid mediators and later cytokines:
    1. Granules contain vasoactive amines that cause vascular dilation and smooth muscle contraction and also proteases that cause tissue damage
    2. Lipid mediators cause vascular dilation and smooth muscle contraction
    3. Later release of cytokines causes inflammation

The two types of response are:

  1. Immediate phase hypersensitivity reactions: characterised by vasodilation and oedema driven by vasoactive amines and lipid mediators
  2. Late phase hypersensitivity reactions: characterised by cellular infiltrate and is cytokine mediated
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8
Q

What is inflammation and what are its clinical features?

A

Inflammation: a key component of normal host defence, which can also occur abberantly and cause tissue injury
- Chronic inflammation with frustrated attempts at healing causes fibrosis (tissue replaced with matrix components such as collagen)

Clinical features:

  • Heat
  • Redness (increased vascularity)
  • Swelling (increased vascular permeability)
  • Loss of function of affection area
  • Pain
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9
Q

Describe the basic elements of an adaptive immune response:

A
  1. Antigen presenting cell e.g. dendritic cell, will present an antigen to a CD4 T cell with a corresponding T cell receptor
  2. This antigen presentation must take place with costimulation e.g. in an inflammatory environment
  3. The activated T cell proliferates and clonally expands
  4. The activated T cell clones acquire effector functions such as producing a particular cytokine profile and providing T cell help to B cells to allow them to generate antibodies against the antigen
    - Regulatory T cells activated by IL-2 produced to stimulate T cell differentiation are activated to help suppress excessive immune responses
  5. After the pathogen no longer is present, there is activation induced cell death
  6. There is resolution of the immune response
  7. Memory T and B cells persist, so if the antigen is encountered again, an adaptive immune response can be generated more quickly
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10
Q

What is the aspect of the immune system associated with autoimmune vs autoinflammatory diseases?

A
  1. Autoimmune diseases are the result of disordered adaptive immunity
    - with involvement from innate immunity

Autoinflammatory diseases result from disorders of innate immunity without necessarily involving adaptive immunity

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11
Q

Give 5 examples of important inflammatory diseases in humans:

A
  1. Type 1 Diabetes
  2. MS
  3. IBD
  4. Rheumatoid arthritis
  5. Glomerulonephritis
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12
Q

What is glomerulonephritis?

A
  • A collection of inflammatory diseases of the glomeruli in the kidney
  • Most types of glomerulonephritis are due to an adaptive immune responses that target nephritogenic antigens
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13
Q

Why is the lglomerulus so susceptible to disease?

A
  • The nature of the glomerulus being a high flow, high pressure filter of the bodies blood
  • The glomeruli are susceptible to collecting antigens and immune responses occuring within them, and are also prone to damage by diabetes, hypertension and other diseases
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14
Q

What occurs when glomeruluar function is abberant?

A
  1. Inflammation of the glomerulus
  2. Leakage of blood and protein into the urinary space and tubules
  3. Loss of filtration leading to renal impairment and fluid retention (due to renal fibrosis)
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15
Q

What are the types of injury that occur in the glomeruli?

A
  1. Injury due to high blood pressure
  2. Immune injury of the kidney: glomerulonephritis
  3. Non-immune injury of the kidneys e.g. diabetes (still involve a local inflammatory event
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16
Q

How does renal scarring occur? What does it result in?

A
  • As a result of chronic inflammation there can be fiboris/sclerosis where kidney structures are replaced with matrix proteins such as collagen
  • This causes the kidney to lose function
  • A higher proportion of glomerular scarring corresponds to a much lower likelihood of survival and renal function
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17
Q

Give examples of glomerulonephritic antigens:

A
  1. Endogenous antigens:
    - E.g. GBM
    - E.g. Lupus antigens
    - E.g. Neutrophil proteins (ANCA)
  2. Desposited immune complexes
    - Involved with lupus nephritis
  3. Planted (exogenous) antigens
    - E.g. streptococcal infection
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18
Q

What is crescentric GN?

