Diseases of the Immune System 1 Flashcards
Features of acute inflammation
Physical- trauma, heat and cold uv, radiation
irritant and corrosive substances
microbial infections
immune mediated hypersensitivity
tissue necrosis
-predominantly tissue residents cells and influx of neutrophils
Features of chronic irritation
Arises when the causative agent cannot be eliminated
- endogenous foreign objects eg gout
- phagocytosis resistance organisms eg TB
-autoimmune conditions
-predominantly T cells, plasma cells, macrophages
-causes tissue damage but also ongoing repair
-tissue injury form oxygen radicals and proteases
-revasculariation due to angiogenic factors
-fibrosis due to GF and fibrogenic cytokines
- continued T cell activity
What Is central tolerance
Thymus
- education and selection of T cells
Bone marrow
-production of selection of B cells
during development of lymphocytes we have mechanisms to prevent the generation of cells which may recognise self antigens
What is peripheral tolerance
Preventing aberrant activation of the immune response in the periphery
additional mechanisms to reduce the chance of mature cells being activated
B cell receptor development
- CLP stem cells
- Early Pro-B cell
-heavy chain rearrangement D-J - Late Pro-B cell
-Heavy chain rearrangement V-DJ - Large Pre-B cell
-VDJ rearrangement and pre-b celll receptor expressed
-rearrangement of functional heavy light chain initiates light chain gene rearrangement
-light chain can undergo successive rearrangements until a functional receptor is formed - Small Pre-B cell
-V-J light chain rearrangement begins - Immature B cell
-Light chain rearrangement finished and IgM expressed on surface - Mature B cell
-immunoglobulin genes rearranged and B cell starts to produce IgD
B cell testing for auto reactivity- NO SELF REACTION
B cell migrates to periphery expressing surface IgD
B cell testing for auto reactivity- multivalent self molecule
Either
receptor editing -> release of mature B cell
clonal depletion-> apoptosis
B cell testing for auto reactivity- Soluble self molecule
B cell migrates to periphery-> anergic in periphery die relatively quickly
B cell testing for auto reactivity - low affinity no crosslinking
B cell migrates to periphery-> affinity for self but doesn’t react in normal conditions
Where does T cell receptor development happen
Thymus
Process of T cell receptor development
- CLP stem cell
- Thymocytes undergo proliferation
- Double negative thymocyte CD3-4-8-
- Double positive thymocyte CD3+4+8+
- Single positive CD4+ export to periphery and single positive CD8+ export to periphery
- Double negative export to periphery
- those which develop in early life and populate in the epidermis. Later in life they become more established in the epithelium and lymphoid organs
How does a double negative thymocyte become a double positive?
- Double negative thymocyte
- Start to rearrange beta chain D-J
- Continue rearrange B chain V-DJ. Express pre-TCR with surrogate alpha. If cell fails to make a successful beta- death
- Stop rearrangement and start to proliferate
- Double positive- start rearrangement of alpha chain
- life Spain of 3-4 days before either selected or apoptosed.
T cell can continue successive rearrangement of alpha until a functioning receptor is produced
What can happen in positive selection of T cell?
Does the TCR recognise self MHC and peptide?
YES- MHC1= CD8+
YES- MHC11= CD4+
NO- apoptosis
What can happen In negative selection of T cell?
Does the TCR bind with a strong affinity to self peptide?
CD8+
YES- apoptosis
NO- released into periphery
CD4+
YES- apoptosis
NO- released into periphery
LOW AFFINITY- natural T reg CD4+CD25+ (anti inflam)
What is AIRE gene and what does it do
Expressed in the nucleus of medullary stromatolites cells- a subset of thymocyte cortical epithelium
it is s transcriptional regulator which induces expression of self proteins in the thymus
- teaches T cells about antigens in the body
What happens if we loose AIRE
Can lead to destruction of tissues
-slow and doesn’t necessarily affect all of them
Describe antigen segregation (peripheral tolerance)
Physical Barrier to the lymphoid system preventing self antigen access
- these tissues often produce TGF-B in homeostatic conditions down regulating any inflammatory responses
Describe activation induced cell death ( peripheral tolerance)
Persistent high levels of activation and IL-2 leads to the up regulation of FAS and FASL proteins on T cells
- binding of FAS and FASL induced cell death
Describe peripheral anergy (peripheral tolerance)
T cell require costimulatory molecule expression in order to become activated
- when they are presented antigen without this- they become anergic
Describe regulatory T cells (peripheral tolerance)
Regulatory T cells suppress the activation of other leukocytes and provide a source of anti-inflammatory cytokines
- they either develop during T cell selection (nTreg) or induced in the periphery by anti-inflammatory cytokines (iTreg)
What do natural T regulatory cell do
Act to prevent an immune response developing to self antigens
receptors of natural T reg cells
T cell receptor
CD4
CD25
CTLA4
transcription factor- FOXP3
4 ways in which natural T reg cells work
COMPETITION
- T cell receptor and CTLA-4 bind to expressed antigen and inhibit activation
CYTOKINE SECRETION
- nTreg secretes IL-10 to alter the phenotype of T helper cell
- stops polarisation of SR T cell
CELL KILLING
- nTregs can release performing and granzymes
IL-2 DEPLETION
- CD-25 has high affinity for IL-2
-preventing SR T cell proliferation
How to induce Tregs
In the absence of pathogens and IL-6
TGF-B produced in tissues
T cell produces TGF-B and IL-10
In gut
-CD103+ dendritic cells in the gut produce TGF-B and retinoids acid to promote FOXP3 expression
- iTregs are present In large numbers and control the population of effector T cells
What happens if there is disregulation of TH17 and Tregs in inflammatory diseases
Th17 cells are associated with several diseases
- rheumatoid arthritis
- lupus
-MS
-IBS
chronic inflammation and tissue damage with continue to promote the expansion of TH17 cells ( IL-6 and Il-1)
IL-17 promotes the release of more pro-inflammatory mediators and MMPs
- disruption of this is a target for treatment of inflammatory diseases
tocilizumab is humanised anti-Il-6 receptor antibody
-disrupts Th17
What is immunosuppression?
