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AUTOIMMUNITY - Coggle Diagram
AUTOIMMUNITY
AUTOIMMUNE DISEASES
systemic- multiple tissues
local- targetted organs
Tcells- cd4-diff using cytokines-> inflammation. CD8- apoptosis of melanocyte and granzyme, lack t reg
B cells-> in bone marrow undergo vdj recom-> autoreactive cell-> if not removed by clonal deletion or receptor editing-> maature and sent to spleen(costim from t cell). smh. cross reactive b cell receptor recog both self antigen and normal antigen and use t cell help.
How does it actually cause disease?
1) ectopic organogenesis(lymphoid structures)->seperated zones of t,b,gc along with plasma cells. common in ra and cns
2) autoantigens presentation to t cells and costimulation and also b cells produce cytokines
3) Immune complex formation- formed from antibodies binding to self or non self antigens.
4) Autoantibodies production by plasma cells- autoantibodies activated by auto antigen-> plasma cell prudcing, gc-> autoantibody-> migrating to bone marrow, autoreactiv memory b cell-> gc-> plasm producing abs in bm.
Pathogenesis by autoantibodies
1) mimic hormone stimulation of receptor.( graves disease-> autoantibodies targetting tshr-> increased activation-> increased thyroid production
2) blocking neural transmission- nmdar( igg antibodies enter csf, mess with synaptic function.
3) uncontrolled microthrombosis
4) altered signalling
5) uncontrolled neutrophil activation- anca vasculities-> autoantibodies targetting pr3 and mpo-> increased neutrophil activation
6) cell lysis - autoimmune haemolytic anaemia-> complment activation, opsonisation or adcc- cold dependant lgM antibody-> when body temp reduced below 32deg-> activates
7) induction of inflammation
RISK FACTORS
Genetic- some genes identified with higher risk(hla) but individual genes only have a very small role in risk. sometimes a gene cause-> alps-fas mutation. aps-1-aire mutation
Environmental- diet, stress, drug, pollutants.
DISEASES
Systemic lupus erythramatosus- systemic disease,mostly in women(9 to 1), high morbidity, epidemiological diff(race, ethnicity). Survivability depends on early organ damage
Manifestations
butterfly rash(malar)
arthritis
CNS inflammation
lupus nephritis- igg deposition in the glomerulus -> recuit immune complexes and cause injury
autoantibodies in sle target molecules inside nuclei(dsdna,ribonucleoprotiens)-> danger sensors tlr7 and9
CYCLIC EXACERBATION OF DISEASE
1) genetic predisposition- genes that encode for clearance of apoptotic cells-> activate pdc+autoreactive b cells. response to ifn-1. + abnormal innate activates adaptive. TLR7 (gain of function-myd88-> b cell activation)+TNFAIP3(loss of function-> increased tnf)
2) Environmental triggers- uv,smoking,localized tissue damage or locallised inflammation(upreg in costim)-> increased activation of auto b cells
3) Innate immune system- dec in macrophage activity, increased net neutrophils, decreased ho-1(dc/mono), increased dc(proinlf-> infa), reduce basophil, reduce ilc2, reduced complement,increase cytokines, inc tlr7
4) Immune complexes- deposition, injury, fcyr interaction, antigen trapping,
5)clinical - (renal, artheroscle,stroke, pulmoanry dmg,steroids)-> irreversible tissue damage, (rash,nephritis,arthritis,cns inflammation, clotting)
current treatment- rituzimab(not effective), bortezomib-plasma cell apoptosis,atiacicept-baff, cart cells targetting
CURRENT AND FUTURE THERAPIES
physical therapy, microbe, nutritional intervention, anti cytokine therapies
one drug may be used for several diseases and one drug may not be suffieicent in pathways
TARGETTED IMMUNOTHERAPY
1) inflammatory cytokines
tnf- physiological and pathological-> bone and cartillage des, inflmmation cytokines, endothelial cell activation
anti tnf blockades(adalimumab)
IL6(gp130)- systemic inflmmation, immunoglobin production, diffof th17cells,osteoclast diff
tocilizumab(anti il6)-> in ra patients that do not respond to anti tnf
IFN-1- activates in response to antiviral response. damps-prr-tlr
anifrolumab- blocks ifnar receptor
2) autoreactive b and t cells
b cell surface markers- cd20,19
rituzimab(ra)- adcc,cd20 link with rdx-. apoptosis, complement dep cytotoxicity, phagocytosis by macrophages
