Lecture 10 Humoral Immunity [humoral response] B cells on → dx into plasma cells → secrete Abs o also dx into memory cell Antigen delivery to follicles in LN o follicles contain follicular B cells o macrophages deliver large Ats from SCS → cortical follicle o small Ats delivered to follicle via [conduits] from SCS → follicle B cell activation o signals for B cell activation BCR signal At binds BCR → SRC kinase (P)s ITAMs → Syk binds 2x-(P)d ITAMs → Syk now act’d BCR crosslinking → on many TFs → B cell px + dx o NFAT, ERK, JNK, p38, NFκB accessory signals, from [Th] o [TD (thymus-dep Ats] unable to induce Ab response w.o T cell help microbes o [TI (thymus-indy Ats] can induce Abs w.o T cells help highly repetitive mlcls that cross link BCR → 2nd signal from direct recognition of common microbial constituent => LPS (binds B-cell TLR) most pathogens have both types of Ats high-affinity, long term humoral responses req. T-dep B cell responses o T-cell-dep Ab response [linked recognition] T cells involved bind same At as B cell → allows B and T to interact → Ab response peptide recognized by Tfh prolly dif from BCR’s but they are present in same At o i.e. B cell may recognize one epitope on At but may present a different epitope from that At for T cell interaxn mech 1. B cell acts as APC (MHC2)→ Th binds at presented epitope → initial T-B interaxn (outside follicle) o T cells also see At from DCs → px 2. B cells leave follicle → px -dx→ o if stays out of follicle → [short-lived plasma cells] → localize to medulla (LNs), red pulp (spleen), lamina propria (mucosa) → release Abs o if re-enters follicle → [germinal center (GC) B cells] 3. GC B cell -dx→ memory cells + long-lived plasma cells (release hi affinity Abs) → localize to bone marrow, gut, lactating mammary gland o B cells mutate in dark zone of GC → B cell w. higher affinity bind At and present to T cells via MHC2 → B cell-CD40 binds Tfh-CD40L, TCR binds MHC2 → B cell receives survival + miotic signals → re-enter dark zone → mutate further [somatic hypermutation] B cells w. higher affinity BCRs interact w. Ats on surface of Foll. DCs better n better → present to Tfh better n better → receive CD40L and CK signals better → favors better and better Abs for At [class-switch recombo] expression of new isotypes w.o ∆ing At specificity dif CKs dif class switches to dif isotypes both above processes req. [AID] activation-induced cytidine deaminase o [memory B cells] higher affinity for At, longer lived us. isotyped (IgG, A) clonal expression + dx speed in 2’ immune response o Secondary humoral immune response IgG memory B cell -dx→ long-lived plasma cells some memory B cells → GCs → SHM + selection → At affinity larger than 1’ response in IgG and maybe IgA/E higher affinity than 1’ response only induced by protein Ats 1’ response induced by all Ats o Abs and host defense [neutralization] prevent R-mediated endocytosis of pathogens toxins, bacteria + virus → coated w. Ab→ cant bind cellR [opsonization] phagocytosis of EC bacteria via FcR → Ig coats pathogen → phagocyte binds Fc and on phagocyte → phagocytosis [C activation] plasma bacteria o IgM pentamer (staple form) and IgG bind At on bacterial surface → C1q binds one IgM or 2+ IgG → on C1r + C1s → C path [ADCC (Ab-dep cell-med’d cytotoxicity)] Ab binds target cell → FcR (NK) bind Ab-target → cross-linking of FcR signals NK to kill target → apoptosis [IgA] major class of Ab on mucosa dimeric IC + EC neutralization; pathogen export from l.p. [pIgR] transcytosis of IgA (l.p → apical surface of epi) o only IgA (and some M) cross epi [Neonatal Fc receptor (FcRn)] transfer passive immunity mother → fetus recycles IgG extends IgG t1/2 transport of IgG in GI only IgG crosses placenta IgE → on mast cells → degranulation → release histamine, CKs, lipid mediators [histamine] blood flow + vasc. permeability [lipid mediators + CKs] initiate local inflammatory responses IgE us. bound to mast cell’s FcϵRI → mast cell act’d when At cross links IgE/FcϵRI complexes
