Sara Paradise updated from Ahmed

IMMUNOLOGY BLOCK I GLOSSARY

Innate Immune system PRR Pattern recognition receptors. Receptors that are present on innate immune cells (neutrophils, macrophages, and dendritic cells) and recognize specific molecular structures (PAMPs) on the outside of the antigen cell wall. Example includes !Rs. !o""#"i$e re%eptors &!LR's( Receptors expressed on outside of " cells which promote wea# " cell acti$ation %& recognizing molecular patterns on th&mus' independent antigens. Acti$ated %& adaptor protein M&()), which fre*uentl& results in +,-" acti$ation. .ithout M&()), !R cannot %ecome acti$ated. his method is does not re*uire /(01 ligand from cell, and produces much wea#er signal (i.e. dont get strong germinal center formation of " cell memor&) $s. acti$ation with /(01 ligand from cell. My)** Adaptor protein located on inside of !R of innate cells to induce +,-" acti$ation of 2!'3 gene. .ithout M&()), there is no acti$ation of !Rs and organism will not %e a%le to deal with infections and dies. Pathogen'associated molecular patterns. Molecular patterns 4 mannose' rich oligosaccharides, peptidogl&cans, and lipol&saccharides coating %acterial cell walls and unmeth&lated /p5 (+A 4 allowing the innate immune s&stem to recognize them as 6non'self.7 -illed %acteria or %acterial extracts added to immunizations to allow dendritic cells to recognize purified antigens such as proteins, since these purified specimens lac# the PAMPs that allow PRRs to recognize them. Allow dendritic cells to %ecome acti$ated to full antigen'presenting status in the a%sence of infection.

PAMP

Ad+u,ant

Comp"ement system 81 proteins produced %& li$er which are in high concentration in %lood9 come together during 6complement acti$ation7 to #ill and clear pathogens from extracellular fluid. 8 pathwa&s include Ag:A% complex,

;;;Ag:lectin complex;;;, and pathogen surface coating. Pro$ides doc#ing site for leu#oc&tes on pathogens and is chemoattractant for neutrophils (/<a, /8a, /0a). Opsoni-ation Process that phagoc&tes (neutrophils, macrophages) use to ma#e pathogen more attracti$e for phagoc&tosis, since the& %oth ha$e negati$e charge. Enhances adhesion %etween an antigen and phagoc&te. Anti%od& or complement proteins (opsonizing proteins) coat antigen cell surface with lipid'li#e doc#ing site, ma#ing it difficult for $iruses to %ind and mar#s for phagoc&te pic#up. Mem%rane attac# complex. (e$elopment of a pore in the lipid %ila&er mem%rane of intruding %acterial cells due to acti$ated complement s&stem, forming transmem%rane channels which can allow defensins and other proteins to #ill pathogen. =suall& found in %lood circulation9 comprise >1')1? of peripheral %lood. Rapid"y attra%ted to site of infe%tion .y %hemo$ines &i/e/ IL#*(0 1here they pha2o%yti-e .a%teria. @hort half'life (die within matter of hours) so must %e replenished %& PM+s in %one marrow. !ea$e p&ogenic %acteria (clumps of dead neutrophils) %ehind9 must %e cleared %& macrophages. (eri$ed from %one marrow and ha$e large, granular morpholog&. ,loat through circulation, where the& recognize and #ill pathogens residing in c&toplasm of host cells (intrac&toplasmic pathogens, especiall& $iruses) 1ithout prior re%o2nition. Contain infections %& #illing infected cell, %ut cannot eliminate the $irus itself. 6-illing Acti$ating Receptor7. Receptor on +- cell which %inds to ligands such as $iral products or malformed proteins to induce #illing of cell $ia perforin enz&me. 5ranz&mes (serine protease) and granul&sin sent into cell $ia holes from perforin, causing apoptosis. 6-illing 2nhi%iting Receptor7. Receptor on +- cell which %inds to MA/ /lass 2 and detects *uantit& to regulate #illing effect of -ARs. 2f lots of MA/ /lass 2 present on cell inhi%its -AR. 2f $er& little MA/ /lass 2 present on cell -AR sta&s acti$e.

MAC

Neutrophi"s

NK %e""s

KAR re%eptors

KIR re%eptors

Innate#"i$e "ympho%ytes induce rapid response e$en though the& are not part of innate s&stem NK#! %e""s B#3 %e""s 4pithe"ia" 5 %e""s

)efensins

Antimicro%ial peptide found on s#in, mucosal tissues9 #ill pathogens $ia cationic charge. "ind to pathogen and puncture cell mem%ranes, altering polarization and #illing cell.

Chemo$ines solu%le factors which attract other cells to site CC CCR6 /lass of chemo#ines containing dou%le c&steine %ond /hemo#ine receptor which is induced %& (endritic cell !R %inding to an Antigen. Attracts l&mphoc&te with integrin to %ind strongl& to 2/AM on endothelial cell surface !&mph +ode chemo#ine. /hemo#ine signal which attracts " cells with mature receptors into AEB !&mph +ode chemo#ine. Along with //!3C, attracts " cells with mature receptors into secondar& l&mphoid organ (i.e. l&mph node) /lass of chemo#ines which contains an extra amino acid %etween them. Most important for innate inflammation. IL#* &C9CL*( C9CL3: Protein released %& macrophages and dendritic cells which attracts neutrophils to infection site $ia chemotaxis !&mph +ode chemo#ine. Attracts " cell into primar& follicle

CCL 73 CCL 38 C9C

Cyto$ines solu%le factors made %& cell !N; fami"y !N; Re%eptor +, receptors recognize c&to#ines of the umor +ecrosis famil& (i.e. /(01 ligand and +,'a). /ells containing these receptors are trimeri% and induce cell to undergo apoptosis. Examples: +,R'2, +,R'22, ;as 2+,!AMMA 2D+. umor necrosis factor alpha. /&to#ine that is secreted %& 'cells, macrophages, and most e$er& immune cell. Aid in re%ruitment of immune %e""s &in%"udin2 eosinophi"s and .asophi"s( to site of in+ury/ ((Macrophage +,'a causes rapid externalization of .ei%el'Palade %odies of endothelium, which contain P'selectin. E'selectin is then expressed allowing endothelial cells to %ind to 2ntegrins on l&mphoc&tes.)) 2f s&stemic infection occurs, +,'a is released from li$er and spleen into %loodstream and causes sepsis E death.