target- BAFF-> acts on BAFFR,BCMA,TACL
treatment- anti BAFF(belimumab)
3) intracellular kinases
JAK- STAT connection. ligand binds to receptor-> jak autophosphorylates it -> stat adaptor dimerises after binding-> binds to dna
small molecule inhibitors of JAK, by competitive inhibition at phosphorylation site(baricitinib)
TREATMENT UNDER INVESTIGATION
cytokine-il23(mirikizumab), ulcerative colitis,crohn's disease
Targetting BAFF-> sle
BTK(kinase targetting)-MS, immune thrombocytopenia
CELL THERAPIES
pg-23 of last slide
TARGETTING METABOLIC PATHWAYS
oxidative phospho-> metformin, mtor-rapamycin
NORMAL IMMUNE SYSTEM
INNATE IMMUNE SYSTEM
-recognize integral components of pathogens and act against it
ADAPTIVE IMMUNE SYSTEM
-can act against never seen before pathogens
-cell mediated-> t cells and humoral-> b cells
T cells
B cell antigen to apc(dendritic cells)->t cells-> release cytokines-> bind to b cells-> class switch + diffentiation
CSR- movement of the VDJ to the next constant region will cause a switch. AID(converts C to U) is the most important enzyme. The switch region upstream of the constant is a repeated sequence(atcg,tggg), repaired by nhej
Igg-cross placenta, a-mucosal imuunity, m-complement, e-helminthic,d-naive b cell
b cells present antigens to t cells via mhc class 2 -> tcr-> activated t cell provides help. 'help'-> cell prolif+cd40l(aid enzymes)_ signals(il4,2,10). cd40-> nfkb pathway
B cells
Rare b cells are selected from a pool by antigen binding. There is huge diversity in receptor specificity. After binding-> clonal expansion and differentiation(antibodies). Most B cells need cd4 T cell. Antibody produced to an antigen changes with time. Multiple B receptors recog antigen, not just one thus mutiple clones are made.
DEVELOPMENT OF B CELLS
We have HSC ( pro b cell0-> first Vh region rearranges then the Vl rearaagnes-> it enters the periphery.-> bind to antigen and get plasma cells and memory cells.
FAILURES IN DEVELOPMENT OF B CELLS
If pro B cells fail to give signal-> then the cell dies. The gene affected could be involved in rearrangement, dna repair. To be sucessful gene must encode for fucntional ig protien chain in surface.
Fail to respond to antigens-> wrong antibodies produced or unable to produce. inherited mutations.
Overactivation/supersentive B cells can be destructive-> autoimmunity and activate T cells. variants in antigen recognition cause this.
Overproliferation even without ag present-> cancer. base pair mutations/ gene rearrangements
GENE REARRANGEMENT
heavy chain V -> choose VDJ
light chain Vj
-pro b cell ( V(DJ))-> pre b cell(IgH with+surrogate light+signaliing iga_b) -> VJ light chain then plasma cell producing antibody
first heavy chain then surrogate light chain
enzyme-> rag1/2
varitation is increased by diff in joining and dna diff(tdt0
WHAT HAPPENS IN THE PROCESS
1) recognition of rss and cleavage- V and J seperated and 2 rss seperated.(rag1/2) 2) artemis/ku70-> join to cell 3)tdt+dna ligase 4-> we have a join between the two and separate loop of signal
ANTIBODIES
we can separate compartments of the antibody. variable region+ ch1+cl forms the fab
we can look at immune responses as polyclonal( response to different isotopes
MONOCLONAL ANTIBODY
How to make it?- reactive b cell added to immortal cell(evergrwoing,myeloma) and isolate.
For selectivity- when put in HAT medium, only the fusion produces the required nucleotides. harvest antibody
Uses- therapeutic-cancer
diagnostic- pregnancy
imaging-> myocardial infarction
immunosuppression- hiv
-early monoclonal mouse derievd-> viewwed as foriegn since constant region effector was not working, massive cell death and cytokine release, short serum half life
Therefore mechanisms to humanize mouse
1) fully mouse(o)
2) replace mouse igh,l constant regions with human constant regions xi
3) replace variable regions-zu
4) graft one variable region and not the other
5) make only using human material
1) make a mouse that makes human igg immunoglobins and kick out existing igg. xenomouse and velocimouse
3) human resistant to a disease-> isolate reactive b cell and produce antibodies
2) Phage display- isolate b cells-> get gene-> phage-> bind to antigens-> select for affinity.