A
  • Crescentic GN is a complication of many forms of GN
  • It involves endocapillary inflammation in the glomerulus and causes rapidly progressive GN
  • It is also characterised by deposition of fibrin and GBM rupture
  • Contributed to by mesangial cells, epithelial cells which proliferate rapidly in the Bowman’s space and secrete pro-inflammatory cytokines
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19
Q

How does chronic inflammation lead to fibrosis?

A
  1. Continuing disruption to tissue architecture
    - Due to immune mediated injury
    - Due to metabolic effects e.g. ROS
  2. Frustrated attempts at healing, healing does not occur as:
    - Leukocytes (macrophages) have an inflammatory not healing phenotype
    - Fibroblast and other cells react to inflammation by producing matrix proteins in a dysregulated manner
  3. Inflammation-independent fibrosis:
    - Occurs when damage is so severe that there is resulting ischemia which drives fibrosis
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20
Q

How are autoimmune diseases such as GN treated?

A
  1. Cyclophosphamide:
    - Chemotherapeutic agent that cross-links DNA
    - Currently best tratment for severe inflammatory autoimmune diseases
  2. Targeted therapies to selectively dampen inflammation:
    - Anti B-cell therapies (anti-CD20)
    - Anti-TNF
    - Complement inhibitors (very promising in stage III trials)
    - Antigen specific treatments (would be most targeted by some way off)
  3. ACE ihibitors are used in GN to slow to progression of the disease to kidney fibrosis
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21
Q

What are toll like receptors?

A
  • These receptors recognise conserved microbial molecules (PAMPs)
  • They also recognise endogenous DAMPs
  • They signal infection/danger and activate innate immune cells
  • By activating and maturing dendritic cells they activate adaptive immunity
  • By helping activate B cells and macrophages they active adaptive immunity
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22
Q

What is the role of macrophage activation in inflammation?

A
  • The activation of TLRs on macrophages triggers inflammation by causing them to release cytokines and chemokines which trigger inflammation:
  • IL-1B: activates vascular endothelium and lymphocytes
  • TNF-a: activates vascular endothelium and increases permeability
  • IL-6: activates lymphocyts and increases antibody production
  • CXCL8: recruits neurotrophils, basophils and T-cells to the site of infection
  • IL-12: activates NK cells and induces the differentiation of Th1 cells
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23
Q

What is the role of neutrophils in inflammation and infection?

A
  • Most abundant leukocyte
  • First responder that rapidly mobilises to sites of infection
  • Phagocytose bacteria
  • Short-lived
  • Pro-inflammatory by producing ROS, cytokines, proteases and anti-microbial peptide
  • Express Fc-y receptors (bind IgG Fc region)
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24
Q

What are NETs?

A

NETs = neutrophil extracellular traps

  • Neutrophils can also die by NETosis whereby they are turned ‘inside out’ and the nucleus content is mixed with cytoplasm and thrown out of the cell
  • This generates a web of nuclear components such as histones, DNA enzymes and cytoplasmic components such as MPO and proteinase 3
  • These NETs have a role in defence and pathology
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25
Q

Describe the process of leukocyte recruitment into a tissue:

A
  1. Neutrophils circulate freely through the blood
  2. Neutrophils tether to the vascular endothelium of a post-capillary venule
  3. The tethering causes the neutrophil to commence slow rolling (due to the interaction of selectin ligand on the neutrophil with the selectin on the endothelial surface)
  4. Full arrest of the neutrophil occurs (inactive integrin is activated and the active integrin of the neutrophil adheres the neutrophil to the integrin ligand on the endothelial cells)
  5. Firm adhesion of the neutrophil occurs due to the action of adhesion molecules (multiple active integrin and integrin ligand interactions and ICAM-1 etc.)
  6. Intraluminal crawling of the neutrophil occurs which causes the neutrophil to crawl between the endothelial cells (but they are also able to move through endothelial cells if needed through dome formation)
  7. The neutrophil is then extravasated into the tissue where it follows the chemokine gradient
26
Q

What is the difference in leukocyte recruitment in the glomerulus vs. conventional vascular beds?