!N;#<

"loc#ing it with +,'F agonists puts the %ra#es on the immune s&stem o$erall (helps auto'immune). C)=> "i2and ;as Re%eptor ;as Li2and /&to#ine that is part of +, famil& and acts as ligand to %ind /(01 and amplif& immune response. 2ntracellular receptor9 %inds ,as ligand to promote cell death $ia %aspases inside the target cell. !igand that can %e expressed %& /(0G cells and %& AC cells. ,as ligand %inding to ,as receptor E cell death. .hen cells get acti$ated, the& express ,as ligand to #ill themsel$es (downregulation). An immunoregulator& c&to#ine made %&
reg

!G;#< !G;#?

cells. @imilar to 2!'C1.

HCI An immuno'regulator& c&to#ine. ransforming 5rowth ,actor ( 5,' J). 2s present in immunologicall& pri$ileged sites where it down'regulates immune acti$ation %& aiding !re2 cell de$elopmentK H3I Promotes !h36 formation along with 2!'L. hC> cells sa$e us from %acterial infections. H8I I2A switching in "'cells, though it ;decreases; their proliferation, since its general function is immunosupressi$e.

Interferons

&pe of protein which interferes 1ith ,iruses and helps other cells recognize that the&re infected. /an %e made %& all cells. 2,+ ma#es it difficult to infect cell so Must %ontains cells9 if cell is alread& infected, it will force cell to express more MA/'/lass 2 so that /&totoxic cellsN+cells can recognize and #ill them /&to#ine secreted %& !@3 cells which ."o%$s ,ira" rep"i%ation &Aanti#,ira"B(/ Also increases expression of /lass 2 MA/ molecules on infected cells (to increase li#elihood of infected cells %eing noticed %& c&totoxic cells). /&to#ine secreted %& !@3 cells which a%ti,ate ma%ropha2es to more acti$el& phagoc&tize their products and induce more eDpression of M@C#I (to increase li#elihood of infected cells %eing noticed %& c&totoxic cells). Promotes formation of AC cells from naO$e 'cells0 and thus is important in dela&ed h&persensiti$it& response. Also promotes isot&pe switching of " cells to 2g53a.

I;N#< and I;N#?

I;N#C

Adhesion Mo"e%u"es Immuno"o2i%a" Synapse 6@&napse7 %etween 'cell and AP/. 2mportant s&napse for naO$e cell. 2ncludes %inding of /(3) on cell to ">.C, ">.3 of AP/. his allows cell to release /(01 ligand, which %inds to /(01 receptor on AP/ and increases its acti$ation. I!IM 2mmunoreceptor &rosine'%ased 2nhi%ition Motifs. ,ound on / !A'0, P(C, and other inhi%itor& structures. @ame as an 2 AM %ut inhi%itor&. "rings in ;phosphatases; which o%$iousl& do the opposite of #inases. 2mmunoreceptor &rosine'%ased Acti$ation Motifs. hese are in$ariant (i.e. not changea%le) proteins found on the c&tosolic side of the C)R:EI2a#I2B %omp"eDes9 contain certain amino acid se*uences with 3 t&rosines re*uired for signal transduction. /an %ind t&rosine #inase and %ecome phosphor&lated to acti$ate recruitment of other #inases within the cell (%oth enz&mes and non'enz&mes, adaptor proteins. On endothe"ium/ 2ntercellular adhesion molecules that are part of 2mmunoglo%ulin superfamil&. Present on the surface of endothelium and %inds proteins of the integrin famil&.

I!AM

ICAM:

ICAM#3 and ICAM#7 Adhesion molecules located on endothelium which %ind to integrins on l&mphoc&tes to allow them into @4FEendothe"ium. "inding causes conformational change in structure of 2/AM, allowing tight %inding to $ascular surface and e$entual extra$asation. FCAM#3 Adhesion molecules located on endothelial cells which %ind to B!A'0 integrin on l&mphoc&te to allow them to access periphera" tissue where inMur& has occurred. =pregulated on cell surface in response to macrophages releasing +,'a c&to#ine (i.e. immune response initiated). On endothe"ia" %e""s/ Dligosaccharides located on the outside of endothelial cells which %ind !'selectin.

Addressins Se"e%tins

On "ympho%ytes su%h as !#%e""s/ 5l&coproteins that ha$e distal lectin'li#e domains %ind to car% groups (/AMs) on endothelial cells. @electin expressed on naO$e cells which 6selects l&mph node7 %& homing l&mphoc&te to AEB. "ind to oligosaccharides (addressins) on endothelial cells. (ownregulated in effector cells in so that cell does not return to l&mph node %ut instead migrates to peripher&.

L#se"e%tin

Inte2rins

On "ympho%ytes/ Molecules on surface of professional AP/s that %ind to cell'adhesion molecules (2/AMs) and extracellular matrix in response to chemo#ine release, pro$iding a strong adhesion to AEB or endothelium at site of inMur&.

! %e""s L;A#3: Part of Ainside#outB si2na"in2 me%hanism. 2ntegrin molecule expressed on cell that %inds 2/AM'C (adhesion molecule) on surface of AP/9 responsi%le for initial %inding %etween AP/ and cell, as at first it %inds with low affinit&, %ut once /R %inds to MA/Npeptide complex on AP/ !,A'CN2/AM undergoes conformational change grows stronger, prolonging cell'to'cell contact. Also functions in endothelial cell adhesionNtransport. (eficienc& leads to poor wound healing. Another t&pe of integrin which %inds to FCAM#3 on acti$ated endothelium at sites of inflammation. =pregulated on cell surface once cells ha$e %een presented with antigen (i.e. naO$e effector cells).

FLA#=

B %e""s B7 inte2rins L;A#3 and CR#: expressed on l&mphoc&te. "inds to 2/AM on acti$ated endothelium to allow extra$asation. "inds to 2/AM on AP/ to allow tight cell'to'cell interactions %etween cells and AP/s. Mono%ytes MAC#3 2ntegrin on monoc&tes which %inds 2/AMs and B/AMs during inflammation

Leu$o%yte Adhesion )efi%ien%y &LA)( (eficienc& where integrins or selectins on l&mphoc&te are mutated9 l&mphoc&tes ha$e trou%le entering tissue so there are recurrent %acterial and fungal infections Adapti,e Immune System C"ona" se"e%tion /entral principle of adapti$e immunit&9 each l&mphoc&te %ears a specific receptor with uni*ue specificit&, and %inding of that receptor with a compati%le antigen will cause l&mphoc&te acti$ation. he differentiated cells deri$ed from an acti$ated l&mphoc&te will %ear receptors of identical specificit& to parental l&mphoc&te

Immuno2"o.u"in

Anti%od& proteins which can occur as either transmem%rane proteins or secreted anti%odies from " cells. /onsist of < main classes: 5MEA(, defined %& their hea$& chain constant region. Aa$e 6immunoglo%ulin domain7, which is a conser$ed motif of C11'CC1 amino acids folded up into a compact structure which is sta%ilized %& intrachain disulfide %onds. , P, Q, F, R -, S he different structures of hea,y %hain constant regions that define the 2g5, 2gM, 2gE, 2gA, and 2g( classes. +ai$e " cells can onl& produce the G isotype &I2M( and 5 &I2)( isotypes/ (iffer in num%er of interchain disulfide %onds, length of hinge region, etc. Dnce the& are presented which antigen, the& can undergo 6class'switching7 to form other t&pes. !ight chains do not undergo class'switching. Part of hea$& and light chains that do not change.

