Nick Andrade

GTS Immunology Alphabet Soup!

Innate immunity:
 CRP, serum amyloid P (SRP), and pentraxin 3 (PTX3)  pentraxins, ACRs; innate immunity
 NLRP3  inflammasome, activates caspase-1
 MyD88, IRAK4, UNC93  proteins in TLR signaling with deficiency-related diseases

Ig and B cell:
 RAG  rearrangement in antibody/antigen receptor creation
 Artemis  involved in rearrangement, has exonuclease activity (N sequences fill in)
 AID  CtoU to spark class switching and somatic hypermutation; deficiency  hyper IgM syndrome
 CD19  expressed on B cells throughout development
 IL-7R  B cell development, expressed through large Pre-B cell stage, downregulation shifts to LC
rearrangement (small pre-B cell stage)
 VCAM1, Kit on B (stem cell factor), CXCR4 on B (CXCL12)  stromal cell binding to B cell for IL-7
targeting in bone marrow
 Btk  pre-B cell receptor signaling, KO yields XLA
 SLP-65  pre-B cell receptor signaling, KO yields pre-B cell ALL
 BAFF  B cell activating factor, important in spleen to go from immature to mature B cell (w/ BCR)
 CD40 (B) and CD40L (T)  B-T signaling, important in forming/maintaining germinal centers in spleen
 BLIMP-1  plasma cell fate (transcription factor)
 Bcl6  memory B cell fate (transcription factor)
 Fas/FasL (B cell/CD4 cell)  signal inducing apoptosis in anergic B cells in the periphery

Complement:
 C1qrs  C2 (cut, backwards name)  C4 (cut)  C3 cut  C5 cut  C678 + many C9 = MAC
o C5-C9 deficiencies  severe Neisseriaceae infections
 Classical C3 convertase = C4b2a; alternative C3 convertase = C3bBb (main amplifier)
 Classical C3/C5 convertase = C4b2a3b; alternative = C3bBbP (+ another C3b according to slide)
 C5a very proinflammatory (anaphylotoxin), C3a/C4a kinda, rest of small pieces unimportant
 MBL/ficolins + MASP-1/2 = C1q + C1r/s for lectin pathway
 Alt: C3(H2O) spontaneously  bind B, D cuts B  C3(H2O)Bb (temp C3 convertase)  C3b binds B, D
cuts B (more)  C3bBb (main) C3 convertase  rest of path the same for MAC
o Factor P stabilizes the C3bBb (C3 convertase)
 Regulation (stuff on our membranes that prevents us from complement-killing our own cells)
o C1INH  C1 esterase inhibitor (inhibits C1r/s); deficiency  hereditary angioedema
o DAF, C4BP, CR1  displace C2a from C4b2a  no C3 cut
o MCP, C4BP, CR1  bind C4b, bring in protease I  C4b cut to C4c and C4d  no C3 cut
o CR1 and factor H  displace C3b from C4b2a3b and help I cut C3b to iC3b  no C5 cut
 H binds sialic acid
o CD59 (aka protectin)  prevents C9s from coming in  no MAC
 Downstream
o CR1  binds C3b  PMN, macro, lympho  adhesion, phago, IL-1, proliferation
o CR3  binds iC3b  PMN, macro, NK  adhesion, chemotaxis, phago, ADCC
o CR2  binds C3dg  B cells, FDCs  antibody production
o C1qR, C5aR  macrophage activation (IL-1,6,8, TNF-a, CRP)
 IL-6  acute-phase proteins from liver
 Tests
o C3 level  depletion is sign of lupus flare (low C3 alternative, low C4 classical)
o CH50 test  low if anything is low or absent in complement system
Nick Andrade
GTS Immunology Alphabet Soup!
Ig effector function
 IgG  transported across placenta, opsonization, complement activation, ADCC
 IgA  transport across mucosal surfaces, neutralization and blocking adherence of viruses/toxins
 IgE  mast cell activation
 IgM  complement activation (secondarily mucosal transport, neutralization, and blocking adherence)
 M cells  follicle-associated epithelium that phagocytoses antigen and presents it to follicle  IgA
 Secretary component (of IgA)  originally epithelium receptor, endocytosed and secreted to join IgA
 Brambell receptor (FcRB)  receptor for placental transport of IgG

T cell recognition
 ITAM  immunoreceptor tyrosine-based activation motif (on TCR, CD3)
 “Anchor residues”  amino acids that fit in deeper pockets of the MHC binding site (X-L-XXXXXX-V)
 TAP  transporter for antigen peptides into the ER (for binding to MHC I)

APCs
 CCR7  receptor on dendritic cells that binds CCL19 and CCL21 on high endothelial veins (HEVs) and
stromal cells of the spleen, lymph nodes, and Peyer’s patches
 ICAM1  binds LFA-1 (integrin) on T cell to facilitate interaction