A
  • In a specialised vascular bed such as the glomeruli, neutrophils sit within the vessels and produce ROS without any rolling
  • In conventional vascuar beds neutrophilis exhibit clear rolling, adhesion and extravasion behaviour
27
Q

Do adult tissue macrophages have different developmental origins?

A
  • Yes, tissue macrophages have different developmental origins to adult bone marrow derived monocytes which are recruited to become adult monocyte-derived inflammatory tissue macrophages
28
Q

What are the 2 main subtypes of macrophages?

A
  1. M1 macrophages:
    - Pro-inflammatory
  2. M2 macrophages:
    - Anti-inflammatory
29
Q

Describe how pro-fibrotic macrophages are formed in chronic inflammation:

A
  1. If the kidney is injured due to hypoxia, M1 (pro-inflammatory) macrophages will be recruited to the site of inflammation and will produce inflammatory cytokines TNF and IL-1B
  2. After a few days without inflammation, these M1 macrophages change their phenotype and become anti-inflammatory/healing macrophages (M2) which produce limited amounts of TGF-B to promote tissue healing and remodelling
  3. If the inflammation is ongoing, M1 macrophages will remain as pro-inflammatory in phenotype or they will change to PRO-FIBROTIC in phenotype which will produce excessive TGF-B which promotes the deposition of excess collagen (fibrosis)
    - The pro-fibrotic macrophages can also act on endothelial cells, pericytes and mesangial/fibroblast cells to make them transition to form myofibroblasts which are central to excessive collagen production
30
Q

What is the role of the complement system in inflammatory disease?

A
  • If there is abnormal auto-antibody deposition on a tissue this can activate the complement system via the classical pathway
  • Complement system activation then activates the effector functions which induce:
    1. Increased vascular permeability and cell-adhesion molecule expression (C3a, C4a and C5a) which leads to the recruitment of pro-inflammatory immune cells, as well as increasing the fluid leakage and extravasion of antibodies and complement into the tissue
31
Q

What contributes to autoimmunity?

A
  • Failure to adequately discriminate self from non-self results in autoimmunity
  • Contributors include genetic factors and infection and environmental exposure
  • These lead to immune dysregulation which ultimately leads to autoimmunity
32
Q

Describe which aspects of the autoimmune system are involved in:

  1. SLE
  2. T1D
  3. Myasthenia gravis
  4. MS
A

SLE-
T-cells: help for pathetic antibody
B-cells: presents antigen to to T-cells
Antibody: pathogenic

T1D-
T-cells: pathogenic
B-cells: present antigen to T-cells
Antibody: present, but role unclear

Myasthenia gravis-
T-cells: help for antibody
B-cells: antibody secretion
Antibody: pathogenic

MS-
T-cells: pathogenic
B-cells: present antigen to -cells
Antibody: present, but role unclear

33
Q

What are the 2 main subtypes of autoimmune disease?

A
  1. Organ specific disease: typically occur when the antigen is presented in a restricted range of cells and tissues
    e. g. T1D, anti-GBM disease, MS, myasthenia gravis
  2. Systmetic autoimmune disease: occurs when the antigen is ubiquitously expressed to many areas in the body are affected e.g. SLE (autoimmune disease in which the body loses tolerance to a wide range of antigens- classically antigens of the nucleus
34
Q

Describe anti-GBM GN (Goodpasture’s disease)

A
  • Autoimmunity to type IV collagen (the NC1 domain of the a-3 chain)
  • This collagen is found in the basement membrane of the kidney, lungs, testis, chordial plexus, neuromuscular junction
  • Goodpasture’s disease typically only affects the lung and kidney (as the other areas are immunoprivleged sites)
  • Textbook antibody mediated disease
  • Typically presents with pulmonary haemorrhage and renal failure (linear antibody staining)
35
Q