@ea,y %hain Li2ht %hain Isotype

Constant re2ion

Faria."e re2ion Part of hea$& and light chains that are $aria%le @yper,aria."e re2ion 8 different parts of $aria%le region (/(RC, /(R3, and /(R8) that are especiall& $aria%le, and confer antigen specificit&. Present on %oth hea$& and light chains and correspond to B(T and BT genes on Aea$& and !ight chains, respecti$el&. /(R8 is most $aria%le of the 8 h&per$aria%le regions, which corresponds to the Moining regions %etween B, (, and T genes. Mono,a"ent /an %ind onl& C Ag Bi,a"ent /an %ind 3 Ags ;rame1or$ re2ion a$a Comp"ementarity )eterminin2 Re2ion &C)( he other part of the $aria%le chain (i.e., the part that is not h&per$aria%le) 4pitope Part of antigen which %inds to anti%od& $ia non'co$alent interactions. ,or "'cells, A% usuall& recognizes part of Ag that is on outsideH recognizes AshapeB or %onformationa" epitope/ ,or 'cells, A% does not necessaril& onl& recognize outside of Ag. "/R. Mem%er of 2mmunoglo%ulin supergene famil&. )imer of heterodimers 4 light chain G hea$& chain lin#ed %& intrachain sulfide %onding x3. /ontains constant region (,c) 4 / terminus 4, which defines its isot&pe and regulates the %iological acti$it& of the molecule, and $aria%le region (,a%) at top end 4 + terminus 4 which %inds antigen.

B#%e"" Re%eptor

!i#es to %ind "on20 linear epitopes found on outside of antigen (conformational epitopes 4 recognize shape). Papain Pepsin !#%e"" Re%eptor Enz&me which clea$es A"DBE intrachain disulfide, so produces 3 mono$alent ,a% fragments Enz&me which clea$es "E!D. intrachain disulfide, so produces C %i$alent ,a% fragment. /R. Mem%er of 2mmunoglo%ulin supergene famil&. /onsists of a heterodimer of a and B %hains (or in some cases and R9 primiti$e receptor) with constant region ,c and $aria%le region ,a%, $er& similar to "/Rs. Also ha$e 8 /(Rs in h&per$aria%le region and antigen %inds to %oth a and " chain. he a and " chains %ind to %oth the peptide and MA/. /Rs recognize antigen as a processed short, linear epitope %ound to MA/ /lass 2 or 22 on the surface of AP/. /R %inds %oth the epitope and MA/. Ber& dangerous antigens which %ind directl& to the framewor# constant region of /R $s. h&per$aria%le region, which is much more common. +o processing of antigens into peptide re*uired. Allows them to acti$ate man&, man& cells to release c&to#ines all at once. 2ncludes staphy"o%o%%a" enterotoDin A and B/

M@C Restri%tion

Superanti2ens

@aptens

@mall molecules such as drug meta%olites, metals, pol&saccharides, and lipids which are recognized %& immune receptors %ut onl& %ecome immunogenic (i.e. initiate immune response) when %ound to carrier protein. Examples include pol&saccharides in $accines, c&closporine in transplant patients, h/5 in pregnanc&, and penicillin. Must use anti'hapten anti%odies to detect presence of these haptens.

Peni%i""in

Penicillin is an anti%iotic that contains %eta'lactams and inhi%it peptidogl&can s&nthesis of the %acterial cell wall. A penicillin allerg& occurs when &our %od& generates an immune response to the hapten'carrier conMugate, causing reactions such as rashes, hi$es, itch& e&es, swollen lips, tongue, or face. Dccurs in 3? of patients. Antigens (haptens) which actuall& cause immune response, %ut onl& when %ound to protein carrier. Example is (+P %ound to "o$in @erum al%umin ("@A). MaMor Aistocompati%ilit& /omplex. /omplex located on " and cells

Immuno2ens

M@C mo"e%u"es

which come in two different $arieties MA/ /lass 2 and MA/ /lass 22. "oth ha$e alpha and %eta region, %ut in MA/ /lass 2 alpha region is enlarged and %inds peptides, $s. MA/ /lass 22 where %oth a and " %ind peptides. Lymphocyte Development RSS Recom%ination signal se*uences. /onser$ed se$enmer and nonamer se*uences flan#ing the exons (so on the introns) of the B, (, and T genes in l&mphoc&tes. "ound %& RA5 proteins and let them #now that exon splicing se*uence is near%&. 6!&mphoid'specific recom%inase genes7. RA5 genes and RA5 proteins are on"y eDpressed durin2 "ympho%yte development9 the& allow and " cells to undergo somatic recom%ination %& causing endonucleol&tic clea$age on the < end of %oth B and T R@@es. his lea$es free 8 DA at their ends, which attac# the < phosphate, creating a hairpin loop on each segment. -u %inds to the ends of the (+A, and associates (+A'dependent P-A and Artemis, which opens the hairpin loops. erminal deox&nucleotid&l transferase. Enz&me associated with RA5 which is expressed during l&mphoc&te de$elopment. Adds and deletes nucleotide segments at the end of flan#ing B, (, and T genes, changing (+A exon structure and increasing di$ersit& of antigen receptors created. /ell can sur$i$e in a%sence of dt.

RAG307

Ku0 Artemis !dt

B %e""s NaI,e B %e""s Pro'" cell rearranges hea$& chain first to %ecome pre'" cell. Rearranges light chain, and if positi$el& selected will lea$e %one marrow as 6naO$e mature " cell7 and go to white pulp of spleen. Express %oth 2gM and 2g( (2g( is due to alternati$e post'transcriptional mR+A splicing, +D gene recom%ination). ,i%ro%last'li#e cells that are associated with " precursor cells in %one marrow9 regulate their de$elopment and maintain signals that #eep " precursor cells ali$e. Pro$ide anchoring sites (adhesion mo"e%u"es0 FCAM#3), growth factors (IL#6(, and chemoattractants (S);#3(/ @omething happens when &ou signal through an antigen receptor in an inappropriate wa&, such as %inding a self antigen. 2t causes the cell to express I2M (G isotype( in low concentrations9 2g( expressed normall&, though cell will e$entuall& undergo apoptosis and die. Dccurs during l&mphoc&te de$elopment if there is an intermediate self'2g5 reaction.