Reduction in the activity or efficacy of the immune response
5 ways in which immunosuppression can occur
AVOID OR RESIST RECOGNITION- herpes
- Down regulate or remove immune mechanisms needed to see the pathogen
-eg reducing MHC1, block complement cascade
DESTROY/INHIBIT HOST RESPONSES- TB,Epstein Barr
- inhibit phagosome formation and resides in macrophages.
-EB can block adhesion of lymphocytes to infected cells
ANTIGENIC VARIATION- influenza
-pathogen has many genes to switch its surface antigens or different strains have very different antigens
PERSIST AT UNDETECTABLE LEVELS- herpes
-virus hides inside host cells and replicates at levels too low to detect. Only re-emerges when host response is low or absent.
PREVENT CYTOKINE EXPRESSION- Epstein Barr
- produce homologous of cytokine eg IL-10 to prevent adaptive immune response
Definition of immunodeficiency
Failure of the immune system to protect the body adequately from infection due to the absence or insufficiency of some component process or substance
Features of primary immunodeficiency
Inherited mutations
INNATE
- deficiencies in complement
- susceptibility to extra cellular bacteria particularly
Neisseria
-problems with phagocytosis
-susceptibility to bacteria and fungi
-TLR signalling
ADAPTIVE
- compromised T/B cells
-general increased susceptibility
- antibodies
-No IgA causes susceptibility to respiratory infections
Features of secondary innumodeficiency
acquired from external factors
DISEASE
- cancer, AIDS, pathogens
ENVIRONMENTAL FACTORS
-starvation, radiation, diabetes
MEDICAL INTERVENTION
- chemo
WHAT IS SCID
Severe combined immunodeficiency
- cannot make T cell dependent antibody responses
What is ADA (SCID)
Enzyme needed for purine metabolism
CLP cannot become thymocyte
CLP cannot become Pro B cell
What is Yc (XSCID)
Common gamma chain for Il receptors
-2,4,7,9,5,21
Thymocyte cannot become Pro T cell
Treatments for X linked SCID
Prophylactic treatment
-sterile environment, antibiotics, immunoglobulin
Bone marrow transplant
-relies on close HLA match and successful reconstitution
Gene therapy
-ADA replaced the gene in peripheral T cells which survived for decade
Process for gene therapy for SCID
- Patients bone marrow is harvested
- Stem cells are extracted from the harvested bone marrow
- Missing gene is transfected into viral vector
- Transformed virus is introduced to cells
- Transformed stem cells are cryopreserved until needed
- Patients bone marrow is depleted to make room for new cells
- Patient receives cells which repopulate the bone marrow and produce the missing protein
What does HIV target?
CD4 and uses CCR5 and CXCR4 as co-receptor
-infects mucosal CD4+ cells and spread to lymph nodes as T cells enriched with CCR5
Disease progression of AIDS
ACUTE PHASE
-influenza like symptoms
-dec circulating CD4
-activation of CD8
-Virus killing and antibody production
CLINICAL LATENCY
-persistent replication of virus
-dec CD4
-virus mutates rapidly
-avoids CD8 cells and antibody responses
AIDS
-6-20 year latency
CD4 cell numbers are at critical level
-patients lose cell mediated immunity
-lose resistance to opportunistic pathogens
-oral candida species are early indicator
What is CART-T cells therapy and what are the benefits with HIV
Genetically engineered for their receptor to recognise a disease specific epitope and induce a cytotoxic response.
Benefits in HIV treatment
- remain active for 6 months (target reactivating HIV)
-independent of MHCI which HIV suppresses
-can access CNS
What are CRISPR and how is it used for HIV
Uses RNA molecules which bind to and target an endonuclease and cause double stranded DNA breaks in the genome
-scan be designed to recognise HIV sequences in the genome
1.adeno-associated virus is engineered to deliver the guide RNA and enzymes into cells
2. Complementary guide RNA binds at the inserted HIV sequence and the endonuclease cuts the DNA
3.segment is excised and DNA repairs