Describe SLE and its pathogenesis:

A
  • Broad range of autoreactivity to many cellular antigens (often nuclear)
  • Clinical features include: malar rash, GN, joint disease, pleuristy etc.
  • Antibody mediated
  • The current model for pathogensis is that:
    1. Genetic predisposition and environmental triggers activate the innate immune system
    2. The innate immune system triggers the adaptive immune system which forms immune complexes (which further activate the innate immune system)
    3. Clinical disease onset occurs
    4. There is increases aberrant amplification pathways and also increased resistance to therapy
    5. Irreversible tissue damage occurs
36
Q

Describe the 2 main layers of tolerance:

A
  1. Central tolerance:
    - Positive and then negative selection of T cells in the thymus
    - Peripheral antigens are expressed in the thymus by AIRE proteins
    - Some autoreactive T-cells will escape
  2. Peripheral tolerance:
    - Regulatory T-cells: mediate peripheral tolerance, driven to differentiate by TFG-B and IL-2. Produces cytokines to protect
    - Antigen segregation/ignorance: the adaptive immune system does not have access to some areas of the body
    - Peripheral anergy: if a TCR is stimulated without co-stimulation, the cell will be anergised and inactivated
    - Functional deactivation: differentiation of Treg cells that limit inflammatory T-cells
    - Induced apoptosis: after cells have served their function in an immune response they are apoptosied
37
Q

How is immune tolerance lost?

A
  • Usually a number of steps:
    1. Genetic susceptibility
    e. g. mutations in HLA
  1. Environmental factors
    e. g. infection, sun damage etc. can result in the loss of antigen segregation
    e. g. lack of CLTA-4 means that co-stimulation is unable to control peripheral tolerance
    e. g. loss of Treg cells (e.g. lack of FOXP3)
    e. g. deficiency in anti-inflammatory cytokines e.g. IL-10 deficiency
    e. g. impaired clonal deletion
  • All result in changes in peripheral tolerogenic mechanisms
38
Q

What are the types of injury autoantibodies cause to result in disease?

A
  1. Injury causes by anti-tissue antibody
    - Antibody binds to self-antigen and Fc portion of antibody activates complement and Fc receptors on inflammatory cells
    - Neutrophil and macrophage mediated injury then occurs
  2. Immune complex mediated injury:
    - Immune complexes are networks of antigen-antibody complexes
    - Immune complexes are often desposited in small, vulnerable blood vessels and their Fc receptors recruit inflammatory cells and neutrophil and macrophage mediated injury then occurs (can cause vasculitis)
  3. Binding of the antibody can cause abnormal physiological responses
    e. g. an autoantibody against the TSH receptor will act as a stimulus for the receptor and cause thyroid cells to make thyroid hormone (causes Graves disease)
39
Q

Describe anti-GBM disease:

A
  • An example of a type II hypersensitivity autoimmune disease (antibody vs antigen)
  • Causes rapidly progressive GN and 70% of people have lung haemorrhage
  • Due to autoreactive antibodies against type IV collagen (a3 NC1)- this is a cryptic epitope and exposed by damage
  • Results in the linear deposition of IgG autoantibodies on the GBM
  • This causes T-cells, macrophages and fibrin to accumulate in the glomeruli
  • Also causes C3 (complement) deposition
  • Results in inflammation and disruption of matrix

Treatment:

  • High dose corticosteroids and cyclophosphamide
  • Plasma exchange
40
Q

Describe SLE: lupus nephritis

A
  • Lupus nephritis is an example of a Type III hypersensitivity immune complex disease
  • Caused by a broad range of autoreactivity to antigens (especially nuclear) which are deposited mainly as immune complexes (but can also be planted)
  • There is self-antigen TLR recognition
  • Type 1 interferon signature (promotes autoimmune response to SLE which stimulates DCs and autoreactive B cells)
  • Disease affects 90% females
  • T and B cells are required
  • GN has variable occurence and severity
  • Causes protein leakage and renal impairment (damage to filtration barrier)
  • Can cause mild to severe proliferation of cells
  • There is widespread granular IgG deposition and an increase in cells and cell matrix
  • Complement activation
  • Leukocyte recruitment (causes release of oxidants, proteases etc.)
41
Q

How do immune complexes form?