Stroma" Ce""s

Aner2y

CCL 73 CCL 38 C9CL3:

/hemo#ine signal which attracts " cells with mature receptors into AEB Along with //!3C, attracts " cells with mature receptors into secondar& l&mphoid organ (i.e. l&mph node) Attracts " cell into primar& follicle

B cell maturation into effector B cells Mar2ina" Jone B Ce""s MU " cells. !ocated Must outside of central arteriole of white pulp of spleen so first to recei$e antigens. (o not de$elop until Lth month of life. !imited antigen receptor repertoire9 onl& recognize %acterial pol&saccharides and few other PAMPs. B3 %e""s " cells which reside in peritoneal and pleural ca$ities. 62nnate'li#e7 in that the& form earl& in fetal life (though after RS cells) and onl& recognize limited num%er of Ags.

!hymus#independent A2 Antigens which present to " cells and cause stimulation without Aelper s. Antigens must form multiple cross'lin#s to " cell to achie$e strong enough stimulation, therefore 2gM is usuall& expressed (penta$alent). Lin$ed re%o2nition he fact that " cells are acti$ated %& cells is due to the fact that cells and " cells recognize different epitopes of the same Antigen. Ex) " cells recognize pol&saccharide and cells onl& recognize protein on MA/.

B7 ;o""i%u"ar a$a Con,entiona" B %e""s " cells which are located in l&mphoid follicles. Must recei$e signal C (specific Ag:A% %inding) as well as signal 3 ( /R:/(01 costimulation) in order to acti$ate. C"ona" 4Dpansion /lonal expansion of " cells occurs in germinal centers 4 site of intense " cell proliferation. !ight zone of follicle is where follicular dendritic cells present to Ag. (ar# zone is " cell proliferati$e zone.

;o""i%u"ar )endriti% Ce""s +on'hematopoeitic fi%ro%last li#e cells which trap antigens and present to "3 cells. Affinity Maturation A@ur$i$al of the fittest7 for " cells. " cells with receptor that has highest affinit& for Antigen will %e induced to continue to proliferate. @e$eral

rounds of somatic mutation in $aria%le region, antigen selection, and high affinit& %inding ma& occur to increase affinit& for antigens and cause " cell proliferation. Somati% @ypermutation (escri%es the fact that /(R coding regions of (+A (antigen'%inding regions) mutate at C,111,111,111 times normal rate during " cell clonal expansion. Re*uires specific enz&me 4 AI) 4 to occur. he mutations are permanent and passed down to progen&. P"asma Ce""s @ecreted anti%od&. Processed %& alternati$e RNA post#trans%riptiona" pro%essin2/ Mechanism that alters constant region (,/) of hea$& chain, switching them from 2gM and 2g( to another t&pe $ia A2( enz&me splicing at gene le$el. (epends on stimulus, help from cells, and c&to#ines. Altering hea$& chain E altering effector acti$it&. =suall& occurs after 3nd Ag exposure. 2sot&pe switching ma& occur again, though cannot switch to more downstream 2g5. @ecreted %& A3 and promotes switching to 2g5C and 2gE ($ia @ A L) @ecreted %& AC and promotes switching to 2g53a @ecreted %& reg and promotes switching to 2gA Enz&me which recognizes 6switch regions7 upstream of /onstant Aea$& /hain locus and can splice them to ma#e different rearrangements (except 2g(, which uses post'transcriptional processing).

Isotype S1it%hin2

IL#= I;N# !G;#? AI) en-yme

@umora" Immune response A-A Anti%od& immune response. +eutralizes toxins, aggregates antigens, A(//, Promote phagoc&tosis, opsonization, and pre$ents %inding of other pathogens $ia M//. I2M K constant region of hea$& chain. Mostl& located in circulation. Expressed on naO$e " cell surface and therefore does not undergo somatic h&permutation. Relati$el& low affinit& for antigen, %ut often used in agglutination reactions and pre$alent in MU" and "C:Ag %inding due to pentameric structure (multi$alent E %inds more antigen). 5 constant region of hea$& chain. Expressed on naO$e " cell surface.

I2)

I2G

constant region of hea$& chain9 can cross placental %arrier. +cells %ind here and acti$ate $ia A(// (Anti%od& dependent cellular c&totoxicit&). < constant region of hea$& chain. Expressed on mature " cell surface and can undergo somatic h&permutation. Aas multiple $alences. ransported across epithelial cells to mucosa or to lumen of lactating %reast, sali$ar& glands, and tear glands, where it can neutralize %acteria and toxins to protect mucosal surfaces. L constant region of hea$& chain. Mast cells %ind here and acti$ate allerg& response.

I2a

I24 ! Ce""s <#%hain "o%us ?#%hain "o%us

/ontains man& B and T mini'genes, as well as one / gene to code for constant and hinge region /ontains man& B, a single (, and man& T mini'genes, as well as one / gene Another t&pe of cell that predominates earl& in de$elopment of fetus, and diminishes in mature adult. More primiti$e and 6innate'li#e7 as the& recognize non'peptide antigens (phospholipids, etc.) presented %& non' classical MA/ molecules. Ma& ser$e as epithelial %arrier in fetus to defend against common micro%es. (eletion or editing of light chain receptors after reaction with self antigen that occurs in primary "ymphoid or2ans. Dccurs in secondar& l&mphoid tissue. /ellular inacti$ation %& wea# signaling with co'stimulus

5#! %e""s

Centra" !o"eran%e Aner2y

Medu""ary epithe"ia" %e""s of Lymph Node Resident macrophage and plasma cells in medullar& cords which are +D hematopoeticall& deri$ed9 li$e here and carr& pieces of protein from peripher&, a""o1in2 ! %e""s to re%o2ni-e se"f anti2en and under2o ne2ati,e se"e%tion/ Corti%a" 4pithe"ia" Ce""s of Lymph Node Resident AP/ cells which are +D hematopoeticall& deri$ed9 present de$eloping dou%le'positi$e /R with antigen peptide on self MA/. Ensures that !CR 1i"" re%o2ni-e peptide presented .y se"f M@C and under2oes positi,e se"e%tion/