THERAPEAUTIC ANTIBODY
1) Naked antibody-target to cancer cells,immune checkpoints
2) engineered - immunocytokine, antibody drug conjugate, immunoliposome, bispecific antibody, car t cells
Antigen receptor affinity- changed by affinity(antigens)+ costimulation(cd91/21)
CLONAL SELECTION
B cell encouters antigen via dendrtic cell (fdc)-> t helper cell binds via cd40l and sends il4 and il21 cytokines for the b cell to differentiate-> some become plasma cells(anitbodies), some rest to become memory b cells and some go to gc to mutate and increase affinity.
RP-> MZ(b cells)-> FO( follicular dend cells,naive b cells)-> PALS( t cells)
IMMUNODEFICIENCY
PRIMARY IMMUNE DEFIENCY
Primary - internal cause- not enenvironmental
Antibody- lack or loss in b humoral immuniy only
pre b cell provide signal to progress-> blocked cause problems-> may be due to rearrangement of signalling
DISEASES
XLi agammaglobulinemia- without b cells
treatment- Intravenous immunoglobin (all igg subclasses+m/a)-> not very effective 80% of petient have serious complications
Subcutaneous immunoglobulin-.>self admin
CID- both, if t cell is affected then both immunity is affected since b cells are activated by cd4 tcells
scid- ada,rag1/2,no t cel;s, recurrent infections(viral,bacterial).HSC transplantation
HYPER IMMUNODEFICIENCY- class switch issues and high conc of IgM and less of IgA or IgG.
1) XL cd40L-cid with cellular,humoral defects, no gc,no immune memory
2) AR CD40- humoral def, no gc,mem
3) ar/ad aid def-(ar-no shm,gc,no csr)(ad-yes shm,no csr)
4) UNG def- downstream of aid, no csr,no shm
CVID( common variable immunodeficiecy)
diagnosis of exclusion- reduced serum immunoglobin, recurrent bacterial infection, bi modal distribution of age of onset(5 and 20)
treatment
monthly infusions of ivig, a single infusion needs 1000 donors
Mostly unknown-some are activation receptors(cd19), signalling pathway molecules(nfkb), negative regulators(lrba)
Germinal center
light region- fdc present antigens to select and dark region- somatic hypermutation by aid (aa change)-> v region. This produced plasma cells and memory b cells.
What happens here?- proliferation- cd40l, somatic hypermutation- random intro of point mutations in V region, affinity maturation, death- the remainder die, memory formation, partioned activites.
development of Gc- a strong signal from thc-> express cxcx4 to migrate to dark zone-> aid mutation-> then cdcx4 reduced then cdc5 increases then migrate to light zone. driven by speicificity and increased number of costimulators
selection is the ability of the b cell to recieve the antigen from the fdc and present it to the thc.
Negative effects of somatic hypermutation
b cell lymphomas originate from GC B cells. unmutated b cell come from cd5+ memory cells. csr then somatic hypermutation-> csr common in t cell dependant b cells.
Origin of b cell cancer more likely due to CSR than SHM( but shm can cause gain of function in nfkb or loss in prdmi.
we can target enzymes and make inhibitors than block pi3k and btk
IMMUNOLOGICAL TOLERANCE
tolerance occurs after TCR assembles.All t cell receptors must show a desgree of varaibility
TCR-> no mhc contact(death by neglect), mhc1 or 2 (positive selection), high tcr affinity(death).
In B cells, strength of BCR affects the fate of b cells undergoing tolerance, self antigen activates editing. but after it becomes non slef reactive-> editing stoped to become selected. Strong signalling-> apop/anergy. peripheral tolerance in b cells in spleen ( signal threshold_survial signals from baff)
MECHANISMS OF TOLERANCE
1) Deletion- kiling of slef reactive cells. usually high affinity ones
2) Anergy- a state of non responsiveness. less affnity
3) Receptor editing- vkjk, no longer self react
4) exhaustion- t cells are made non responsive with excess of antigens