A
  • More likely if there is antigen: antibody equivalence
  • Requires soluble antigen in large amounts
  • Ongoing release of antibody
  • Location of deposition depends on size and charge of complex
42
Q

What is ANCA associated vasculitis and GN?

A
  • ANCA = autoantibodies to neutrophil cytoplasmic granules
  • ANCA is a marker for small vessel vasculitis- this can be pathogenic
  • Involves a number of organs: classically the kidney and lungs are most commonly and severely affected
  • There are 2 main patterns of antigens:
    1. C-ANCA
  • Classical
  • Usually anti-proteinase-3
  1. P-ANCA
    - Perinuclear
    - Usually anti-MPO
    - Makes pus green
43
Q

What is the involvement of ANCA in vasculitis?

A
  1. Loss of tolerance to proteinase-3 or MPO occurs
  2. Autoreactive CD4+ T cells help B cells
  3. An infection ligate TLR- primes neutrophil and exteriorates MPO/Pr3
  4. ANCA then activates the neutrophils causing them producing ROS, become adhesive and undergo cytoskeletal changes
  5. The neutrophils then degranulate and injure the glomerlus
  • MPO specific CD4+ effector T cells recognise MPO planted as an antigen and induce injury by further recruitment and activation of leukocytes (mainly macrophages)- causing type IV hypersensitivity (results in rapidly progressive hypersensitivity)
44
Q

Describe Th1 cells:

A
  • Differentiation induced by IL-12 and IFN-y
  • Key effector functions: intracellular infection, classical DTH, autoimmunity and rejection
  • Produces IFN-y and other cytokines
45
Q

Describe Th2 cells:

A
  • Differentiation induced by IL-4
  • Key effector functions: parasitic infection and allergy
  • Produces IL-4, IL-5 and IL-13
  • Very good at activating eosinophils (IL-5)
46
Q

Describe Th17 cells:

A
  • Differentiation induced by IL-6 and IL-21
  • Produces IL-17 and IL-22
  • Key effector function is extracellular infection, tissue injury, autoimmunity and rejection
47
Q

Describe Treg cells:

A
  • Requires Foxp3 to differentiate
  • Produce IL-10, TGF-B and IL-35
  • Key effector functions: limiting peripheral tissue injury, peripheral tolerance and graft tolerance
48
Q

What is the role of T helper cell subset and T. leprosy infection?

A
  1. Tuberculoid leprosy
    - Low infectivity
    - Normal serum antibody levels
    - Strong T cell response
    - Strong Th1 response (IFN-y)
    - Effective as T. leprosy is an intracellular bacteria
  2. Lepromatous leprosy:
    - High infectivity
    - High antibody response
    - Low or absent T cell response
    - Strong Th2 response (particularly IL-4)
    - The pathogen is not effectively cleared as it is intracellular and IL-4 suppresses macrophage function
49
Q

What is a Type IV hypersensitivity reaction?

A
  • This is an adaptive immune response
  • Requires prior sensitisation (effector/memory T cells produced)
  • Delayed onset
  • Involves D4+ and/or CD8+ T cells
  • Does not require antibody
  • Important in diseases such as T1D (CD4+ and CD8+), RA, MS (Th17 predominant), Crohn’s
  • Response often involves granuloma formation
- Major effectors: 
CD4+ T cells 
Th1 cytokines (IFN-y) 
Macrophages and macrophage derived cytokines 
Fibrin deposition

Example is mantoux test mechanism to TB

50
Q

What is crescentic GN?