2f /R recognizes MA/'/lass 2 /() sends signal for /R to continue de$elopment and %ecome /()G9 if /R recognized MA/'/lass 22 /(0 sends signal for /R to continue de$elopment and %ecome /(0G. M@C Restri%tion/ AIR4 )efi%ien%y Autoimmune regulator deficienc& which causes causing rare autoimmune pol&endocrine s&ndrome 4 &pe 2 (AP@'C). A2RE is a transcription factor expressed in th&mic medullar& epithelial cells that a""o1s spe%ia"i-ed %orti%a" epithe"ia" APC's to present protein or protein fra2ments in thymus that are norma""y on"y eDpressed in the periphery/ (eficienc& E lac# of protein in corticall& medullar& cells that allows peptide presentation lac# of central tolerance (no neg. selection) autoimmune pro%lems in peripher& Go"di"o%$s !heory Mo"e%u"ar !e%hniMues ;"o1 Cytometry Ma#e cell suspension, add A%s, add proteins. Appl& laser9 if the A% has attached to Ag, it will fluoresce and &ou can count num%er of antigens. Allows &ou to anal&ze the patterns of protein expression on a or " cell %ased on anti.ody interactions with the proteins on the cell surface. Ex) categorizing different stages of cell de$elopment: ta#e from th&mus, mush it up, ma#e a single'cell suspension, la%el A%s with fluorescent anti%odies that recognize either /(0 or /(). Dne axis is loo#ing at whether the cell expressed /() protein, further out on the x'axis, cells express /(). Dn the &'axis, cells that express the anti%od& thats associated with expression of the /(0 protein appear. Mono%"ona" Anti.odies Produced %& a single clone of " l&mpho&ctes. =suall& produced %& ma#ing h&%rid A%'forming cells from a fusion of non'secreting m&eloma cells with immune spleen cells. !a% artifact or sign of malignanc&, as there is outgrowth of single clone of cell (+on'hodg#in l&mphoma). =sed to ma#e drugs in mice. he pro%lem is that if &ou gi$e human a mouse A%, human will react. /hange (+A to allow mouse A%s to ma#e it loo# more li#e human A% so no response occurs. Po"y%"ona" Anti.odies hese anti%odies recognize multiple epitopes of antigens so the& can acti$ate multiple l&mphoc&te clones of di$erse specificit&. +ormal h&moc&te de$elopment (i.e. positi$e or negati$e selection) depends upon the strength of the signal the cell recei$es from its microen$ironment.

immune response to influenza, as Ag has multiple epitopes and multiple A%s will %ind. A22"utination Final T cell maturation C)*N ! %e""s /luster of differentiation ). Receptor't&pe displa&ed on /&totoxic Recognize ,ira" antigen presented %& peptide M@C C"ass I complex on surface of infected cell and %ind to them $ia 2/AM interactions. Dnce %ound, C!L's %ecome polarized and release granules containing perforin (puncture cell mem%rane), 2ran-yme (serine protease to chop up (+A), and 2ranu"ysin to #ill cell rapidl& $ia apoptosis. Produce c&to#ines such as I;N' to express MA/ /lass 2 on target cell and to increase macrophage acti$ation. Also express ;as "i2and to regulate and #ill l&mphoc&tes. Apoptosis 6Programmed cell death7. /ell destro&s itself from within %& using nucleases to shred (+A into pieces of 311 %ps, clea$ing %etween nucleosomes. Also can #ill $iral (+A in host cell. Aggregation or clumping of antigenNanti%od& complexes. =se 2gM in la%orator& tests %ecause it is penta$alent and can crosslin# multiple Ags.

C)=N ! %e""s

cells which contain man& su%classes, categorized %& the c&to#ine that the& release. Recognize a $ariet& of antigens presented %& MA/ /lass 22 molecules on surface of infected cell. AIN;LAMMA!ORY /(0 cells7.

!@#3

Prin%ipa" ;un%tion Acti$ate macrophages (see 6macrophage acti$ation7 under AP/ section) $ia I;N# , which recognizes %acterial antigens on macrophage surface and stimulate their micro%icidal acti$it& and #ill engulfed %acteria. @&nergizes with 2,+'a released from macrophages to allow diapedesis of macrophages into site of inMur&. Also acts as co'stimulator for naO$e " cells allowing them to ma#e more anti%odies and undergo isot&pe switching. !@#7 Aelper cells whose main function is to acti$ate " cells to produce A%s through isot&pe switching9 initiates allerg& response and attac#s parasitic worms.

@ecretes IL#=EIL#3:, which acti$ates " cells to %ecome I24. IL#= initiates the a""er2y response %& causing isot&pe switching to 2gE and crosslin#ing of 2gE on "cells to ,c receptors on mast cells, causing them to degranulate and release histamine, prostaglandin, and leu#otrienes. IL#3: acti$ates go%let cells to secrete mu%us. Also secretes c&to#ine ILO, which promotes " cell to displa& I2A for eosinophil maturation and degranulation. Regulated %& GA!A#: ,. S!A!P !@#36 Acti$ated %& IL#=9 causes promotion of 5A A'8 and isot&pe switching to 2gE.

Effector cells whose main function is to re%ruit neutrophi"s to %"ear .a%teria from eDtra%e""u"ar spa%es E 6clean'up crew7. @ecretes IL#36 and IL#P, which allow more AC> de$elopment %& upregulating transcription factor ROR ! and recruit more neutrophils to site of %acterial infection to clean up. (e$elopment induced %& !G;#? and IL# P. Ma& ha$e a role in autoimmune diseases such as /rohns, 2"@, Rheumatoid arthritis, and M@.

!re2

Regulates num%er of l&mphoc&tes %& downregulating macrophage and dendritic cell acti$ation. A$oids autoimmune responses. (e$elop in response to !G;#? which increase production of ;O9 ,. @ecrete !G;# ? and IL#3> to inhi%it AC. !igand that is part of +, famil& and is important in inducing apoptosis of "ympho%ytes to terminate immune response once it has %een completed. /&totoxic cells and helper cells contain ,as receptor. ,as ligand %inding to ,as receptor E apoptosis. Mutation in ,as gene produces l&mphoproliferati$e disease in which cells cant %e cleared.

