tolerance and immunodeficiency - diseases of the immune system 1

briefly explain 3 ways the body deals with threats to the IS:

• pathogens

• intracellular pathogens

• large pathogens

what are the 4 symptoms of inflammation

Redness (Rubor) - Vasodilation, Increased blood flow
Heat (Calor) - Increased Blood flow
Pain (Dolor) - Release of soluble mediators, oedema, cellular infiltration
Inflammation (Tumor) - Vasodilation, Oedema, Cellular infiltration

what are the three main aims to inflammation in the body

• towards the pathogen

• towards tissues 2

1. Localise and eliminate the causative agent
2. Limit tissue injury
3. Repair tissue

what do these do during inflammation:

• hypothalamus

• fat and muscle

• liver

• bone marrow

hypothalamus

• increases body temperature

fat and muscle

• protein and fat metabolism for energy

liver

• acute phase protein synthesis

bone marrow

• increased neutrophil mobilisation

what is a consequence to the body when the pathogen replicates too quickly or if the damage is too big

If the pathogen is replicating too quickly or the damage is great, cytokines are produced in large amounts and have systemic effects to produce and recruit more immune cells.

• big damage to the body/dissemination of a pathogen can cause serious over-activation of innate defences → can lead to severe sepsis, shockkk, death

what are 3 examples of clinical situations around inflammation

• Conditions caused by a something external – pathogen or hypersensitivity

• Conditions caused by a reaction/damage to ourselves – autoimmunity and chronic
  inflammatory conditions

• Conditions where a response cannot be raised – Immunodeficiency

(chicken pox, eczema, chrohns disease, rheumatoid artritis)

what are the two types of inflammation

AI, CI

• what are they each caused by, examples

acute inflammation

• Physical - e.g. trauma, heat, cold, UV, radiation
  Irritant and corrosive substances
  Microbial Infections
  Immune mediated hypersensitivity
  Tissue necrosis - e.g. ischemia from myocardial
  infarction

chronic inflammation

• Arises when the causative agent cannot be eliminated.

• Endogenous foreign objects eg Gout

• Phagocytosis resistant organisms eg TB

• Autoimmune conditions

which immune cells are responsible for acute and chronic inflammation

acute I

• mainly tissue resident cells and influx of neutrophils

chronic I

• T- cells, plasma cells, macrophages

• Tissue injury from oxygen radicals and proteases. Revascularisation due to angiogenic factors
  Fibrosis due to growth factors and fibrogenic cytokines
  Continued T cell activity

B cells receptor development

• name each stage before mature B cell

CLP-SC, EP-BC, LP-BC, LP-BC, SP-BC, IBC, MBC

• what happens to b cell receptor light and heavy chains

common lymphoid progenitor

early pro-b cell

late pro-b cell

large pre-b cell

small pre-b cell

immature b cell

mature b cell

Rearrangement of a functional heavy chain initiates Light chain gene rearrangement

what is the central tolerance process

• what general disease does this prevent

• when the immune system gets rid of developing t and b cells that react against the body’s own antigens

• autoimmune disease

where do t and b cells undergo central tolerance

• T cells: Undergo central tolerance during maturation in the thymus.

• B cells: Undergo central tolerance during development in the bone marrow.

what are the 4 ways B cells are tested for auto reactivity before leaving the bone marrow

• when theres no reactivity to self molecules

• binding to multivalent self molecules 2

• binding to soluble self molecules

• low affinity to self molecules but no cross linking

• if there is no self-reaction → b cell migrates to the periphery expressing the surface IgD

• b cells that have multiple binding sites (multivalent) will bind to antigens, if they strongly bind to self molecules the b cell will EITHER undergo clonal deletion or receptor editing (to release a mature b cell)

• b cells that bind to soluble self molecules will migrate to the periphery, become anergic and die v quickly

• b cells with low affinity to self molecules and no cross linking are kept incase of a pathogen that has a similar antigen, it has no co stimulatory molecule activation

T cell receptor development

• where does this take place

• what process do thymocytes undergo to increase number

• what are the two chains called in the t cell receptor

• what happens to these two chains

• what is a double negative and double positive thymocyte

• thymus

• proliferation

• alpha and beta chain

• they get rearranged

• double negatIve is an immature t cell with no cd4 or 8 receptors

• double positive thymocyte expresses both cd4 and 8 receptors

double positive thymocyte: positive selection

• what happens when D+T binds to MHC1,2 or doesnt bind (during positive selection)

double positive thymocyte binds to self MHC to see if it recognises it

• BINDS TO MHC1 → CD8+ cytotoxic t cell

• BINDS TO MHC2 → CD4+ t helper cell

• doesnt bind means no activation so APOPTOSIS

negative selection: CD8+ CD4+ (makes the 2 t cells for IS)

cytotoxic

• what happens if TCR binds with strong affinity to SELF peptide 2

helper cell

• what happens if TCR binds with strong affinity to SELF peptide 3 (3rd is w/low affinity)