A
  • A severe form of GN
  • Powerful immune response
  • Crescents consisting of leukocytes, proliferating epithelial cells, mesangial cells and fibrin form in the Bowman’s space
  • Due to Anti-GBM, Immune complex diseases and ANCA-associated vasculitis (most common)
  • Can therefore be due to type II, type III or type IV hypersensitivity (planted MPO and T-cells)
  • Potential outcomes:
  • Rapid irreversible renal failure
  • Renal failure and death
  • Need for immunosuppressive treatments
51
Q

What are the 2 most common non-specific immunosuppressive agents commonly used in treating immune disease?

A
  1. Corticosteroids e.g. prednisolone
    - binds to intracellular receptors
    - inactivates pro-inflammatory gene transcription
    - activates anti-inflammatory genes
  2. Cyclophosphamide:
    - converted into phosphoramide mustard
    - Alkylating agent that cross-links DNA
    - Used in lower doses for immune disease (but not often)
52
Q

What is the current paradigm for treatment of autoimmune diseases?

A
  1. Induce remission:
    - Switch off local inflamamtion
    - Modify the underlying inflammatory response
    - Remove cause (if possible)
    - Modify pathological autoimmune response
  2. Maintain remission:
    - Ongoing treatment (but of lesser intensity
    - Avoid known triggers of disease (e.g. SLE- UV sunlight)
    - Limit consequences of tissue inflammation e.g. prevent ongoing fibrosis
    - Manage drug toxicities/side effects
53
Q

How is ANCA-associated vasculitis typically treated?

A
  1. Induction of remission:
    - Rituximab (anti CD-20) which targets B-cells + glucocorticoids
    - Cyclophosphamide + glucocorticoids

Maintenance:

  • Switch to methatrexate (lower intensity) and wean off glucocorticoids
  • Continue Rituximab and wean off glucocorticoids
54
Q

What are the main side effects of immunosuppression?

A
  1. Metabolic:
    - Hypertension
    - Diabetes mellitus (insulin resistance)
    - Cosmetic (facial swelling)
    - Increases appetite
    - Osteopororis
  2. Immune:
    - More severe infections
    - Unusual infections
    - Bone marrow suppression
    - Increased risk of malignancies
55
Q

How do glucocorticoids reduce local inflammation?

A
  • Reduces the inflammation caused by inflammatory cytokines
  • Decreases NO
  • Decreases prostoglandins involved in inflamamtion
  • Reduces adhesion molecules (reduces emigration of leukocytes from vessels)
  • Increases endonucleases- induces apoptosis of lymphocytes and eosinophils
56
Q

How does Azathioprine work?

A
  • Blocks purine synthesis (especially in lymphocytes)
  • “Mid-range” immunosuppressant
  • Often used for moderate disease, steroid sparing and maintenance treatment
57
Q

What are potential options for more targeted therapies to treat autoimmune disease?

A
  1. Biological therapies:
    - Monoclonal antibodies, recombinant proteins
    e. g. Anti-TNF in RA: works in nearly all people with RA
    e. g. Anti-TNF, Anti-C5a/R, Anti-IL-1 for glomerular disease
  2. Cell therapy
    e. g. stem cells, Tregs, regulatory macrophages
  3. Small molecule inhibitors
58
Q

How do biological signatures in SLE change?

A
  • There is an effort to identify variable presentations and tissue involvement with distinct patterns in SLE- most have failed (variable presentations)
  • As SLE progresses, neutrophil-related gene signature increases (due to potentially neutrophil mediated injury, NETosis and dysregulation of NETosis)
  • Therefore targeting neutrophils in SLE may be a better way to treat disease
59
Q

How is the activation of T-cells determined?

A

Active CD8+ cells: signalling through TCR- more likely to flair

Quiet CD8+ T cells:
signalling through IL-7, less likely to flair

60
Q

What potential therapies are avaliable for fibrosis?

A
  • Very important
  • Not current
  • Need therapies for inflammation independent fibrosis

BMS 3052 (8 decks)

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