;as "i2and

)e"ayed Inf"ammatory Response 2f pre$iousl& infected with antigen, acti$ated AC will release c&to#ines and a%ti,ate ma%ropha2e, causing inflammator& response. 2t is dela&ed %ecause it ta#es a few da&s for hC cells to induce macrophage response. Ex) " test. +aO$e cells would not ha$e this effect %ecause there would not %e enough to recognize " antigen. hC cells release 2,+' to induce expression of $ascular adhesion molecules, +,'F and J to cause local tissue destruction and increased expression of adhesion molecules, chemo#ines to recruit macrophages to site of antigen, and 2!'8N5M'/@, to produce monoc&tes %& %one marrow stem cells.

Conta%t @ypersensiti,ity (ela&ed h&persensiti$it& response for things li#e poison i,y. Poison i$& is pentadecacatechol, lipid solu%le chemical that penetrates s#in and reacts with proteins, creating haptenated proteins (altered self) which can %e ta#en up %& !angerhans cells (s#in macrophages) and %rought to l&mph nodes to present antigen. 2mmune response is therefore not generated on first exposure, %ut upon multiple exposures AC cells are recruited to site. ! %e"" primin2 6Memor& response. cells7 which ha$e seen antigen %efore. /ause inflammator&

Cyto$ines re"eased .y Professiona" APC's IL#= IL#P IL#37 !G;#? /&to#ine secreted %& APC's which induces , GA!A#: to ma#e more !@7 cells. Also promotes isot&pe switching of " cells to 2gE and 2g5C. /&to#ine, along with !G;'? (and sometimes 2!'38), secreted %& APC's which increases ROR ! , to ma#e more !@36. /&to#ine produced %& mature dendriti% %e""s and ma%ropha2es/ 2ncreases production of !#.et, which ma#es more !h3/ /&to#ine produced %& APC's in response to pathogen %inding of !R, i.e. /auses production of ;oDP: ,, which ma#es more !re2 %e""s.

C)'s
C)R: %omp"eD Part of /R @ignaling complex. /onsists of: @eterodimer of 50 L @eterodimer of L 0 C @omodimer of %hain Each component is necessar& for the initial transport of an < ? heterodimer to the surface of a cell and for signal transduction (note: the& do +D %ind antigen). C)= /luster of differentiation 0. Expressed %& !#he"per %e""s. 2ncludes man& su%'t&pes li#e hC (2!'C3 and 2,+'V promotionNproduction), h3 (2!'0 promotionNproduction), and hC> (2!'L, 5,'W promoteNproduce). /luster of (ifferentiation ) is a receptor't&pe expressed %& CytotoDi% !# Lymph%ytes &C!Ls(/ hese cells sample MA/ /lass 2 presented peptides and apoptose $irall& infected cells. /ontains granules with perforin, granz&mes, and granul&sin to degrade $iral antigens and induce apoptosis.

C)*

C)38E73

Analogous to /(0N/() for 'cells, these are co'stimulator& molecules located on " cells that %ind to MA/'peptide complexes to facilitate 2 AM in 2ga and 2g" complexes. XXXXXXXXXXXXXXXXXXXXXXXXXY /(3) found on '/ells. Most important co'stimulator& signal %etween them and the dendritic cells (AP/) to a%ti,ate the !#Ce"". "ind to the "> motif of AP/s. Aematopoietic stem cells. RootNprogenitors ha$e this 2 thin#. /(01 %inds /(01!. /(01!(ligand) is expressed on activated 'cells, /(01 found on the "'/ellsNAP/s. 2nteraction is important to promote 2sot&pe @witching and a%ti,ate the B#%e"" ("'cells are AP/s). Also acti$ate macrophage and dendritic cells and release 2!'C, +,'F, and 2,+' V. All src famil& #insases share certain structure including an @A3, @A8, and inhi%itor& domain in the signal transduction pathwa&. /s# phosphor&lates the 2 2M motif, causing inhi%ition9 /(0< is a phosphatase that dephosphor&lates it and uninhi%its the signaling pathwa&.

C)7O C)7*EB6

C):=N0C):*# C)=>EC)=>L

C)=OECs$

ILs
IL#3 2nterleu#in'C. Pro#inf"ammatory %yto$ine secreted %& macrophages during innate immune response (though it can %e acti$ated %& cell /(01 ligand). ,unction to enhance response and induce acute'phase protein secretion. /onsidered an endo2enous pyro2en/ ;IL-1 & IL-1: increase endothelial adhesion to allow leukocytes to migrate to target site of infx and can re-set the hypothalamic thermoregulatory center. * is assoc with increased sensitivity to pain that comes with fever and activated by inflammasome complex. IL-1R: modulates IL- inflammatory and immune rsp by !-" IL- 1 2nterleu#in'3 growth factor that is important in acti$ating naO$e cells, apges it promotes clonal expansion and production of more high'affinit& 2!'3 receptors as well as secretion of more 2!'3 $ia autocrine acti$it&. Produced %& h3 helper cells. Promotes differentiation into h3 cells while inhi%iting hC formation. Promotes isot&pe switching (to 2gE). Produced %& (%ronchial) epithelial cells under influence of acti$ated Mast /ells. 2s a c&to#ine that acti$ates eosinophils and promotes their formation in %one marrow. 2s ;+D ; a chemoattractant.

IL#7:

IL#= IL#O:

IL#P:

@ecreted %& macrophages and dendritic cells during innate immune response. Promotes !h36 formation (so does 5,'J) to enhance response and induce acute'phase protein secretion. 2nhi%its hC Z h3 formation. /&to#ines located in the microen$ironment of the de$eloping and " cell that are important for maintainin2 de,e"opment9 a""o1 ! %e""s to .e%ome Memory %e""s/ 2f missing, $er& %ad immunodeficienc& disorder since &oure not a%le to ma#e memor& cells. An immunoregulator& c&to#ine made %& parasitic worms. cells. Also made %& certain

IL#6

IL#3> IL#37

reg

Proinflammator& c&to#ine that promotes hC de$elopment from a naO$e 'cell. 2nhi%its h3 de$elopment. 2,+'V does this as well. /an %e acti$ated %& cell /(01 ligand. /&to#ine which is also important for memor& cell sur$i$al.