CD8+

• YES → apoptosis

• NO → CD8+ released into periphery

CD4+

• YES → apoptosis

• NO → CD4+ released into periphery

• LOW AFFINITY → CD4+CD25+ = NATURAL TREG

what disease type is polyendocrinopathy-candidiasis-ectodermal dystrophy

• its caused by a defect in which transcription factor

• what type of protein does the TF induce expression of

• what happens in this disease

autoimmune disease

• AIRE - TF autoimmune regulator

• induces expression of self proteins in the thymus

• when the IS attacks endocrine tissues eg, pancreatic insulin producing cells

(central tolerance)

peripheral tolerance

explain the 4 types of ways the we prevent autoimmunity in the body

• antigen segregation

• activation induced cell death (IL2)

• peripheral anergy (co stim)

• regulatory T cells (n/iTreg)

antigen segregation

• physical barrier to lymphoid system preventing self antigen access

• these tissues usually produce TGFB in homeostatic conditions to downregulate inflammation

activation induced cell death

• persistent high levels of activation of IL2 → upregulates FAS and FASL

• FAS FASL binding induces apoptosis

peripheral anergy

• T cells need co stimulation to be activated

• if t cell recognises a self antigen but no costimulatory molecules it will become anergic

n regulatory T cells

• these suppress the activation of other leukocytes and provide a source of anti-inflam cytokines

• they develop during T cell selection (nTreg) or are induced in the periphery by anti-inflammatory cytokines (iTreg)

how are natural T regultory cells produced

• what is their main role in autoimmunity

• during negative selection

• when the CD4+ has a low affinity to self peptides

role:

• to prevent immune response to self antigens

name the 4 ways nTregs prevent autoimmunity

C, CS, CK, IL2 D

COMPETITION

CYTOKINE SECRETION

CELL KILLING

IL2 DEPLETION

explain the 4 ways n Tregs prevent autoimmunity

• competition

• cytokine secretion

• cell killing

• IL2 depletion

competition

• TCellReceptor and CTLA-4 bind to express antigen and inhibit activation (of macrophage)

cytokine secretion

• nTreg secretes IL10 to alter the phenotype of the T helper cell

cell killing

• nTregs can release performin and granzymes

IL2 depletion

• CD25 receptor on nTreg has a high affinity for IL2 to prevent SR T cell proliferation (self reactive T cell)

• what cytokine is produced by tissues in the absence of pathogens and IL6

• when antigens are presented by dendritic cells in these conditions what do t cells differentiate into

• TGFB

• inducible Tregs

• they can produce iL10 and TGFB

• they can ctrl the ppn of effector T cells

• which T cell is associated with autoimmune diseases

• what symptom can this cause CI

• what can it be treated with

• Th17 IN HIGH LEVELS

• chronic inflammation and tissue damage

• drugs that promote anti inflam cytokines

• give examples of autoimmune diseases

• what ILs does Th17 increase

• what is TCZ and what does it do

• rheumatoid arthritis, systemic lupus, erythematosus, multiple sclerosis, psoriasis and inflammatory bowel disease

• IL6 IL1 and MMPs

• Tocilizumab (TCZ) is a humanized anti-IL-6 receptor
  antibody, disrupts Th17 cells

• what is immunosuppression

• Immunosuppression is a reduction in the activity or efficacy of the immune response

• Explain the stages of phagocytosis and give examples of pathogens that disrupt these stages

• what is immunodefficiency

• failure of the immune system to protect the body adequately from infection, due to the
  absence or insufficiency of some component process or substance

primary immunodeficiency

• what is this. a consequence of

• what are the two types of immune responses where deficiencies can occur

• I: give 3 processes that can be affected

• A: name the cells/proteins that can be affected

• inherited mutations

• innate and adaptive

innate

• Deficiencies in complement -susceptibility to Extracellular 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

secondary immunodeficiency

• how is this acquired, 3 examples

• Disease
  Cancer, AIDS, pathogens

• Environmental Factors
  Starvation, radiation, diabetes

• Medical Intervention
  Chemotherapy

problems with lymphocyte generation

• what does SCID stand for

• what does this mean

Severe Combined Immunodeficiency

• Have defects In T Cell development and cannot make T-Cell dependent antibody responses

Enzymes in lymphocyte generation, proteins

X linked SCID

• what does a mutation prevent the production of

• what are the implications of this

• how do you treat this 3

• mutation stops the production of the interleukin receptor gamma chain (Yc)

• blocks vital signalling for immune development

• Prophylactic treatment – Sterile environment, antibiotics, immunoglobulins.
  Bone Marrow Transplant – Relies on close HLA match and successful reconstitution
  Gene therapy – First trial in 1990s with adenosine deaminase (ADA) SCID replaced the gene in peripheral T cells which survived for a decade

explain the process of gene therapy for SCID

what does AIDS stand for

• HIV target cells that express what receptor

• what co receptors are involved

• which type of body tissue is targeted

• how does it spread through the body

• HIV targets cells which express CD4

• uses CCR5 or CXCR4 as a co-receptor

• Infects mucosal CD4+ cells

• spreads in lymph nodes as T cells enriched with CCR5

what are the 3 stages of HIV infection (AP, CL, AIDS)

• what happens to the CD4/8 levels in each

• what are the two infections called, early/late O I

new therapies

• what does CAR-T stand for

  • what are they engineered to do

  • 3 benefits

• CRISPR/Cas9

  • what does it use to breaks in the genome

  • how can it be used against HIV