Lymphocyte activation
 T cells moving to lymph nodes
o L-selectin binds GlyCAM-1 and CD34 on epithelium  rolling
o LFA-1 to ICAM-1 on epithelium  adhesion
 T cells interacting with APCs
o LFA-1 (integrin) binds ICAM1 on APC
o CD2 binds LFA-3 on APC

T cell development
 AIRE  autoimmunity regulatory element, turns on genes not normally expressed in the thymus in order to
negatively select against T cells that would react against peripheral self antigens
o E.g. - express insulin so T cells that react to insulin can undergo clonal deletion

Viral dynamics
 APOBEC3G  like AID (turns Cs to Us in DNA)  retroviral DNA products degraded/have stop codons
 Vif  HIV gene that associates with APOBEC3G and promotes its degradation
 Tetherin  catches virus during budding and tethers it to membrane
 Vpu  HIV gene that associates with tetherin and promotes its degradation

T cell signaling
 Lck  associates with CD4 using Zn2+, helps bring in ZAP70
 ZAP70  docks on TCR zeta chain (at ITAMs) after Lck phosphorylates zeta chain (and ZAP70)
o Deficiency  selective T-cell defect (STD)  persistent infections
 LAT  activated by ZAP70  PLC (DAG  NF-kB; IP3  NFAT) and MAPK (Erk  AP-1) pathways
o Reminder: MAPK is GRB2  SOS  Ras  Raf  MEK  Erk
 CD28 binds B7 on APC  costimulation
 CTLA4 binds B7 on APC  inhibition
 B cell homologues
o CD3 zeta chain is Ig alpha/beta chain
o Lck is Blk
o ZAP-70 is Syk
o LAT is BLNK
o CD28 is CD19
o CTLA4 is FcγRIIB
Nick Andrade
GTS Immunology Alphabet Soup!
CD4 T cell types
 Guiding signal  STAT  CD4 type  signature cytokines  function
 IL-12 and IFN-g  STAT4  TH1  IL2, IFN-γ, TNF-α  cell-mediated immunity
o Also bind CD40 on macrophages with CD40L to activate
o IFN-γ shuts down TH2 fate
 IL-4  STAT6  TH2  IL-4, IL-5, IL-10, IL-13  humoral immunity
o Also bind CD40 on B cell with CD40L to promote differentiation to plasma cell / class switch
o IL-4  class switch to IgG1 and IgE
o IL-5  class switch IgA
o IL-10 shuts down TH1 fate
 IL-6 (+ ?)  STAT3  TFH  IL-4, IL-21, IFN-γ  help B cells w/ affinity maturation/class switching
 TGF-β  STAT5  Treg  ?  immune regulation, tolerance toward self
 TGF-β and IL-6 (less certain)  STAT3  TH17  IL-17, IL-22  neutrophil activation, extracellular
pathogen defense, and tissue injury
o Produce CCL20 to attract more TH17 cells (binds CCR6)
 CD40L deficiency  X-linked hyper-IgM syndrome (HIM) because of failure to class-switch B cells
o No germinal centers in lymph nodes

T cell effector function

 IL-2R alpha chain  responsible for high affinity
 IL-2R gamma chain  common chain for many cytokine receptors
o Deficiency  X-linked SCID
 Cytokines signal via Jak-STAT
o Deficiency  Jak3-deficient SCID
 Fas/FasL pathway: FasL on T cell binds Fas on target cell  FADD (Fas associated death domain)
activated in cytoplasm  caspase-8  caspase-3  I-CAD cleaved  CAD cleaves DNA
o Defect  autoimmune lymphoproliferative syndrome (ALPS), VERY rare

NK Cell stuff
 Activating receptors  have ITAMs, main one is FcγRIII
 Also activated by sensing upregulated MICA/MICB in cancer via NKGD2
 Inhibitory receptors  have ITIMs, bind MHC-I (virus evades CD8 by lowering MHC-I  NK cell kills)

T cell tolerance
 CD25  marker of regulatory T cells
 Foxp3  activation turns on ability for Tregs to suppress CD8 T cell activation
o Deficiency  autoimmunity
 IL-10  role in inhibiting autoimmune responses (TGF-β too)

Cellular communication
 CCL21  from HEV, brings DCs to lymph node
 CCL18 and CCL19 (SLC, ligand for CCR7)  from DCs, brings in lymphocytes
 CX3CL13 (BLC)  from follicular DCs, attract B cells (secreted after B cells activate follicular DCs)

Immunological memory
 Central memory cells express L-selectin (binds GlyCAM1) and CCR7 (binds SLC aka CCL21) to guide
them to the lymph nodes
 IL-7R seems to be important for quick response to secondary challenge
 IL-7 and IL-15  can’t lose both or Tmem cells won’t divide and they’ll die
 PD-1 and LAG-3  “exhausted” phenotype, expressed when Tmem encounters persistent antigen

Autoimmunity
 Dsg3  holds tight junctions together in epithelium; anti-dsg3  pemphigus vulgaris