IL#3O IL#36

2mportant for remo$al of staph and candida. 2n APE/E( patients %od& is producing anti%odies to 2!'C>, resulting in candidiais and ectodermal d&stroph&.

i!nal Transduction I!AM 2mmunoreceptor &rosine'%ased Acti$ation Motifs. hese are in$ariant (i.e. not changea%le) proteins found on the c&tosolic side of the /(R8N2ga' 2g" complexes9 contain certain amino acid se*uences with 3 t&rosines re*uired for signal transduction. /an %ind t&rosine #inase and %ecome phosphor&lated to acti$ate recruitment of other #inases within the cell (%oth enz&mes and non'enz&mes, adaptor proteins. his complex is also found on the ,cER2 and ,cgammaR222 immune receptors of +- cells, macrophages, neutrophils, mast cells, and %asophils. I2a#I2B SRC Part of "/R signal transduction complex. @R/s are t&rosine #inase enz&mes which phosphor&late t&rosines after ligand %inds. hese proteins are post'translationall& modified to include a fatt& acid tail, and therefore are attracted to lipid rafts in cell mem%ranes. Example: /R E lc# @R/ t&rosine #inase Lipid Rafts Aeterogeneous regions within the plasma mem%rane which $ar& in fluidit&, and therefore re2u"ate and promote protein'protein interactions

as well as cell signaling complex formation. 5P2'lin#ed proteins (proteins that associate upon %inding of signal ligand) and ac&lated proteins such as src'famil& #inases are often found in lipid rafts. Adaptor proteins Proteins which are non'enz&matic, %ut form part of macromolecular "/R and /R signaling complex

Re%eptor !yrosine Kinases Aa$e their own inherent enz&matic acti$it& and can transduce signal to inside of cell on their own. Examples: Epidermal 5rowth ,actor (E5,) receptor, 2nsulin receptor Re%eptor#asso%iated !yrosine Kinases /ell receptors which do not ha$e their own enz&matic acti$it&, so must recruit other molecules to the site of the receptor to transduce messages inside the cell $ia 6second'messenger7. /ontains regions which interact with phosphor&lated t&rosines, prolines on adaptor proteins, and cell mem%rane. Examples: Antigen receptors, ,c receptors, c&to#ine receptors S@7 domain S@: domain Region of receptor associated - which %inds to phosphor&lated (acti$ated) t&rosines Region of receptor'associated - which %inds to proline amino acids on adaptor protein.

S%affo"din2 proteins @tructural proteins which contain multiple t&rosine phosphor&lation sites and therefore recruit multiple signaling proteins to %ind to it. ,acilitate complex formations that facilitate cell signaling. .here does scaffolding occurYYY Immuno"o2i%a" synapse Co#re%eptors 2n addition to /RN"/R %inding to MA/'peptide complex, these A!@D %ind MA/'peptide complexes, sta%ilizing their association and recruiting t&rosine #inases to the A2RY

T"R i!nal Transduction

C)=EC)*

/an act as co'stimulator& molecules for /Rs9 %ind MA/'antigen complex after ligand %inding, assisting 2/AMs of /(8s to %ecome phosphor&lated %& !c# @R/ famil& t&rosine'#inase which associates specificall& with ' cell /(0 (MA/ /lass 22) or /() (MA/ /lass 2) co'receptors, promoting the phosphor&lation of 2 AM on /(8 complex. 2nitial phosphor&lation e$ent. Adaptor protein which is recruited after phosphor&lation of !c# and ,&n9 %inds to -eta %hain off of /R in c&toplasm. Acti$ated %& UAP'>1 to clea$e P2P3 into two products, (A5 Z 2P8 (iac&lgl&cerol. P!/' clea$es P2P3 into (A5 and 2P89 (A5 acti$ates ras, which phosphor&lates protein to acti$ate +,-" transcription factor, which %inds to promoter region of 2!'3 gene turning on its transcription. Part of small 5 protein class in all cells. Kinase that phosphor&lates a protein to acti$ate +,-" transcription factor, which %inds to promoter region of 2!'3 gene turning on its transcription. 2mportant for acti$ating MAP #inase. 2nositol triphosphate. P!/' clea$es P2P3 into (A5 and 2P89 2P8 %inds to receptors on the ER, releasing /a3G into c&tosol. /alcium then %inds to receptors on plasma mem%rane to increase /alcium entr& into cell and %inds calmodulin to modulate acti$it&. Phosphatase which, when %ound %& /alcium in response to 2P8, dephosphor&lates +,A , allowing transcription of 2!'3 gene. ranscription factor. /alcineurin dephosphor&lates +,A , allowing it to migrate into nucleus where it %inds to promoter region of 2!'3 to allow transcription to occur.

L%$ Q ;yn

JAP#6> PLC# )AG

Ras

IP:

Ca"%ineurin N;A!

Cy%"osporin AE;KO>P (rugs which %loc#s calcineurin acti$it& so it cannot depshophor&late +,A and it is stuc# in the c&toplasm9 ."o%$s transcription of 2!'3 gene IL#7 2ene 2nterleu#in 3 gene. l&mphoc&tes ma#e 2!'3 a few hours after the& are stimulated to help them proliferate and clonall& expand. ranscription occurs due to the %inding of transcription factors (N;A!, +,-", Ap'C) to promoter region of the gene.

Production of 2!'3 gene results in production of 2!'3 receptor, which 2!'3 c&to#ine can %ind to in autocrine'li#e wa& to induce cell proliferation, differentiation, and sur$i$al of cells into effector cells. IL#7 !;'s ASi2na"B 3 +,A , +,-", Ap'C. An&thing that %loc#s their production will downregulate 2!'3 gene transcription. Acti$ation of signal transduction cascade as descri%e in steps a%o$e9 defined as %inding of /R to AP/ MA/Npeptide complex allows %e"" to .e%ome a%ti,ated/ /o'stimulator& molecule that is alwa&s present on surface of nai$e cells allows %e"" sur,i,a"/ /(3) %inds to "> molecule on AP/ and sends signals to induce cell acti$ation. /auses proliferation, differentiation, and sur$i$al %& pro$iding signal for cell not to undergo negati$e selection and promoting %etter 2!'3 transcription and translation. -nown as 6signal 37, with signal C %eing the signal produced %& the /R %inding to the AP/ MA/Npeptide complex. ASi2na" :B Production of c&to#ines allows differentiation

C)7*0 ASi2na" 7B

B6/3C)*>0 B6/7EC)*P Molecule on surface of AP/ that interacts with /(3) costimulator& molecule on cell. 3 t&pes include ">.C and ">.3 (a#a /()1 and /()L). B"R#s C)38E73 Analogous to /(0N/() for 'cells, these are co'receptor molecules that %ind to MA/'peptide complexes to facilitate 2 AM in 2ga and 2g" complexes. /R3C is also #nown as /R3. @R/ famil& &rosine #inase. Phosphor&lates 2 AM of 2gaN2g" after cross'lin#ing of co'receptor and "/R &rosine phosphatase which dephosphor&lates an inhi.itory t&rosine residue, promoting phosphor&lation of 2 AM. Dnce acti$ated with antigen, /(0< changes from large form into smaller form, /(0<RD. his difference allows us to 6count7 naO$e $s. antigen'experienced cells.

Lyn C)=O

Si2na" 3 C)=>0 ASi2na" 7B

Antigen presentation to /(01 on cell surface of " cell /o'stimulator& molecule on surface of " cell that %inds to the th&mus'dependent antigen, internalizes /(01'Ag complex, processes protein into pieces, and re'presents protein on MA/' /lass 22 molecule on cell surface. 2f /(0G cell has /R that recognizes the epitope, it will express /(01 ligand. /(01 ligand %inds to /(01 on " cell, which sends signals to induce " cell proliferation, differentiation, and sur$i$al. Criti%a" se%ond si2na"in2 step for B %e""s that is re*uired for isot&pe switching, germinal center formation, and " cell memor&. /(01 is also on cell surface of AP/ macrophages and dendritic cells, which allows cells to help them acti$ate %& expressing /(01 ligand. Allows AP/s to produce pro'inflammator& c&to#ines such as +,'a, 2!'C3, and 2!'C. /(01 is mem%er of tumer necrosis superfamil& (!N; superfamil&). !rimeri-es when interacts with ligand, facilitating signal transduction %& the cell. Acti$ation of +, superfamil& causes acti$ation of +,-" ,, inducing 2!'3 gene transcription.

RAKES!A!

TA-s (6Rust another Kinases7) are found on the c&toplasmic tail of [half'a'dimer proteins on a cell. .hen c&to#ines successfull& %ind to %oth half'dimers of and " receptors, the assem%led whole 6dimeri-es7. his %rings t1o RAKs ad+a%ent to each other so that the& can Mac#'each other on (ie: phosphory"ate each other). hus acti$ated, S!A!s (transcription factors) can now in turn %e phosphor&lated %& the acti$ated TA-s. hese S!A!s dimeri-e and 2o to the nu%"eus 1here they promote 2ene eDpression/

APC's )endriti% Ce"" Lan2erhan Ce""s Ma%ropha2es Ma%ropha2e A%ti,ation Macrophage acti$ation is tightl& regulated %& hC cells. hC cells re*uire cell'to'cell contact with macrophages to recognize pathogen, which is in macrophage phagosome. Macrophages re*uire two signals for acti$ation: I;N# from !@3 %e""s, and %inding of /(01 ligand onto /(01 receptor. Dnce acti$ated, macrophages undergo a num%er of changes to enhance their micro%icidal 2mmature dendritic cell that li$es on the s#in

acti$it&. he& produce /\/!3 and !N;#a, which attracts more macrophages to site and allows diapedesis through endothelium. 2ncreased expression of ">, /(01, MA/ class 22 molecules, and +, receptors signal latent cells and increase immune response. Macrophages secrete IL#37, which increases production of AC effector cells and 2ro1th fa%tors IL#: and GM#CS;, which increase macrophage production in %one marrow. Macrophage acti$ation is strongl& inhi.ited %& IL#3> and !G;#? (produced %& !re2 cells). 2n diseases such as tu%erculosis, ma& produce 2ranu"oma (mass of macrophages surrounded %& hC cells) due to ina%ilit& of macrophages to #ill antigen. hC cells continue to get recruited to site, producing large anatomical lesion.

Others
S3P @phingosine'C'phosphate9 molecule floating around !&mph +ode which ma& %ind to cell, if @CP receptor present. 2f @CP receptor +D present, the cell will sta& in l&mph node. (rug that %loc#s @CP receptor is immune suppressor drug. Anti%od&'dependent /ell /&totoxicit&. +- /ells ha$e ,cVR and eosinophils ha$e ,cQR (receptors). Anti%odies (2g5 and 2gE) %ind to antigen, and now the +- G Eosinophil cells can %ind to these receptors and cross'lin# for u%er'#illing potentialK A%'dependent, /ell'/&totoxicit& Autoimmune l&mphatic proliferati$e disease. (amaged ,asN,as! results in alps. Auto'2mmune /&tosine (eaminase. /R2 2/A! enz&me for @omatic A&permutationK Auto'2mmuneRE is expressed in the th&mus. Allows the production of short strips of peptides from areas that 'cells would not otherwise %e a%le to sample (ie: insulin). "one'Marrow ransplant. Aas %etter outcome than chemo in leu#emia #ids (<1? $s 31? !eu#emia'free sur$i$al). (rug gi$en to help mo%ilize the stem cells within R"/s. .hen har$esting R"/ stem cells from actual flowing %lood rather than %one marrow. 5raft Bersus Aost (isease. ]ou #now what that is. 2nhi%itor& co'stimulator& molecule 4 /(3)s e$il twin %rother. =seful in maintaining peripheral tolerance. 2 2M motif. "inds ">.C and ">.3

A)CC

ALPS: AI) AIR4

BM! GCS; GF@) C!LA#=

P)3 RAKES!A!

!i#e / !A'0 ^ an inhi%itor& co'stimulator& molecule. "inds to P(C' !igand. 2 2M motif. TA-s (6Rust another Kinases7) are found on the c&toplasmic tail of [half' a'dimer proteins on a cell. .hen c&to#ines successfull& %ind to %oth half' dimers of and " receptors, the assem%led whole 6dimeri-es7. his %rings t1o RAKs ad+a%ent to each other so that the& can Mac#'each other on (ie: phosphory"ate each other). hus acti$ated, S!A!s (transcription factors) can now in turn %e phosphor&lated %& the acti$ated TA-s. hese S!A!s dimeri-e and 2o to the nu%"eus 1here they promote 2ene eDpression/ 2nhi%itor& receptors on +- /ells. ,c'Receptor found on " cells that %inds to anti%od& stems, %ut then ;inhi%its; the "'cells acti$ation than#s to its 2 2M motifs. +aO$e 'cells in the presence of 5,'J can express ,oxP8. @eparate from that fact, some /(0G cells in the th&mus during de$elopment also express ,oxP8 (_<?). Proof: ]ou ta#e a mouses th&mus awa& (after /()G,/(0' or /()', /(0G cells are formed, %ut ;%efore /(0G,/(3<G cells) and it gets Autoimmune diseases up the &in'&ang. !ac#ing ,oxP8 leads to 2PE\. ,A@ E the death receptor. ,A@! E ,A@ ligand. hese are %oth present on 'cell surfaces. .hen the& %ind with each other the cell gets the apoptosis singal and commits apoptosis. Dccurs at the end of immune response.

KIR mo"e%u"es ;%CRIIB ;oDP:

;ASE;AS#L